Plasma Proteins Clinical Utility

Transcription

Plasma Clinical
Utility
Proteins and
Interpretation
Wendy Y. Craig, Ph.D.
Thomas B. Ledue, B.A.
Robert F. Ritchie, M.D.
Foundation for Blood Research
Supported by an educational grant
from Dade Behring Inc.
Preface
For the medical practitioner, the measurement of plasma
proteins can be a powerful clinical assessment tool for detecting, diagnosing, and monitoring diseases and patophysiological
processes. A disturbance in the interrelationship among these
proteins can indicate the presence of infection, inflammation,
malnutrition, or other types of autoimmune diseases. Because
plasma protein determinations can provide valuable information
early in the course of a disease, patient outcomes can be
improved and the cost of patient care can be reduced. We
hope this guide provides you with the information you need
to fully utilize this clinical assessment tool.
Acknowledgements
The authors would like to thank the following persons for
their assistance with the review and editing of this booklet:
A. Myron Johnson, M.D.; Sue E. LaPierre, B.S.; Phyllis M. Boucher;
Walter C. Allan M.D.; Rhonda Spiro M.D.; Marjorie Boyd, M.D.;
and Elizabeth Knauft, M.D.
General Information
Valid reference materials do not exist for all of the serum
proteins included in this document. As such, the reference
ranges presented throughout Section II should only be
considered as guidelines. Each laboratory should establish
their own reference intervals based on their population,
methodology, and available reference materials.
Contents
SECTION I.A.: Non-Disease-Specific Effects on Serum Proteins
INFLAMMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
OVERVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
GENERAL APPLICATIONS OF PROTEIN ANALYSIS IN
INFLAMMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
SPECIFIC APPLICATIONS OF PROTEIN ANALYSIS IN
INFLAMMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
SERUM PROTEIN INTERPRETATIONS CONFOUNDED
BY INFLAMMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
DRUG AND HORMONE EFFECTS ON SERUM PROTEINS . . . . . . . .12
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
NUTRITIONAL ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20
OVERVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20
FACTORS CONFOUNDING PROTEIN DATA
IN NUTRITIONAL ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . .21
ASSESSMENT AND MONITORING OF NUTRITIONAL STATUS . . .22
NUTRITIONAL MARKERS IN PROGNOSIS . . . . . . . . . . . . . . . . . .23
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24
SECTION I.B.: Clinical Disease and Serum Protein Use
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE . . . . . . . . . . . . . .27
OVERVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27
CARDIOVASCULAR DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27
ACUTE MYOCARDIAL INFARCTION . . . . . . . . . . . . . . . . . . . . . . .29
ISCHEMIC STROKE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33
ENDOCRINE DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38
DIABETES MELLITUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38
THYROID DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .40
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42
GASTROINTESTINAL DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45
PROTEIN-LOSING GASTROENTEROPATHY . . . . . . . . . . . . . . . . .45
GASTROINTESTINAL MALIGNANCY . . . . . . . . . . . . . . . . . . . . . .46
CHRONIC INFLAMMATORY BOWEL DISEASE . . . . . . . . . . . . . . .48
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49
HEMATOLOGIC DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52
MONOCLONAL GAMMOPATHY . . . . . . . . . . . . . . . . . . . . . . . . . .52
ANEMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .58
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60
LIVER DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65
INHERITED LIVER DISEASES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65
VIRAL HEPATITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .67
Contents
CHRONIC LIVER DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .68
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71
NEUROLOGIC DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .75
MULTIPLE SCLEROSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .75
PARAPROTEINEMIC NEUROPATHY . . . . . . . . . . . . . . . . . . . . . . . .76
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77
PULMONARY DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78
CHRONIC OBSTRUCTIVE PULMONARY DISEASE . . . . . . . . . . . .78
ASTHMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79
LUNG CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .80
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .80
RENAL DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .82
NEPHROTIC SYNDROME . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .82
CHRONIC RENAL FAILURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .83
GLOMERULONEPHRITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85
HEMOSTATIC BALANCE IN RENAL DISEASE . . . . . . . . . . . . . . . .87
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .88
RHEUMATIC DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .93
ANKYLOSING SPONDYLITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .93
JUVENILE RHEUMATOID ARTHRITIS . . . . . . . . . . . . . . . . . . . . . . .93
MIXED CONNECTIVE TISSUE DISEASE . . . . . . . . . . . . . . . . . . . . .94
OSTEOARTHRITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95
POLYMYALGIA RHEUMATICA/GIANT CELL ARTERITIS . . . . . . . .96
POLYMYOSITIS/DERMATOMYOSITIS . . . . . . . . . . . . . . . . . . . . . . .96
RHEUMATOID ARTHRITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .97
SJÖGREN’S SYNDROME . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .98
SYSTEMIC LUPUS ERYTHEMATOSUS . . . . . . . . . . . . . . . . . . . . . . .99
SYSTEMIC SCLEROSIS/SCLERODERMA . . . . . . . . . . . . . . . . . . . . .100
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101
SECTION II: General Information on Serum Proteins
ALBUMIN (Alb) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .107
ALPHA-1-ACID GLYCOPROTEIN (Orosomucoid) (AAG) . . . . . . . . .108
ALPHA-1- ANTICHYROMOTRYPSIN (ACT) . . . . . . . . . . . . . . . . . . .109
ALPHA-1-ANTITRYPSIN (AAT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .110
ALPHA-1-MICROGLOBULIN (Protein HC) (A1M) . . . . . . . . . . . . . . .111
ALPHA-2-MACROGLOBULIN (A2M) . . . . . . . . . . . . . . . . . . . . . . . . .112
ANTITHROMBIN III (AT III) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113
APOLIPOPROTEIN A-1 (Apo A-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . .114
APOLIPROTEIN B (Apo B) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .115
BETA-2-MICROGLOBULIN (B2M) . . . . . . . . . . . . . . . . . . . . . . . . . . .116
CERULOPLASMIN (Cp) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117
COMPLEMENT COMPONENT (C3) . . . . . . . . . . . . . . . . . . . . . . . . .118
Contents
COMPLEMENT COMPONENT (C4) . . . . . . . . . . . . . . . . . . . . . . . . .119
C1 ESTERASE INHIBITOR (C1 INH) . . . . . . . . . . . . . . . . . . . . . . . . . .120
C-REACTIVE PROTEIN (CRP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121
CYSTATIN C (Cys C) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .122
FERRITIN (FER) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123
FIBRINOGEN (FIB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124
FIBRONECTIN (FN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125
HAPTOGLOBIN (Hp) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126
HEMOPEXIN (HPX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .127
IMMUNOGLOBULIN A (IgA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128
IMMUNOGLOBULIN D (IgD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .129
IMMUNOGLOBULIN E (IgE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130
IMMUNOGLOBULIN G (IgG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .131
IMMUNOGLOBULIN M (IgM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .132
IMMUNOGLOBULIN LIGHT CHAINS (kappa/lambda) . . . . . . . . . . .133
LIPOPROTEIN(a) [Lp(a)] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134
MANNOSE-BINDING PROTEIN (MBP) . . . . . . . . . . . . . . . . . . . . . . .135
MYOGLOBIN (MYO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .136
PLASMINOGEN (PSM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .137
PREALBUMIN (Transthyretin) (PAL) . . . . . . . . . . . . . . . . . . . . . . . . . .138
RETINOL-BINDING PROTEIN (RBP) . . . . . . . . . . . . . . . . . . . . . . . . .139
RHEUMATOID FACTOR (RF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .140
SERUM AMYLOID A (SAA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .141
SOLUBLE TRANSFERRIN RECEPTOR (sTfR) . . . . . . . . . . . . . . . . . . .142
TRANSFERRIN (Tf) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .143
REFERENCES FOR REFERENCE RANGES . . . . . . . . . . . . . . . . . . . . .144
Introduction
The book has been divided into 2 sections: the clinical use of these
tests from the bedside and a section about the individual members of the
family themselves. As will be seen, few of the measurements can be used
alone as an understandable tool for clinical evaluation. Most are but one
facet of the evaluation of a particular problem, but a very powerful set of
tools nonetheless, often providing information that cannot be retrieved
in any other manner. Of particular importance is the ability of serum
protein evaluation to detect subclinical disease or disease yet to appear.
As medicine evolves in this new era of cost-effectiveness, this ability
to detect hidden or early disease will become increasingly important.
Judicious and timely use of serum protein testing can provide information
on our patients who have as yet undeclared disease that may be blunted
or prevented completely, before it becomes a serious problem.
The study of serum proteins has underscored the importance of
including age and gender as pivotal pieces of information required
before interpretation is attempted. The new dicta for reimbursement
also have underscored the importance of conveying your clinical concern at the time a blood sample is sent for analysis. This information is
not only the gatekeeper for reimbursement but also provides valuable
information to those of us who convert laboratory numbers to words
of clinical value to you. Knowing the clinical concerns about a patient
can direct interpretive thinking in appropriate and very different
directions than without such council.
From the contents of this book, you may find several analytes that are
unfamiliar to you but nonetheless valuable in your present patient care.
By following the flow of the text you will find reference to the sections
on the new individual protein for additional information.
Our sensitivity to the quality of laboratory testing has been heightened
in recent years as laboratory regulation; superior methods and participation in quality assurance programs have become mandatory for
accreditation and licensure. These features of course extend to the
performance of serum protein tests. What is not as yet controlled is
the ability of a laboratory provider to properly interpret what these
valuable tests mean to your patient’s care. It is our hope that the clinical portion of this book will assist in directing you to better appreciate
the worth of these tests without relying on the thinking of others.
i
Introduction
This collection of information on the topic of serum proteins and their
value to the medical practitioner represents a distillation of the present
knowledge on this growing topic. Unlike many other laboratory measurements, serum proteins are interrelated in a complex and extremely
informative manner when the key to their interaction is appreciated.
The following pages aim to provide a guide to the use of serum proteins for clinicians.
Introduction
Introduction
Consistent quality laboratory performance has always been an elusive
goal for clinical laboratories. Modern equipment, new high-performance kits and reference materials have permitted tremendous advances
in laboratory medicine. However, one crucial area remains outside our
ability to provide adequate control. Collectively it can be referred to
as preanalytical variables. Included in this cluster of issues are many
items to which we often pay little regard, instead relegating it to our
staff. Unfortunately, one or more issues can conspire to destroy the
value of laboratory values on which we rely for clinical insight. They
fall into several areas:
PATIENT PREPARATION: A patient should come for phlebotomy in as
near a true fast as possible: after a light meal the evening before; before
breakfast; having refrained from smoking cigarettes, drinking coffee or
tea; and avoiding physical exertion. Each of these conditions can alter
the concentrations of blood analytes significantly. Daily medication
should be taken with water as prescribed.
• A subject should be seated for at least 15 min prior to venipuncture.
• Venipuncture should be accomplished without prolonged tourniquet
application.
• The whole blood sample should not be frozen, shaken vigorously or
remain above refrigerator temperature for more than 30 min before
separation.
• Red blood cells should be separated as soon as possible after clotting,
decanted and introduced into a vial no more than 3× the volume of
the sample. If centrifuged, the tubes should be capped to prevent
evaporation.
• If testing cannot be accomplished within the working day the sample
should be frozen at -20°C.
SAMPLE SHIPMENT: For tests that must be sent to outside laboratories the conditions during transport are important to ensure that
sensitive analytes arrive at the point of testing as close to the native
state as possible. Most laboratory couriers take particular care to
protect samples when in their care. Other methods of transport to
more distant sites may not receive such care.
TIME FOR TESTING: Apart from emergency procedures, tests for
prognostication or detailed diagnosis should not be performed in the
acute period of an illness. Fluid shifts, medication effects, the catabolic
state of many acute illnesses or the administration of fluids, including
blood or blood products, will have major effect upon analyte concentrations and as a result affect the interpretation to the point of
prompting erroneous conclusions (ie, misdiagnosis).
ii
Introduction
iii
Introduction
DOCUMENTATION: It cannot be emphasized too strongly that a
sample must be accompanied by sufficient documentation to inform the
laboratory staff of the clinical circumstance for which the test is being
sent, and above all, the particulars of the patient, such as age and sex.
Without this information, the results of often expensive testing can be
lost to generic interpretation. Since the laboratory should be viewed
as a consultative service, our communication with these consultants
should recognize this need for facts of concern.
Introduction
Abbreviations
A1M: α1-Microglobulin (Protein HC)
A2M: α2-Macroglobulin
AAG: α1-Acid glycoprotein
AAT: α1-Antitrypsin
ACT: α1-Antichymotrypsin
α-GM1: Anti-GM1 ganglioside
AIDS: Acquired immunodeficiency syndrome
Alb: Albumin
α-MAG: Anti-myelin-associated glycoprotein
AMI: Acute myocardial infarction
ANA: Antinuclear antibody
Apo A-I: Apolipoprotein A-I
Apo B: Apolipoprotein B
Apo B100: Apolipoprotein B100
Apo B48: Apolipoprotein B48
Apo(a): Apolipoprotein(a)
APR: Acute phase response
AS: Ankylosing spondylitis
ASCVD: Atherosclerotic cardiovascular disease
AT III: Antithrombin III
B2M: β2-Microglobulin
C1 INH: C1 esterase inhibitor
C1q: Complement component C1q
C3: Complement component C3
C4: Complement component C4
CABG: Coronary artery bypass graft
CAD: Coronary artery disease
CAPD: Continuous ambulatory peritoneal dialysis
CIBD: Chronic inflammatory bowel disease
CMV: Cytomegalovirus
CNS: Central nervous system
COPD: Chronic obstructive pulmonary disease
Cp: Ceruloplasmin
CREST: Calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly,
telangiectasia
CRF: Chronic renal failure
CRP: C-reactive protein
CRYO: Cryoglobulin
CSF: Cerebrospinal fluid
CV: Cardiovascular
CVD: Cardiovascular disease
Cys C: Cystatin C
d: Day
DIC: Disseminated intravascular coagulation
DM: Diabetes Mellitus
DNA: Deoxyribonucleic acid
dsDNA: Double stranded DNA
iv
Abbreviations
Introduction
ENA: Extractable nuclear antigen
EP: Electrophoresis
ESR: Erythrocyte sedimentation rate
ESRD: End-stage renal disease
FER: Ferritin
FEV1: Forced expiratory volume (1second)
FHF: Fulminant hepatic failure
FIB: Fibrinogen
FN: Fibronectin
FVC: Forced vital capacity
GCA: Giant cell arteritis
GFR: Glomerular filtration rate
GI: Gastrointestinal
GN: Glomerulonephritis
h: Hour
HAV: Hepatitis A virus
HbA1c: Hemoglobin A1c
HBV: Hepatitis B virus
HC: Heavy chain
HCV: Hepatitis C virus
HD: Hemodialysis
HDL: High density lipoprotein
HDV: Hepatitis D virus
HH: Hereditary hemochromatosis
HIV: Human immunodeficiency virus
Hp: Haptoglobin
HPX: Hemopexin
H-S: Henoch-Schönlein
ICU: Intensive care unit
IgA: Immunoglobulin A
IgD: Immunoglobulin D
IgE: Immunoglobulin E
IgG: Immunoglobulin G
IgM: Immunoglobulin M
JRA: Juvenile rheumatoid arthritis
κ: Kappa light chain
λ: Lambda light chain
LC: Light chain
LDL: Low density lipoprotein
LDL-C: LDL-cholesterol
Lp(a): Lipoprotein(a)
MBP: Mannose-binding protein
MCTD: Mixed connective tissue disease
MG: Monoclonal gammopathy
MGUS: Monoclonal gammopathy of unknown significance
MI: Myocardial infarction
MS: Multiple sclerosis
v
Introduction
Abbreviations
Mr: Molecular mass
MYO: Myoglobin
NS: Nephrotic syndrome
OA: Osteoarthritis
PAD: Peripheral artery disease
PAL: Prealbumin (transthyretin)
PBC: Primary biliary cirrhosis
Pi: Protease inhibitor
PLG: Protein-losing gastroenteropathy
PM/DM: Polymyositis / Dermatomyositis
PMR: Polymyalgia rheumatica
POEMS: Polyneuropathy, organomegaly, endocrinopathy, myeloma,
skin changes
PSM: Plasminogen
PVD: Peripheral vascular disease
RA: Rheumatoid arthritis
RAST®: Radioallergosorbent test
RBP: Retinol-binding protein
RF: Rheumatoid factor
r-huEPO: Recombinant human erythropoietin
RNP: Ribonucleoprotein
SAA: Serum amyloid A
SBE: Subacute bacterial endocarditis
SLE: Systemic lupus erythematosus
SPE: Serum protein electrophoresis
sTfR: Soluble transferrin receptor
T3: Triiodothyronine
T4: Thyroxine
TIBC: Total iron binding capacity
Tf: Transferrin
TfR: Transferrin receptor
TH: Thyroid hormone
TIA: Transient ischemic attack
TPN: Total parenteral nutrition
TS: Transferrin saturation
UC: Ulcerative colitis
WD: Wilson’s disease
vi
INFLAMMATION
Overview
General applications of protein analysis in inflammation
Specific applications of protein analysis in inflammation
Serum protein interpretations confounded by inflammation
OVERVIEW
CRP
++
AAG AAT
+
+
FER
+
C3/C4
+/-
FIB
+/-
Hp
+/-
IgG, IgA, IgM
++
PAL
—
Tf
-
Alb
-
Many of the changes in serum protein levels seen in inflammation are
the expression of the acute phase response (APR). The APR is accompanied by clinical signs and symptoms (fever, malaise, fatigue, weight
loss, redness, swelling, and pain) that may not become evident until
after detectable protein changes have occurred.1 The classical findings
of leukocytosis and elevated ESR also may not be seen until later
(fibrinogen, the principal cause of an elevated ESR, is a slow reacting
acute phase protein). In the APR, characteristic changes in hepatic
protein synthesis include decreases in albumin, prealbumin, apo B,
apo A-I, RBP, and transferrin production. There are marked increases
in serum levels of CRP and SAA, with more modest increases in
α1-acid glycoprotein, ceruloplasmin, complement component
C3/C4, α1-antitrypsin, α1-anti chymotrypsin, fibrinogen,
plasminogen, haptoglobin, and ferritin.2
The APR occurs in a coordinated manner, with early (<6 hours)
increases in CRP and SAA, and later (2 to 5 days) changes in the other
proteins. If the APR follows an isolated insult, levels normalize in the
same order. Thus, in early recovery, CRP decreases while immunoglobulin and haptoglobin levels are increasing; later, CRP is low and levels
of late-reacting proteins are high/decreasing. In chronic
inflammation/infection, levels remain abnormal.
GENERAL APPLICATIONS OF PROTEIN ANALYSIS IN
INFLAMMATION
ACUTE PHASE RESPONSE
Evaluation of the APR is valuable in the detection, diagnosis, prognosis,
and therapeutic monitoring of diseases that involve tissue damage and
inflammation and is more specific than clinical signs alone.1 A single
study detects inflammation, but serial profile measurements give the
best diagnostic/prognostic information.1 As the APR is nonspecific,
data must be interpreted in the context of the clinical question.3
1
Section I.A.
Changes in Protein Levels
Section I.A.
Examples:
• CRP is increased early in the APR from whatever cause. Levels are
elevated in meningococcal disease,4 urinary tract infection, crush or
burn injury, tumor necrosis, etc.2,5-7
• CRP measurement is very helpful in the diagnostic work-up for
appendicitis.8 CRP is elevated in all appendicitis patients by 12 hours
from onset of symptoms,9 and appendicitis is unlikely if both CRP
and leukocyte count are normal.10
• In obstetric patients with premature rupture of the membranes, a rise
in CRP is a very early warning of intrauterine infection.7
• A high ferritin level in the 3rd trimester of pregnancy is associated
with preterm delivery and is a marker of maternal infection.11
• CRP measurement can be used to differentiate between active
disease and infection in systemic lupus erythematosus (SLE). In these
patients, elevated CRP indicates infection, not inflammation caused
by SLE itself.7,12
Exceptions:
Complement C3 and C4 are elevated in the late APR, except under
conditions where consumption occurs. C3 levels may be depressed in
infection, particularly septicemia.13 In chronic bronchitis, patients with
the lowest C4 have more protracted respiratory infections and are
more likely to have emphysema.14
• Fibrinogen levels increase with inflammation causing elevated ESR,
except in protein-calorie malnutrition15 and in the presence of
coincident consumptive coagulopathy, such as DIC.16
• Haptoglobin is increased in uncomplicated infection, except where
there is coincident intravascular hemolysis.17
IMMUNOLOGIC RESPONSE
In chronic infections such as tuberculosis, deep fungal disease, and
pyelonephritis, there is a polyclonal increase in all immunoglobulins.
The extent depends on the type and duration of infection.18
• IgA is important in mucosal immunity19 and increases most commonly
ingastrointestinal, respiratory, or urinary tract mucosal inflammation.20,21
• Protein electrophoretic findings may include oligoclonal
banding (severe infection, such as viral hepatitis22 or HIV23),
monogammopathy (common in HIV positive patients, particularly
those with Kaposi’s sarcoma24,25), and immune complexes (severe,
recurrent, or chronic infection26).
• Other immunologic findings may include antinuclear antibodies
(chronic viral infection, especially viral hepatitis)27 and type III
cryoglobulinemia (many viral, bacterial, and fungal infections).28
2
SPECIFIC APPLICATIONS OF PROTEIN ANALYSIS IN
INFLAMMATION
DETECTION OF INFECTIONS IN HIGH RISK PATIENTS
Alb
N/-
FER
N/+
Tf
N/-
IgG
+/-
B2M
N/+
Section I.A.
CRP
+/++++
Infection is a serious concern in susceptible individuals such as
neonates, hypogammaglobulinemic patients, neutropenic patients on
chemotherapy, and after bone marrow transplantation. For instance,
typical symptoms may not be evident in newborns with infections;29
thus, protein measurements are particularly useful.
ACUTE PHASE RESPONSE
• In neonatal and perinatal infection, monitoring CRP levels is useful to
exclude infection and minimize unnecessary or prolonged antibiotic
therapy.30 Serial CRP measurement may help in the early diagnosis of
necrotizing enterocolitis in preterm infants.31 CRP is also useful for
differentiating infection and graft-versus-host disease after bone marrow transplantation.30 Generally, CRP >40 mg/L suggests infection,
while levels >100 mg/L mean definite infection.3,32,33 Note, however,
that neonate CRP levels are typically elevated within 36 hours of a
vaginal delivery.34
• Moderate to severe hypoalbuminemia is common during recovery
from many acute diseases and in acute leukemia and it is closely
related to the patients’ infections.35
• High ferritin and low transferrin are seen with the development of
systemic fungal infections among patients with hematologic malignancies.36 In adults and children with HIV, elevated ferritin indicates
advanced or progressive disease.37
• In HIV, viral load is correlated with β2-microglobulin (B2M) levels38
as the result of high cell turnover. B2M levels increase with HIV
disease progression and act as a marker for progression to AIDS.39
These levels are highest among HIV patients with current infection.40
• IgG is elevated in HIV-infected children with acute bacterial or viral
superinfection.41
• In newly diagnosed acute lymphocytic or myelogenous leukemia,
low serum IgG before chemotherapy predicts increased risk of death
due to septic complications.42 In chronic lymphocytic leukemia, low
IgG is associated with severe or multiple infections,43 and predicts
nosocomial bacterial sepsis in low birth weight infants.44
3
DIAGNOSTIC DIFFERENTIATION OF BACTERIAL AND VIRAL
FEBRILE ILLNESS
Section I.A.
CRP
+/++++
SAA
+/++
AAG
N/+
AAT
N/+
• CRP44 and other acute phase proteins including α1-antitrypsin, and
α1-acid glycoprotein* levels are elevated in bacterial infection and
much less frequently in viral diseases.3,45 Because viral infections, particularly of the respiratory tree, are frequently complicated by bacterial
superinfection, modest CRP elevation may be seen. Furthermore, CRP
levels in viral and bacterial infection overlap, so the test is not entirely
diagnostic for bacterial infection. Nonetheless, CRP levels >100 mg/L
strongly suggest that an infection is bacterial or fungal but not viral.3,46
• Serum-amyloid A (SAA) levels are usually elevated in both viral
and bacterial infection.47
* α1-acid glycoprotein is typically elevated in the 3rd trimester of pregnancy, and this
may confound its interpretation in the context of infection or inflammation.48
THERAPEUTIC MONITORING
CRP
++
AAG
++
AAT
+
Hp
++
Alb
-
PAL
—
Tf
-
• Serial CRP measurement is the best way to evaluate effectiveness of
treatment in bacterial infections in all age groups.49,50 After successful
antibiotic treatment, CRP declines in less than 4 days; if unsuccessful,
CRP levels fail to diminish.51.52
• A panel of acute phase proteins, including early (CRP, α1-acid
glycoprotein), early-mid (albumin), mid (prealbumin, transferrin, α1-antitrypsin), and late-reacting (haptoglobin, complement
C3) analytes is useful for deciding when therapy for closed infections
can be safely discontinued. This is when all values have returned
to normal in the expected sequence.51
DETECTION OF INFECTIOUS COMPLICATIONS AFTER SURGERY OR TRAUMA
CRP
++
PAL
--
AT III
+/-
• Serial CRP measurement is useful for the early detection of postoperative infections.52 With no infection, CRP begins to decline 49
hours after uncomplicated surgery.53 The APR resolves completely
within 2 weeks.53,54
4
• Prealbumin levels are typically lowest 6 to 8 days after surgery.
After this period, decreasing prealbumin levels may indicate infection.55 Similarly, persistently low prealbumin after Day 8 is associated
with death in burn victims, mostly from infectious complications.56
INVESTIGATION OF RECURRENT INFECTION
lgG
+/-
IgA
+/-
IgM
+/-
C3
N/-
MBP
N/-
Evaluation of serum proteins associated with the immune response is
crucial in the investigation of recurrent infection.
• Immunoglobulin deficiencies causing recurrent infections may be
genetic or acquired. X-linked agammaglobulinemia is associated with
decreases in all immunoglobulins.59 In common variable immune
deficiency, which presents as recurrent infections in the second to
fourth decades, all immunoglobulins may be low, but this is variable;
IgA is usually low; IgG is often low; IgM may be low or normal.59
• Selective deficiencies are also seen. IgA deficiency is associated with
an increased frequency of sinopulmonary and gastric infections59
although many subjects are asymptomatic. IgG deficiency is associated
with recurrent infections,60 often severe when levels are less than 3 g/L.
• In immunodeficiency with hyperimmunoglobulin-M there is low/no
IgG or IgA. The disease results in recurrent pyogenic infections60
and may be inherited or acquired (eg, congenital rubella).
• Multiple myeloma and Waldenström’s macroglobulinemia are associated with the presence of monoclonal immunoglobulins. Both
cause an acquired immunoglobulin deficiency (levels of normal
immunoglobulins may be <20% expected) and may predispose to
recurrent infections.61
OPSONIZATION/PHAGOCYTOSIS
• A rare inherited C3 deficiency is associated with recurrent infections
with pyogenic bacteria.62
• Low serum levels of mannose-binding protein (MBP) (genetic or
acquired) may result in recurrent infections in adults and children.63
5
Section I.A.
• Low antithrombin III (AT III) may be useful in predicting infection,
mortality, or both in severely injured patients.57 AT III levels rise by
~20% during the first 48 hours after admission for trauma; those with
low initial AT III levels are more likely to have infections or sepsis.57
Low AT III is usually due to disseminated intravascular coagulation
(DIC), which is often secondary to sepsis.58
DETECTION AND MONITORING OF SEPSIS AND SEPTIC SHOCK
Section I.A.
CRP
+++
AT III
-/—
PSM
-
FIB
N/-
C3/C4
—
FN
-
Sepsis refers to generalized infection, including the bloodstream. The
stimulation of the APR results in the same physical and laboratory
changes as those produced by more localized infection. Septic shock is
systemic collapse in response to endotoxin. This condition illustrates
the APR at its most dramatic. Hematologic changes in these patients
are primarily neutropenia, thrombocytopenia, and DIC. There are also
abnormalities in coagulation activation and fibrinolysis activation and
inhibition. Nonsurvivors of sepsis are typically those who develop a
more marked activation of coagulation and a more intense inhibition
of fibrinolysis.64
• CRP is very high in septic shock, and levels do not differ between
survivors and nonsurvivors.65 It is also high in sepsis of more than
a few hours duration. Daily CRP measurement is useful to detect
sepsis in ICU patients (CRP>50 mg/L suggests sepsis) and to predict
sepsis in children with burns.66,67 CRP can be used to follow resolution
of sepsis, with decreases preceding clinical resolution.68
• Other acute phase proteins may show changes that are atypical for
the APR, due to their consumption as part of the pathologic process.
- Sepsis causes profound complement activation, principally of the
alternative pathway. Thus, C3 is reduced in sepsis; C3 and C4 may
be decreased in septic shock.69
- Septic shock is associated with low AT III.70 Survivors have higher
AT III than nonsurvivors64 (AT III <60-70% of normal predicts poor
outcome70). Decreases in AT III indicate sepsis-associated DIC.58
- Plasminogen levels are also low in sepsis/septic shock with a
trend to normal in survivors.64
- Fibrinogen levels increase late (3 to 4 days) in the APR, but as
levels decrease due to consumption by DIC3,71 the APR-related
increase may not be seen.
- Low fibronectin is associated with a worsening prognosis in septic
conditions and is useful in the early diagnosis of neonatal sepsis.72,73
SERUM PROTEIN INTERPRETATIONS CONFOUNDED BY
INFLAMMATION
• Evaluation of cardiovascular disease (CVD) risk: Levels of apo B
(and LDL-C) and apo A-I (and HDL-C) are decreased in recent acute
illness and Lp(a) may be increased. Do not use these lipoprotein
measurements to evaluate CVD risk within 2 weeks of acute illness.74-76
6
• Evaluation of iron status: Current or recent infection (eg, upper
respiratory infection with fever) is associated with increased ferritin
and decreased transferrin.The ability of ferritin to detect iron deficiency anemia is reduced during inflammation, and it is always advisable to measure CRP concurrently to rule this factor out.77,78
• Diagnosis of rheumatoid arthritis: High levels of rheumatoid
factor (RF) are often seen in HIV infection, hepatitis B & C,
syphilitic arthritis, and some monoclonal gammopathies.26,79 RF
data should also be interpreted with caution in patients exposed
to tropical infectious diseases.80
LABORATORY STUDIES
Diagnosis
Monitoring
CRP
IgG, IgA, IgM
C3/C4
SPE
CRP
Albumin
PAL
B2M*
IgG, IgA, IgM
AAG
Hp
C3/C4
Sepsis
Other*
FIB
PSM
AT III
FER
SAA
Cryoglobulin
* See text for specific applications.
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DRUG AND HORMONE EFFECTS ON SERUM PROTEINS
Because certain drugs can alter serum protein levels, it is important to
take medication into account when interpreting the results of serum
protein analysis. In this section, we have excluded drugs such as lipidlowering medication, whose specific effects on serum proteins are
intuitive, based on the primary purpose of the drug. We also do not
discuss drugs that cause changes in serum proteins secondary to a
drug-induced disease, such as alcohol-induced cirrhosis.
AGENT
PROTEIN
Alcohol
Apo A-11
Androgens
Androgens2,3
AAT 2,3
A2M4
AIba4-6
Apo A-I7
Apo B7
AT III8
C34
Cp3
FIB8
Hpb,2,3,4
Lp(a)9
PAL4,10,11
PSM4,8
Tf 3,4,12
Anti-epileptics
ACE inhibitors
FIB18
Nonselective
-blockersc
Apo A-I17,19,20
Thiazide-type
diuretics
Apo B17,19,21
-Blockers with
intrinsic sympathetomimetic activity
Apo A-I19,22
-Blockers
+
COMMENTS
a
Effect depends on
clinical status.
b
Large increase (156%).4
Apo A-I13
Cp14, 15
FIB16
Anti-hypertensives17
12
-
Apo B20,23
c
β1-selective agents have a
lesser effect on apo A-I.14
AGENT
PROTEIN
Corticosteroids
AAG2
-
+
COMMENTS
Alb10,24-27,a
Apo A-128
Apo B 28
C3/C429
Section I.A.
Cp30
CPR31-33
FIB33
Hp2
IgA29
IgG29
IgM29
Lp(a)34
PAL35,36
Cyclosporin
Apo B37
IgE38
NSAIDS
AAG39
CRP39-41,d
d
Effect seen with long-term (6 weeks) 40
but not short-term (7 days) 41 therapy
Hp39
Tobacco use
e
Effects are dose dependent.
Apo A-1e,43-45
Apo B
e,43-45
CRP46
FIB47
Hp42
IgE48
13
AGENT
PROTEIN
-
+
COMMENTS
Estrogen
Oral
Contraceptivesf
AAG49,50
f Older preparations caused
elevated apo b and (+/-)
decreased apo Al. Newer
preparations have modified
Proportions of estrogens
and progestins and lower
doses, and have only minor
effects. 19
AAT50
Alb50
Section I.A.
Apo A-151,52
Apo B51,52
AT lll53
Cp50,54,55
FER56
g
Depending on androgeni c
activity 61 of preparation,
may see increase 55,59 or
no effect. 60
FIB53,57
Hp50,58
PALg,55,59,60
Tf 50
Pregnancy
AAGh,50,62,63
h
Increased in 3rd trimester. 64
AATi,2,65,66
50,66,67
Alb
A2M j
Apo AI 69,70
Apo B 69,70
C3/C4 71
i
There are large, dose
dependent increases in AAT
and Cp, which are not due to
an APR as CRP, Hp, and AAG
are low/normal. Thus, CRP,
Hp, and AAG distinguish
pregnancy/estrogen effects
from the APR.
Cp i,2,50,66
j
No effect 50 and slight 66 or
significant 68 increases have
been reported.
CRP k
FIB 65
Hp 50,62,74
Lp(a) 69,75
k
Elevated in labor and
delivery. 72,73
PAL 1,76
l rd
3
trimester 72
Tf 50,66
Hormone
Replacement
Therapy
AAG77
AAT i,2,78
A2M79,80
Alb81
Apo AI
m,19,82,83
Apo B m,19,82,83
AT IIIm,84
Cp i,2,78
CRP 85
FIB 86,87
Hp 77
Lp(a) 88
PAL 10
Tf 10,89
14
m
oral preparation has a
greater effect than intramuscuar or subcutaneous.
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18
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78. Bergink EW Crona N, Dahlgren E, Samsioe G. Effect of oestriol, oestradiol
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79. Horne CHW, Mallinson AC, Goudie RB.The effect of oestrogens and
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82. Sonnendecker EW, Polakow ES, Benadé AJ, Simchowitz E. Serum lipoprotein
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83.Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of
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84. Bonduki CE, Lourenco DM, Baracat E, et al..The effect of estrogen-progestin
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19
Section I.A.
70. Desoye G, Schweditsch MO, Pfeiffer KP, Zechner R, Kostner GM. Correlation
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Metab Res. 1989;21:334-337.
NUTRITIONAL ASSESSMENT
Overview
Factors confounding protein data in nutritional assessment
Assessment and monitoring of nutritional status
Nutritional markers in prognosis
OVERVIEW
Changes in Protein Levels in Malnutrition
Alb
---
PAL
---
Tf
---
RBP
---
C4
N
C3
--
CRP
+
A2M
+
AAT
+
Hp4
+
As the body does not maintain non-functional stores of protein, any
gain or loss of protein means a change in system functionality. Thus, in
severe protein-energy malnutrition (PEM), cardiac function may be
impaired, as may the immune system (malnourished patients are more
susceptible to infections and anemia).1,2 PEM may result from either
malnutrition or from increased metabolic expenditure/nutritional losses
(e.g. fever, infections, burns, trauma, hyperthyroidism, cancer, surgery,
sepsis, malabsorption, diarrhea).1-4
In developed countries, PEM is most common in the hospitalized elderly5
and is usually related to increased metabolic expenditure or nutritional
losses, rather than to under-nutrition. Although the condition is typically
not as severe as either marasmus or kwashiorkor, it remains an important
clinical finding that can have a negative impact on both morbidity and mortality.6-8 The identification and monitoring of PEM in hospitalized patients
leads to improved treatment, with better outcome and shorter hospital stay.9
Kwashiorkor (nutritional edema), a rare, extreme cause of PEM, is due to
inadequate protein intake with low/normal calorie intake and is most
frequent in children. Clinical characteristics include edema and hair and
skin pigment changes; laboratory findings include hypoalbuminemia
20
(<2.8 g/L) and elevated gamma globulins. In marasmus (nutritional
atrophy) protein intake is adequate, but total calorie intake has been
chronically low. Clinical characteristics are weight loss, with muscle
wasting, but no edema; serum protein levels are mildly reduced or
even normal.1,2
Section I.A.
Indices used to assess and monitor PEM include:2,10,11
• body weight
• weight loss
• total lymphocyte deficiency
• anthropometric measurements
• total body nitrogen
• serum protein marker
The ideal protein marker would have:5,12
• small body pool
• rapid turnover
• levels that decline with PEM
• levels that increase rapidly in response to nutritional support
• levels not confounded by other influences.
Tests presently in use include albumin, prealbumin, transferrin, and
retinol-binding protein.11,12 None of these should be used alone.
FACTORS CONFOUNDING PROTEIN DATA IN NUTRITIONAL
ASSESSMENT
Nutritional status is not the only factor that modulates serum protein
levels; therefore, it is important to take other clinical issues into
account when interpreting protein data in the context of nutritional
assessment. Protein levels can be interpreted in terms of nutritional
status only when confounding conditions have been excluded.13
Acute phase response
• Albumin, transferrin, prealbumin, and retinol-binding protein
levels are decreased in the APR. The extent of change depends on the
severity of inflammation or necrosis.
Renal disease
• Serum levels of albumin, transferrin, and prealbumin are often
decreased in renal disease (see Renal Disease).
• Serum retinol-binding protein is increased in chronic renal
failure.14 Thus, absolute levels of retinol-binding protein cannot be
used to assess nutritional status, but monitoring changes may be
useful in stable patients.12
Liver disease
• Serum levels of albumin, prealbumin, transferrin, and retinolbinding protein are decreased in liver disease (see Liver Disease)
and become insensitive markers of PEM in these patients.
21
Other
• Albumin and prealbumin data may be confounded by the administration of intravenous fluid15 or whole blood.
Section I.A.
• Exogenous and endogenous glucocorticoids cause increased prealbumin, which may be a confounding factor in the stressed patient.16
• In iron deficiency anemia, serum transferrin levels are elevated and
may mask the effects of malnutrition.17
• Drug effects on serum proteins should be considered. For example,
transferrin levels are decreased by certain drugs, such as aminoglycosides, tetracycline, and some cephalosporins.5,18
• Estrogen (oral contraceptives, pregnancy, and hormone replacement
therapy) causes increases in transferrin and retinol-binding
protein levels.19
• Hyperthyroidism causes decreased levels of prealbumin20 and
retinol-binding protein.10 A high glucose concentration feeding
formula may decrease serum fibronectin levels.10,21
ASSESSMENT AND MONITORING OF NUTRITIONAL STATUS
Alb
-/--
Tf
-/--
PAL
-/--
RBP
-/--
FN
-/--
CRP
N
SHORT-TERM ASSESSMENT
• Very low prealbumin (<50 mg/L) may indicate severe protein depletion and levels <170 mg/L indicate that nutritional supplementation
may be beneficial.9 Due to its short half-life (2 days), small pool size,
high essential amino acid content, and rapid response (5 days) to supplementation, prealbumin is the protein most frequently used for
short-term assessment of PEM.12 It is a better indicator of protein
nutritional status and positive nitrogen balance than albumin or transferrin16,22 and is also more sensitive (i.e. shows a greater increase) in
response to total parenteral nutrition of the malnourished patient.23,24
Prealbumin is NOT useful for nutritional assessment in patients with
liver disease or acute inflammation (below).25,26
• Retinol-binding protein has a short half-life (12 hours) and small
body pool size; levels respond quickly (<5 days) to nutritional therapy
and are used to monitor short term changes in nutritional status.5,27-29
As a marker for PEM, low retinol-binding protein has comparable
sensitivity to prealbumin, but is more likely to be affected by renal
disease (below).5,14 Levels of these two proteins are highly correlated
(in the absence of renal disease), as they form a complex.19 Retinolbinding protein may be more sensitive to energy restriction than
protein depletion.19
22
• Fibronectin has a short half-life (15 hours).5 Low levels respond
more rapidly to refeeding than prealbumin or retinol-binding protein10,30
and may indicate acute nutritional deficiency before there has been
severe depletion.30 Fibronectin is particularly useful in nutritional panels
as it is not synthesized exclusively by the liver.5
LONG-TERM MONITORING
• In both adults and children, very low albumin (<21 g/L) may indicate
severe malnutrition, either primary or secondary;5,33,34 however, many
factors cause low albumin, so a single albumin measurement is not
very useful in assessing short-term nutritional status.5 Furthermore,
albumin has a long half-life (20 days) and levels respond slowly to
nutritional supplementation.1,11 Thus, albumin measurement is more
appropriate for monitoring patients in a long-term care setting.5,35,36,37
• Very low transferrin (<1 g/L) may indicate severe protein depletion.
Although it has a shorter half-life (8 to 9 days) and responds more
rapidly than albumin,5,12,29 transferrin does not detect changes in nutritional status within 2 weeks of beginning total parenteral nutrition.38
LABORATORY TESTING IN NUTRITIONAL ASSESSMENT*
Short-term assessment
Long-term monitoring
Validation of markers
PAL
Alb
CRP
FN RBP
Tf
*In addition to anthropomorphic measurement, hematologic testing,
and total body nitrogen testing, if applicable.
NUTRITIONAL MARKERS IN PROGNOSIS
Alb
-/--
PAL
-/--
Although low levels of the serum proteins used as nutritional markers
often predict clinical outcome, these changes may be related more to
severity of the APR (or, in hemodialysis, to dilutional effects39) than to
the degree of malnutrition.
23
Section I.A.
• Elevated CRP indicates the presence of an APR,31 which is a potential
confounding factor when using serum protein testing in nutritional
assessment. Thus, CRP measurement can usually be used to discriminate between nutritional problems and inflammation as the cause of
decreased albumin, prealbumin, transferrin, retinol-binding protein, or
fibronectin levels.5,26,32 In clinical situations known to be associated
with an APR (eg abscess, inflammatory arthritis, septic shock, sepsis,
trauma), declining CRP levels may indicate that short half-life proteins,
such as fibronectin, retinol-binding protein, and prealbumin, may have
become useful as nutritional markers.5 An exception is in cases of
chronic inflammation.
• Low albumin level is seen in many diseases and is associated with
increased risk for mortality and morbidity.11,36,37,40
Section I.A.
• In patients with advanced cancer receiving total parenteral nutrition,
a faster increase in serum levels of transferrin, retinol-binding
protein and prealbumin predicts a better prognosis.41
• Low prealbumin is more sensitive than albumin and transferrin as a
predictor of postoperative morbidity in children.42
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1. Baron RB. Protein-energy malnutrition. In: Bennett JC, Plum F, eds.
Cecil Textbook of Medicine. 20th ed. Philadelphia, PA:WB Saunders Co;
1996;2:1154-1158.
2. Torún B, Chew F. Protein-energy malnutrition. In: Shils ME, Olson JA,
Shike M, eds. Modern Nutrition in Health and Disease. 8th ed.
Philadelphia, PA: Lea & Febiger; 1994;2:950-976.
3. Uderzo C, Rovelli A, Bonomi M, et al. Nutritional status in untreated
children with acute leukemia as compared with children without
malignancy. J Pediat Gastroenterol Nutr. 1996;23:34-37.
4. Rhoads JE, Alexander CE. Nutritional problems of surgical patients.
Ann NY Acad Sci. 1955;63:268-275.
5. Spiekerman AM. Nutritional assessment (protein nutriture).
Anal Chem. 1995;67:429R-436R.
6. Bistrian BR, Blackburn GL, Hallowell E, Heddle R. Protein status of
general surgical patients. JAMA. 1974;230:858-860.
7. Bistrian BR, Blackburn GL,Vitale J, Cockran D, Naylor J. Prevalence
of malnutrition in general medical patients. JAMA. 1976;235:1567-1570.
8. Reilly JJ Jr, Hull SF, Albert N,Waller A, Bringardener S. Economic
impact of malnutrition: a model system for hospitalized patients.
J Parenter Enter Nutr. 1988;12:371-376.
9. Mears E. Outcomes of continuous process improvement of a nutritional care program incorporating serum prealbumin measurements.
Nutrition. 1996;12:479-484
10. Haider M, Haider S. Assessment of protein-calorie malnutrition.
Clin Chem. 1984;30:1286-1299.
11. Bistrian BR. Nutritional assessment. In: JC Bennett, F Plum, eds. Cecil
Textbook of Medicine. 20th ed. Philadelphia, PA: WB Saunders Co;
1996;2:1151-1154.
12. Spiekerman AM. Proteins used in nutritional assessment. Clinics Lab
Med. 1993;13:353-369.
13. Johnson AM. Low levels of plasma proteins: malnutrition or inflammation? Clin Chem Lab Med. 1999;37:91-96.
24
14. Smith FR, Goodman DS.The effects of diseases of the liver, thyroid,
and kidneys on the transport of vitamin A in human plasma. J Clin
Invest. 1971;50:2426-2431.
15. Spiekerman AM. In: Nutritional Assessment: the key to wellnourished outcomes. Proceedings of an educational symposium.
Dade Behring; 1999.
17. Kalantar-Zadeh K, Kleiner M, Dunne E, et al.Total iron-binding
capacity-estimated transferrin correlates with the nutritional subjective global assessment in hemodialysis patients. Am J Kidney Dis.
1998;31:263-272.
18. Rubin J, Deraps GD,Walsh D, Adair C, Bower J. Protein losses and
tobramycin absorption in peritonitis treated by hourly peritoneal
dialysis. Am J Kidney Dis. 1986;8:124-127.
19. Rask L, Anundi H, Böhme J, et al.The retinol-binding protein. Scand J
Clin Lab Invest. 1980;40(suppl 154):45-61.
20. Bartalena L, Robbins J.Variations in thyroid hormone transport proteins and their clinical implications. Thyroid. 1992;2:237-245.
21. Saba TM, Blumenstock FA, Shah DM, et al. Reversal of opsonic deficiency in surgical, trauma, and burn patients by infusion of purified
human plasma fibronectin. Correlation with experimental observations. Am J Med. 1986;80:229-240.
22. Bourry J, Milano G, Caldani C, Schneider M. Assessment of nutritional proteins during the parenteral nutrition of cancer patients.
Ann Clin Lab Sci. 1982;12:158-162.
23.Winkler MF, Pomp A, Caldwell MD, Albina JE.Transitional feeding: the
relationship between nutritional intake and plasma protein concentrations. J Am Diet Assoc. 1989;89:969-970.
24. Carpentier YA, Barthel J, Bruyns J. Plasma protein concentration in
nutritional assessment. Proc Nutr Soc. 1982;41:405-417.
25.Teppo AM, Maury CPJ. Serum prealbumin, transferrin, and
immunoglobulins in fatty liver, alcoholic cirrhosis, and primary biliary
cirrhosis. Clin Chim Acta. 1983;129:279-286.
26. Sann L, Bienvenu F, Bienvenu J, Bougeois J, Bethenod M. Evolution of
serum prealbumin, C-reactive protein, and orosomucoid in neonates
with bacterial infection. J Pediatr. 1984;105:977-981.
27. Cavarocchi NC, Au FC, Dalal FR, Friel K, Mildenberg B. Rapid
turnover proteins as nutritional indicators. World J Surgery.
1986;10:468-473.
25
Section I.A.
16. Moskowitz S, Pereira G, Spitzer A, Heaf L, Amsel J,Watkins J.
Prealbumin as a biochemical marker of nutritional adequacy in
premature infants. J Pediatr. 1983;102:749-753.
Section I.A.
28. Carlson DE, Cioffi WG Jr, Mason AD Jr, McManus WF, Pruitt BA Jr.
Evaluation of serum visceral protein levels as indicators of nitrogen
balance in thermally injured patients. J Parenteral Enteral Nutr.
1991;15:440-444.
29. Ingenbleek Y, van den Schriek HG, de Nayer P, de Visscher M.The
role of retinol-binding protein in protein-calorie malnutrition.
Metabolism. 1975;24:633-641.
30. Scott RL, Sohmer PR, MacDonald MG.The effect of starvation and
repletion on plasma fibronectin in man. JAMA. 1982;248:2025-2027.
31.Thompson D, Milford-Ward A,Whicher JT.The value of acute phase
protein measurements in clinical practice. Ann Clin Biochem.
1992;29:123-131.
32. Ikizler TA,Wingard RL, Harvell J, Shyr Y, Hakim RM. Association of morbidity with markers of nutrition and inflammation in chronic haemodialysis patients: a prospective study. Kidney Int. 1999;55:1945-1951.
33. Starker PM, Gump FE,Askenazi J, Elwyn DH, Kinney JM. Serum albumin
levels as an index of nutritional support. Surgery. 1982;91:194-199.
34. Grant JP, Custer PB,Thurlow J. Current techniques of nutritional
assessment. Surg Clin North Amer. 1981;61:437-463.
35. Georgieff MK, Amarnath UM, Murphy EL, Ophoven JJ. Serum transferrin levels in the longitudinal assessment of protein-energy status
in preterm infants. J Pediatr Gastroenterol Nutr. 1989;8:234-239.
36. Holmes R, Maachiano K, Agarwal N, Savino J. Nutrition know-how.
Combating pressure sores-nutritionally. Am J Nursing. 1987;87:
1301-1303.
37. Pinchcofsky-Devin GD, Kaminski MV Jr. Correlation of pressure
sores and nutritional status. J Am Geriatr Soc. 1986;34:435-440.
38. Seltzer MH, Bastidas JA, Cooper DM, Engler P, Slocum B, Fletcher HS.
Instant nutritional assessment. J Parenteral Enteral Nutr. 1979;3:157-159.
39. Dutton J, Campbell H,Tanner J, Richards N. Pre-dialysis serum albumin is a poor indicator of nutritional status in stable chronic
haemodialysis patients. Edtna-Erca J. 1999;25:36-37.
40. Anderson CF, Wochos DN.The utility of serum albumin values in
the nutritional assessment of hospitalized patients. Mayo Clin Proc.
1982;57:181-184.
41. Inoue Y, Nezu R, Matsuda H,Takagi Y, Okada A. Rapid turnover
proteins as a prognostic indicator in cancer patients. Surgery Today.
1995;25:498-506.
42. Leite HP, Fisberg M, Novo NF, Nogueira EB, Ueda IK. Nutritional
assessment and surgical risk markers in children submitted to
cardiac surgery. Revista Paulista de Medicina. 1995;113:706-714.
26
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE
Overview
Cardiovascular disease
Acute myocardial infarction
Ischemic stroke
OVERVIEW
CARDIOVASCULAR DISEASE
In this section, protein measurements relevant to the identification and
monitoring of patients with or at risk for cardiovascular disease (CVD),
including coronary artery disease (CAD) and peripheral artery disease
(PAD), are discussed. Cerebrovascular disease is discussed separately
in the topic Ischemic Stroke.
ACUTE PHASE RESPONSE IN CVD
CRP
+
SAA
+
AAT
+
FIB
+
Cp
+
FN
+
AAG
+
Inflammation is important in the etiology and pathology of ASCVD.2
It is also important in the short-term outcome of acute coronary
syndromes. For example, the presence of inflammation is an important
and independent determinant of short-term outcome in unstable angina3 and is associated with increased risk of a recurrent event after MI.4
• CRP is higher in CAD and PAD due to chronic inflammation.2,5
It is markedly elevated in MI6 due to the presence of necrosis, and
levels are higher in unstable than in stable angina.7 Elevated CRP
(>200 mg/L) predicts cardiac rupture after MI8 and is associated
with recurrent events in the first year after MI9 and after stenting.10
It also is predictive of poor outcome in acute coronary syndromes
(unstable angina and non-Q-wave MI).11
• Increases in SAA after angioplasty are associated with increased risk
for restenosis.12
27
Section I.B.
Atherosclerotic cardiovascular disease (ASCVD) is characterized by
atheromatous lesions in the artery walls. These plaques are believed to
develop as a result of injury to the arterial epithelium, which leads to
an inflammatory process and the accumulation of lipids. Rupture of an
unstable plaque causes thrombosis, arterial blockage, and the more
severe clinical consequences of unstable angina, myocardial infarction
(MI), and stroke.1 As a result, the serum protein measurements of
greatest relevance in ASCVD are those related to hyperlipidemia,
inflammation, tissue necrosis, and thrombosis.
• Elevated (α1-acid glycoprotein is associated with lower limb PAD5
and stable angina pectoris.13
• (α1-Antitrypsin,14 fibrinogen,15 ceruloplasmin,16 and fibronectin17
levels are elevated in CAD. Elevated fibrinogen is also associated with
PAD.18,19
IMMUNOLOGIC RESPONSE IN CVD
IgA
+
lgG
+
Section I.B.
• Elevated IgG, but not IgM, predicts MI in middle-aged, dyslipidemic
men.20
• IgA is elevated in severe ASCVD21 and is higher in subjects with
previous major ischemic events compared with controls.22 Total
IgA predicts MI in middle-aged, dyslipidemic men.20
SERUM PROTEIN RISK FACTORS FOR CVD
ApoB
+
Apo
-
Lp(a)
+
FIB
+
CRP
+
C3
+
Cp
+
Alb
-
AT III
-
PROTEIN RISK FACTORS RELATED TO HYPERLIPIDEMIA
• Apo B, the protein associated with the LDL particle, mediates the
uptake of LDL by the LDL receptor.23 Elevated apo B is a significant
risk factor for CVD in both retrospective and prospective studies.24
Apo B can be used to monitor the effectiveness of lipid lowering
therapy.25 Since levels reflect LDL particle number, its measurement
may provide additional information to LDL-C measurement.26
• Apo A-I is the major structural protein of HDL. Apo A-I is an
inverse prospective risk factor for MI.24,27 Low apo A-I is associated
with higher mortality and MI incidence after coronary artery bypass
graft surgery.28
• Lp(a) is elevated in ASCVD. Levels in the upper quintile are a
significant independent prospective risk factor for MI (fatal and nonfatal)29 and PVD30. Elevated levels are associated with stroke (see
Ischemic Stroke) and may also be associated with CVD in renal
disease.31 The majority of studies show that elevated Lp(a) does not
predict restenosis after percutaneous transluminal coronary angioplasty or stenting.32
28
PROTEIN RISK FACTORS RELATED TO INFLAMMATION
• Elevated fibrinogen is a prospective risk factor for ASCVD.33,34 The
risk for refractory unstable angina is increased with elevated fibrinogen.35
• A higher CRP level within the “normal” range is a strong independent prospective risk factor for CVD36,37 and PVD38 and adds to the
predictive power of lipoprotein measurements in determining risk for
first MI.39 Elevated CRP levels predict major CV complications in
patients with unstable angina3 and predict the recurrence of ischemic
events after CABG.10
• Low albumin has been reported to be a prospective risk factor for
CVD.39 It is also associated with an increased incidence of CVD in
hemodialysis patients.40
PROTEIN RISK FACTORS RELATED TO THROMBOSIS
• Low AT III predisposes to thrombosis and is associated with
increased risk of future coronary events in angina pectoris.44
• Elevated fibrinogen, either due to or independent of the APR,
increases thrombotic risk.45
PROTEINS ASSOCIATED WITH DISEASE SEVERITY IN CVD
Apo A-I
-
Apo B
+
Lp(a)
+
Alb
-
AAG
+
CRP
+
AT III
+
FIB
+
PROTEIN RISK FACTORS RELATED TO HYPERLIPIDEMIA
• Low apo A-I levels may correlate with angiographic severity of
CAD better than HDL.46 High apo B levels also correlate with the
degree of coronary stenosis,47 and the apo B:apo A-I ratio is a
stronger correlate of disease severity by angiography than lipoprotein
measurements.46
• Elevated Lp(a) levels correlate with the degree of arterial stenosis, as
measured by coronary angiography.48
PROTEIN RISK FACTORS RELATED TO INFLAMMATION
• Albumin has an inverse relationship with CAD severity by angiography.49
• In chronic arterial ischemia of the lower limbs, α1-acid glycoprotein
and CRP levels increase with the severity of ischemia.5
29
Section I.B.
• The relationship between ferritin and ASCVD is controversial and
data from prospective studies vary. It has been reported that ferritin
predicts the 5-year progression of carotid atherosclerosis41 and that
it is a significant risk factor for CVD,42 but most studies report no
relationship with ASCVD.43
PROTEIN RISK FACTORS RELATED TO THROMBOSIS
• Increased fibrinogen is associated with PAD and shows a strong
correlation with the extent of occlusive disease.19
• AT III levels decrease with disease severity in men.50
LABORATORY TESTING IN CVD
Risk factor evaluation and monitoring (if levels abnormal)
Apo B
FIB
Lp(a)
CRP
Apo AI
AT III
Section I.B.
ACUTE MYOCARDIAL INFARCTION
Serum protein measurements related to tissue damage and inflammation are useful in the diagnosis of acute myocardial infarction (AMI) and
in the evaluation of prognosis.
ACUTE PHASE RESPONSE IN AMI
CRP
+++
AAT
++
AAG
++
CER
+
FER
++
Hp
-/+
Tf
Alb
--
--
• CRP measurement provides important prognostic information in
AMI; however, by itself elevated CRP is too nonspecific a finding to
be diagnostic. At admission, the degree of elevation of CRP predicts
the timing of the event and risk of complications. CRP increases
markedly 8 to 24 hours after MI; levels peak at 3 to 4 days51 and
correlate with infarct size in the absence of thrombolytic therapy.52
Decreases in CRP within 3 days of AMI indicate that thrombolytic
therapy has been successful.53 In patients with chest pain, elevated
CRP indicates increased risk for poor CVD outcome.54
• Haptoglobin levels are elevated at admission for MI. Levels then
decrease, suggesting acute hemolysis, and reach a minimum ~10 hours
after admission. Haptoglobin then increases again over the next
36 hours, due to the APR.55
• Serum levels of the other acute phase proteins demonstrate changes
typical for a severe APR. α1-Antitrypsin, α1-acid glycoprotein,
ferritin, and ceruloplasmin levels increase after AMI, while
transferrin, prealbumin, and albumin levels decrease.56-58
PROTEINS USEFUL IN THE DIAGNOSIS OF AMI
• Serum myoglobin is an early marker for AMI (not myocardial
ischemia) and increases within 1 to 3 hours of injury.59 The response
in the first 24 hours is correlated with infarct size in patients with
normal renal function,60 and the time to peak myoglobin levels is
30
shorter in patients with thrombolytic therapy and reperfusion than in
those without.61 As myoglobin is also released by skeletal muscle, it is
not totally specific62 and should be used in combination with markers
specific for cardiac muscle, such as troponin T and CK-MB.63,64
Serial testing is important with any marker.65 Negative serial myoglobin studies effectively rule out MI.66
SERUM PROTEIN INTERPRETATIONS CONFOUNDED BY THE APR IN AMI
Apo B
-
Apo AI
-
Lp(a)
+
• Apo B decreases after MI and returns to normal after resolution of
the APR (~ 2 months).69,70
• Apo A-I levels are below baseline at 48 hours after MI and remain
low for 2 months.69,70
• Lp(a) levels are below baseline at 48 hours after MI; at 192 hours
Lp(a) rebounds above baseline7 and remains elevated for at least
4 weeks.69,70
LABORATORY TESTING IN AMI
Diagnosis and monitoring
Prognosis
Myoglobin
CK-MB
CRP
CRP
Troponin T/l
ISCHEMIC STROKE
Although fewer data are available for ischemic stroke, most studies
report findings similar to those seen in other cardiovascular diseases,
reflecting the atherosclerotic etiology of these conditions. Note: The
following data do not necessarily apply to stroke of other etiology, such
as hemorrhagic stroke.
ACUTE PHASE RESPONSE IN ISCHEMIC STROKE
CRP
+
Alb
-
FIB
+
FER
+
• Elevated CRP is an independent predictor of survival after ischemic
stroke; survival is worse if CRP>10 mg/L.71 Elevated CRP may
indicate the extent of cerebral infarct in stroke.72
31
Section I.B.
Unless measured within 48 hours of admission for AMI, lipoprotein
measurements are not useful for the detection and monitoring of
hyperlipidemia for the first 2 months after AMI.67,68
• Elevated fibrinogen is associated with increased risk for ischemic
stroke and increased risk of thromboembolism in both prospective
and retrospective studies.73
• In acute ischemic stroke, high ferritin in the first 24 hours of
hospitalization is related to poor prognosis.74
IMMUNOLOGIC RESPONSE IN ISCHEMIC STROKE
• Isolated elevation of IgA may be seen.75
Section I.B.
SERUM PROTEIN RISK FACTORS FOR ISCHEMIC STROKE
• Elevated fibrinogen is associated with increased risk for ischemic
stroke and increased risk of thromboembolism.73
• Elevated CRP is an independent predictor of survival after ischemic
stroke: survival is worse if CRP>10 mg/L.71
• Decreased albumin is associated with increased risk for ischemic
stroke.76
• Low apo A-I, high apo B, and high Lp(a) are associated with ischemic
stroke and carotid atherosclerosis in retrospective studies.76-80
• Elevated fibrinogen is associated with ischemic stroke in both
prospective and retrospective studies.73,81-83 Most acute phase proteins
normalize gradually after stroke, but fibrinogen remains significantly
elevated and is associated with increased risk for recurrent vascular
events.45,84 Elevated fibrinogen is also associated with TIA and minor
ischemic strokes.85
PROTEINS ASSOCIATED WITH DISEASE SEVERITY
• Elevated Lp(a) is associated with the severity of carotid stenosis and
of cerebral artery lesions by angiography in patients with cerebrovascular disease in some,81,86 but not all,87,88 studies.
• In the early phase of cerebral ischemia, elevated plasma fibrinogen
levels are related to the severity of clinical status and to the extent of
brain vascular damage.89 Fibrinogen level is also related to the severity
of cerebral artery stenosis.73
• Elevated CRP is associated with the severity of carotid atherosclerosis.90
LABORATORY TESTING IN ISCHEMIC STROKE.
Risk factor evaluation
Prognosis
Apo B Apo A-I
FIB CRP
32
FIB
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41. Kiechl S,Willeit J, Egger G, Poewe W, Oberhollenzer F. Body iron stores and
the risk of carotid atherosclerosis: prospective results from the Bruneck study.
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42. Salonen JT, Nyyssonen K, Korpela H,Tuomilehto J, Seppanen R, Salonen R.
High stored iron levels are associated with excess risk of myocardial infarction
in eastern Finnish men. Circulation. 1992;86:803-811.
43. Sempos CT, Looker AC, Gillum RF. Iron and heart disease: the epidemiologic
data. Nutr Rev. 1996;54:73-84.
44.Thompson SG, Fechtrup C, Squire E, et al. Antithrombin III and fibrinogen as
predictors of cardiac events in patients with angina pectoris. Arterioscl Thromb
Vasc Biol. 1996;16:357-362.
45. Meade TW. Fibrinogen in ischaemic heart disease. Eur Heart J.
1995;16(suppl A):31-35.
46. Garfagnini A, Devoto G, Rosselli P, Boggiano P, Venturini M. Relationship
between HDL-cholesterol and apolipoprotein AI and the severity of coronary
heart disease. Eur Heart J. 1995;16:465-470.
47.Tsuji A, Ikeda N, Nakamura T. Plasma lipids, lipoproteins and apolipoproteins
and sudden cardiac death. Int J Legal Med. 1999;112:151-154.
48. Budde T, Fechtrup C, Bösenberg E, et al. Plasma Lp(a) levels correlate with
number, severity, and length-extension of coronary lesions in male patients
undergoing coronary angiography for clinically suspected coronary atherosclerosis. Arterioscl Thromb. 1994;14:1730-1736.
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Section I.B.
38. Ridker PM, Cushman M, Stampfer MJ,Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular
disease. Circulation. 1998;97:425-428.
49. Narang R, Ridout D, Nonis C, Kooner JS. Serum calcium, phosphorus, and
albumin levels in relation to the angiographic severity of coronary artery
disease. Int J Cardiol. 1997;60:73-79.
50. van der Bom JG, Bots ML, van Vliet HH, Pols HA, Hofman A, Grobbee DE.
Antithrombin and atherosclerosis in the Rotterdam study. Arterioscl Thromb
Vasc Biol. 1996;16:864-867.
51. Sturk A, Hack CE, Aarden LA, Brouwer M, Koster RR, Sanders GT. Interleukin6 release and the acute-phase reaction in patients with acute myocardial
infarction: a pilot study. J Lab Clin Med. 1992;119:574-579.
Section I.B.
52. Pietila K, Harmoinen A, Hermens W, Simoons ML,Van de Werf F,Verstraete M.
Serum C-reactive protein and infarct size in myocardial infarct patients with a
closed versus an open infarct-related coronary artery after thrombolytic
therapy. Eur Heart J. 1993;14:915-919.
53. Andreotti F, Hackett DR, Haider AW, et al.Von Willebrand factor, plasminogen
activator inhibitor-1, and C-reactive protein are markers of thrombolytic
efficacy in acute myocardial infarction. Thromb Haemost. 1992;68:678-682.
54. Ferreiros ER, Boissonnet CP, Pizarro R, et al. Independent prognostic value of
elevated C-reactive protein in unstable angina. Circulation. 1999;100:1958-1963.
55. Bernard DR, Langlois MR, Delanghe JR, De Buyzere ML. Evolution of haptoglobin concentration in serum during the early phase of acute myocardial infarction. Eur J Clin Chem Clin Biochem. 1997;35:85-88.
56. Moroz C, Bessler H, Katz M, Zahavi I, Salman H, Djaldetti M. Elevated serum
ferritin level in acute myocardial infarction. Biomed Pharmacother. 1997;51:
126-130.
57. Singh TK. Serum ceruloplasmin in acute myocardial infarction. Acta Cardiologica.
1992;47:321-329.
58. Maeda S,Abe A, Seishima M, Makino K, Noma A, Kawade M. Transient changes of
serum lipoprotein(a) as an acute phase response. Atherosclerosis. 1989;78:145-150.
59. Polanczyk CA, Lee TH, Cook EF,Walls R,Wybenga D, Johnson PA.Value of
additional two-hour myoglobin for the diagnosis of myocardial infarction in
the emergency department. Am J Cardiol. 1999;83:525-529.
60.Wodzig KW, Kragten JA, Hermens WT, Glatz JF, van Dieijen-Visser MP.
Estimation of myocardial infarct size from plasma myoglobin or fatty acidbinding protein. Influence of renal function. Eur J Clin Chem Clin Biochem.
1997;35:191-198.
61. Jurlander B, Clemmensen P, Ohman EM, Christenson R,Wagner GS, Grande P.
Serum myoglobin for the early non-invasive detection of coronary reperfusion
in patients with acute myocardial infarction. Eur Heart J. 1996;17:399-406.
62. Plebani M, Zaninotto M. Diagnostic strategies in myocardial infarction using
myoglobin measurement. Eur Heart J. 1998;19 (suppl N):N12-15.
63. Agrawal B. The use of cardiac markers in acute coronary syndromes.
Scand J Clin Lab Invest. 1999;230 (suppl):50-59.
64. Kost GJ, Kirk JD, Omand K. A strategy for the use of cardiac injury markers
(troponin I and T, creatine kinase-MB mass and isoforma, and myoglobin) in
the diagnosis of acute myocardial infarction. Arch Pathol Lab Med.
1998;122:245-251.
36
65.Adams JE 3rd, Miracle VA. Cardiac biomarkers: past, present, and future.
Am J Crit Care. 1998;7:418-423.
66. Gornall DA, Roth SN. Serial myoglobin quantitation in the early assessment of
myocardial damage: a clinical study. Clin Biochem. 1996;29:379-384.
67. Ryder RE, Hayes TM, Mulligan IP, Kingswood JC,Williams S, Owens DR. How
soon after myocardial infarction should plasma lipid values be assessed? BMJ
Clin Res Ed. 1984;289:1651-1653.
68. Buckley BM, Bold AM. Managing hyperlipidemia. BMJ. 1982;285:1293-1294.
69. Mbewu AD, Durrington PN, Bulleid S, Mackness MI.The immediate effect of
streptokinase on serum lipoprotein(a) concentration and the effect of myocardial infarction on serum lipoprotein(a), apolipoproteins AI and B, lipids and Creactive protein. Atherosclerosis. 1993;103:65-71.
71. Muir KW,Weir CJ, Alwan W, Squire IB, Lees KR. C-reactive protein and outcome after ischemic stroke. Stroke. 1999;30:981-985.
72. Beamer NB, Coull BM, Clark WM, Hazel JS, Silberger JR. Interleukin-6 and
interleukin-1 receptor antagonist in acute stroke. Ann Neurol. 1995;37:800-805.
73. Qizilbash N. Fibrinogen and cerebrovascular disease. Eur Heart J. 1995;16
(suppl A):42-45.
74. Davalos A, Fernandez-Real JM, Ricart W, et al. Iron-related damage in acute
ischemic stroke. Stroke. 1994;25:1543-1546.
76. Gillum RF, Ingram DD, Makuc DM. Relations between serum albumin concentration and stroke incidence and death.The NHANES I Epidemiologic Followup study. Am J Epidemiol. 1994;140:876-888.
77. Nishino M, Sueyoshi K,Yasuno M, Abe H, Hori M, Kamada T. Risk factors for
carotid atherosclerosis and silent cerebral infarction in patients with coronary
heart disease. Angiology. 1993;44:432-440.
78.Willeit J, Kiechl S. Prevalence and risk factors of asymptomatic extracranial
carotid artery atherosclerosis. A population-based study. Arterioscl Thromb.
1993;13:661-668.
79. Sharrett AR, Patsch W, Sorlie PD, Heiss G, Bond MG, Davis CE. Associations of
lipoprotein cholesterols, apolipoproteins AI and B, and triglycerides with
carotid atherosclerosis and coronary artery disease.The Atherosclerosis Risk
in Communities (ARIC) study. Arterioscl Thromb. 1994;14:1098-1104.
80. Jurgens G,Taddei-Peters WC, Coltringer P, et al. Lipoprotein(a) serum concentration and apolipoprotein(a) phenotype correlate with severity and presence
of ischemic cerebrovascular disease. Stroke. 1995;26:1841-1848.
81. Heinrich J, Assman G. Fibrinogen and cardiovascular risk. J Cardiovasc Risk.
1995;2:197-205.
82. Kannel WB,Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease.The Framingham study. JAMA. 1987;258:1183-1186.
37
Section I.B.
70. Husain M, Armstrong PW, Connelly PW, Hegele RA. Lipoprotein(a) and
apolipoproteins B and AI after acute myocardial infarction. Can J Cardiol.
1995;11:206-210.
83. Ernst E. Fibrinogen as a cardiovascular risk factor - interrelationship with
infections and inflammation. Eur Heart J. 1993;14(suppl K):82-87.
84. Beamer NB, Coull BM, Clark WM, Briley DP,Wynn M, Sexton G. Persistent
inflammatory response in stroke survivors. Neurology. 1998;50:1722-1728.
85. Qizilbash N, Jones L,Warlow C, Mann J. Fibrinogen and lipid concentrations as
risk factors for transient ischaemic attacks and minor ischaemic strokes. BMJ.
1991;303:605-609.
86. Nomura S. Lipoprotein(a) in cerebrovascular and coronary atherosclerosis.
Hiroshima J Med Sci. 1995;44:133-139.
87. van Kooten F, van Krimpen J, Dippel DW, Hoogerbrugge N, Koudstaal PJ.
Lipoprotein(a) in patients with acute cerebral ischemia. Stroke. 1996;27:1231-1235.
Section I.B.
88. Markus HS, Kapadia R, Sherwood RA. Relationship between lipoprotein(a) and
both stroke and carotid atheroma. Ann Clin Biochem. 1997;34:360-365.
89. D’Erasmo E, Pisani D, Romagnoli S, Ragno A, Acca M. Clinical and prognostic
significance of hyperfibrinogenemia in cerebral ischemia. J Med. 1998;29:115-123.
90. Heinrich J, Schulte H, Schonfeld R, Kohler E, Assmann G. Association of
variables of coagulation, fibrinolysis and acute phase with atherosclerosis in
coronary and peripheral arteries and those arteries supplying the brain.
Thromb Haemost. 1995;73:374-379.
ENDOCRINE DISEASE
Diabetes mellitus
Thyroid disease
DIABETES MELLITUS
Diabetes mellitus (DM) comprises a group of syndromes with abnormal
carbohydrate metabolism, all characterized at some point by hyperglycemia. Changes in serum protein levels are related to inflammation,
to secondary complications (renal or cardiovascular disease), and to
the metabolic effects of abnormal insulin and glucose levels.
ACUTE PHASE RESPONSE (APR) IN DM
Alb
-
Hp
+
CRP
+
AAG
+
PSM
+
C3
+
SAA
+
FIB
+
FER
N/+
Cp
+
Apo B
N/++
Apo AI
-
• The acute phase proteins CRP,1,2 α1-acid glycoprotein,2,3 plasminogen,4 complement C3,5 ceruloplasmin,6,7 haptoglobin,2
and serum amyloid A3 are modestly elevated in DM, while albumin
is decreased,2 suggesting chronic inflammation. α1-Acid glycoprotein
and CRP are higher in type 2 DM with Syndrome X (hypertriglyceridemia, hypertension, obesity, and insulin resistance) than in
those without.3
38
• Albumin level is low and CRP is elevated in diabetics with persistent ischemic foot ulcers.8 CRP may be useful for monitoring
these patients.
• Fibrinogen9 is elevated and apo A-I10,11 is decreased in DM. Both are
associated with increased cardiovascular risk.7
• Changes in apo B levels are not characteristic of the APR. Levels are
usually normal in well-controlled type I DM,12 but elevated in type 2
DM13 and accompanied by hyperlipidemia, particularly in Syndrome X.
•
Note: DM is a prominent symptom of hereditary ceruloplasmin deficiency.16
IMMUNE RESPONSE IN DM
lgG
+
lgA
+
lgM
+/-
C4
-
• Diabetics may exhibit hypergammaglobulinemia.17 At the time of
diagnosis of type 1 DM, IgM18 levels are often increased; in established
disease, levels may be one half that of normal controls.19 IgA (~83%)
and IgG (35%) are elevated in DM.19
• Autoantibodies, including ANA and anti-islet cell antibodies, may be
seen in type 1 DM.20
PROTEIN CHANGES RELATED TO GLUCOSE CONTROL IN DM
AT III
-
PAL
-
RBP
-
Cp
+
FIB
+
IgA
+
Apo B
++
• Antithrombin III (AT III) levels are decreased with hyperglycemia
in both type 1 and type 2 DM.21
• Prealbumin and retinol-binding protein (RBP) levels are low in
type 1 DM, but normalize with improved glucose control.22,23 In contrast, RBP is elevated in type 2 DM, but there is normal availability of
retinol; thus, vitamin A status is normal.24
• Ceruloplasmin25 and IgA19 levels increase with poor glucose control.
39
Section I.B.
• Type 2 DM is often associated with elevated ferritin.14 In newly
diagnosed type 1 DM, there may be transient increases in ferritin
that normalize over time. Levels are not related to glucose control.
In evaluating diabetics for hemochromatosis, ferritin should be
measured in stable DM and not at the time of diagnosis.15
PROTEIN CHANGES RELATED TO RENAL COMPLICATIONS IN DM
Alb
-/--
IgG
-
IgA
-
IgM
+
A2M
N/+
FN
+
Apo B
++
Apo(a)
N/++
FIB
+
• Albumin: urine microalbumin level is a sensitive marker for
evolving diabetic nephropathy.26 Mild decreases in serum albumin
levels may occur in DM with renal disease27 with more marked
decreases if the nephrotic syndrome develops.28
• IgG and IgA levels decrease if the nephrotic syndrome develops.29
Section I.B.
• α2-Macroglobulin, IgM, and apo B are increased in the nephrotic
syndrome.29,30,31
• Apo B, apo A-I, and fibronectin are increased in glomerular
dysfunction.32,33 Apo B levels predict the progression of microalbuminuria.34 Lp(a) is elevated with renal disease35 in type 1 DM. In
type 2 DM, this is mostly seen only in the nephrotic syndrome.36
(See Renal Disease.)
• Fibrinogen is increased in diabetic nephropathy.37
LABORATORY STUDIES IN DM*
Etiology
Monitoring
Monitoring
Risk factors
Cp**
Renal
See pp.55-61
Other
CRP PAL**
AAG IgG, IgA, IgM
Apo B
Apo A-I
FER**
Lp(a)
FIB
* In addition to standard diabetes-related measurements, such as glucose
tolerance test, fasting blood glucose, HbA1c, and fructosamine.
** See text for specific clinical circumstances.
THYROID DISEASE
Many of the effects of thyroid disease on serum protein levels are
related to an increase in metabolic rate due to thyroid hormone (TH),
which alters protein synthesis and degradation.
THYROID HORMONE (TH) BINDING PROTEINS
• Prealbumin binds insignificant amounts of T3 (triiodothyronine), but
binds 15% of serum T4 (thyroxine).38 Total levels of TH may fluctuate
with serum levels of prealbumin. The patient remains euthyroid, since
the level of free hormone does not change.
• Albumin contributes to TH transport in serum.TH causes increased
albumin turnover with no net effect on serum levels; however, in
myxedema albumin shifts into the extravascular space.39
40
• Protein variants: Prealbumin genetic variants can result in
euthyroid hyperthyroxinemia due to increased T4 binding. Familial
dysalbuminemic hyperthyroxinemia causes a benign euthyroid
hyperthyroxinemia due to increased affinity of the albumin variant
for T4.40 As a result, it may be difficult to interpret thyroid function
tests, which could possibly be misinterpreted as thyrotoxicosis41
unless free T3 and T4 are measured.42
HYPOTHYROIDISM
Apo B
++
Apo A-I
++
Lp(a)
++
AAT
--
• α1-Antitrypsin (AAT) is decreased in hypothyroidism; thus, there is
decreased inhibition of serum elastase activity.48
HYPERTHYROIDISM
AAT
+
FER
+
PAL
-
Apo B
-
Apo A-I
-
Lp(a)
-
B2M
+
IgA
-
IgM
-
IgG
-
IgE
N/+
• AAT48 and ferritin49 are increased and Lp(a), apo AI, apo B, and
prealbumin are decreased in hyperthyroidism.43-45,50
• In thyrotoxicosis, increased immunoglobulin catabolism can lead to
decreased serum levels of IgG, IgM, and IgA.51
• β2-Microglobulin (B2M) is elevated in untreated Graves’ disease and
in hyperthyroidism due to high cell turnover (eg, in diffuse toxic goiter or toxic adenoma).52
• Levels of the above proteins are normalized by therapy.45,46,53
• Patients with Graves’ disease may have elevated ANA titers20 and
elevated IgE.54
LABORATORY STUDIES IN THYROID DISEASE*
Cardiac risk factor evaluation
Apo A-I
Apo B
Lp(a)
* In addition to standard thyroid function tests
41
Section I.B.
• Hypothyroidism is a well-known cause of secondary hyperlipidemia.43
Lp(a), apo B, and apo AI are increased in overt and subclinical
hypothyroidism with levels being normalized by TH treatment.44-47
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GASTROINTESTINAL DISEASE
Protein-losing gastroenteropathy
Gastrointestinal malignancy
Inflammatory bowel disease
In gastrointestinal (GI) disease one or more processes, including
inflammation, protein loss through the intestine, malabsorption, and
nutritional factors, may modulate serum protein levels.
PROTEIN-LOSING GASTROENTEROPATHY
Cp
-
Tf
-
Alb
-
IgG
-
IgA
-
IgM
-
Hp
+/-
A2M
+/-
Numerous GI diseases are characterized by protein loss across the gut
epithelium. Patients present with hypoproteinemia and dependent
edema secondary to the drop in plasma oncotic pressure. While some
GI protein loss is normal in healthy individuals, the greater losses associated with increased mucosal permeability, mucosal erosions/ulcerations, or lymphatic abnormalities can be a major clinical concern (see
the following list). Dilated lymphatics in the GI tract result from
abnormal vessels (eg, congenital lymphangiectasis) or blockage causing
increased intestinal lymph flow and stasis.1 Protein-losing gastroenteropathy may also occur after surgical repair of a functional single
ventricle (Fontan procedure)2 or after thoracic duct damage.
• Mucosal permeability: SLE*, Whipple’s disease, celiac disease,
acute viral gastroenteritis, AIDS-associated gastroenteropathy, intestinal bacterial overgrowth or parasitosis, giant hypertrophic gastritis,
eosinophilic gastroenteritis, H. pylori infection, Henoch-Schοnlein
purpura.
45
Section I.B.
54. Molnar I, Horvath S, Balazs C. Detectable serum IgE levels in Graves’ ophthalmopathy. Eur J Med Res. 1996;1:543-546.
• Mucosal erosions/ulcerations: α-Chain disease, amyloidosis, benign
gastric ulcer, Crohn’s disease, erosive gastritis, carcinoid syndrome,
ulcerative colitis, neurofibromatosis.
Section I.B.
• Abnormal lymphatic hemodynamics: Congenital or secondary
lymphangiectasia, cardiac disease such as constrictive pericarditis,
tricuspid insufficiency, congestive heart failure, Crohn’s disease,
intestinal lymphangiectasis secondary to lymphoma or filariasis,
Whipple’s disease, sclerosing mesenteritis, lymphenteric fistula,
intestinal endometriosis.3
Intestinal protein leakage is independent of protein size in most cases.
The change in serum protein levels is more closely related to the
nature of the pathology. In diseases where mucosal integrity is damaged, transudate fluid is lost; in lymphangiectasis, lymph and thus a large
amount of immunoglobulin is lost.
PROTEIN CHANGES IN INCREASED INTESTINAL MUCOSAL PERMEABILITY
• Ceruloplasmin, transferrin, and albumin, together with IgG, IgA,
and IgM, show a marked decrease in PLG.3
• Haptoglobin levels decrease except in the presence of an APR, when
levels may actually increase despite GI loss.4
• α2-Macroglobulin (A2M) levels decrease except in the presence of
concurrent renal disease with preferential retention of large molecules,
in which case increased A2M may be seen (all other proteins low).4
* Protein-losing gastroenteropathy may be the presenting symptom in childhood
SLE; thus, children with PLG should be evaluated for SLE. Conversely, proteinlosing gastroenteropathy should be considered in SLE with unexplained edema
or hypoalbuminemia.5
LABORATORY TESTING IN PROTEIN-LOSING GASTROENTEROPATHY
SPE
Alb
A2M
Total protein
The most frequent diagnostic test for PLG is fecal α1-antitrypsin level
(α1-antitrypsin is not degraded by intestinal proteinases). There is a
lesser role for serum protein analysis.
GASTROINTESTINAL MALIGNANCY
CRP
++
46
AAG
++
AAT
+
ACT
+
C3/C4
N/-
FER
+/--
Alb
-
Tf
-
IgG,A,M
+/--
Serum protein changes in GI malignancy reflect the effects of the APR,
together with changes secondary to malnutrition and fluid loss. In
addition, certain malignancies may be accompanied by the appearance
of a monoclonal immunoglobulin, which disappears after successful
treatment of the tumor.
ACUTE PHASE RESPONSE IN GI MALIGNANCY
The acute phase proteins are useful for evaluating prognosis and monitoring progress of malignant disease.
• In gastric cancer, increased AAT after surgery and during chemotherapy may indicate disease progression,11 while isolated elevation of
ACT is significantly related to lymphatic metastasis.12
• Transferrin levels are low in GI cancer compared to controls and
other cancers.13
• Low albumin is a well-recognized complication of juvenile polyposis.14
It is also a significant determinant of survival in metastatic colorectal
cancer patients.15
IMMUNOLOGIC RESPONSE IN GI MALIGNANCY
• In colorectal and gastric cancer, elevated IgG and IgM may correlate
with longer survival and time to disease progression.16,17
• Monoclonal gammopathy in serum or urine is typical for intestinal
lymphoma; serum levels of normal, polyclonal immunoglobulins
may be decreased.18
• Serum immunoglobulins may be decreased in immunoproliferative
small intestinal disease. Rare in the USA, this unusual disease may
progress to malignancy and is characterized by the presence of α
heavy chain protein (Fc portion of the α1 subclass of IgA).19
• Elevated β2-microglobulin is a useful prognostic marker in early stage
primary gastric lymphoma.20 Its measurement should be included in
the staging of patients with primary extranodal gastric non-Hodgkin’s
lymphoma, because high levels indicate shorter survival.21
47
Section I.B.
• CRP and α1-acid glycoprotein are elevated in malignancies that
provoke a strong APR, and are often useful in preoperative staging.6,7
A normal CRP result is 93% specific to exclude stage D tumors of
the colon7 and is associated with better prognosis/survival rates.8
The acute phase proteins, particularly CRP, are also important predictors of the early stages of tumor recurrence in patients with
apparently curative surgery for colorectal cancer.9 This effect may be
confounded in patients using ibuprofen, which reduces CRP levels in
colorectal cancer.10
PROTEIN CHANGES DUE TO COMPLICATIONS OF GI MALIGNANCY
• Blood loss associated with GI neoplasms can cause decreased serum
ferritin levels, as well as low serum iron and increased transferrin
levels (this may be offset by the APR, which causes increased ferritin
and decreased transferrin). Low serum ferritin has been reported to
be associated with increased prospective risk for both colorectal22
and stomach cancer.23 Also, levels are lower in advanced than in early
colorectal cancer.24
LABORATORY TESTING IN GI MALIGNANCY*
Section I.B.
Staging
Prognosis
Progression/Recurrence
CRP FER
CRP Alb
CRP
AAG SPE
ACT β2M
AAT
*See text for disease associations of the listed measurements.
CHRONIC INFLAMMATORY BOWEL DISEASE
UC
Crohn’s
CRP
+/++
+/++
SAA
+++
+++
AAG
+
+
FN
+
+
FIB
+
++
IgE
+
N/+
IgM
+
Alb
N/-
RBP
-
AT III
-
Chronic inflammatory bowel disease (CIBD) comprises 2 major
disorders, Crohn’s disease and ulcerative colitis (UC). In UC, there are
recurrent episodes of mucosal inflammation in the colon and rectum,
while in Crohn’s disease the inflammation is transmural and may
extend along the entire GI tract. Presenting features of both diseases
include growth retardation (children), abdominal pain, diarrhea, malnutrition and weight loss, rectal bleeding (more common in UC), and
variable anemia; men and women are affected equally (typical age at
presentation, 15 to 40 years). In Crohn’s disease, the transmural
inflammation can also lead to fibrosis, obstruction, perforation, and
fistulae. With regard to changes in serum proteins, the APR, proteinlosing gastroenteropathy, and malabsorption are prominent features.
ACUTE PHASE RESPONSE IN CIBD
• CRP and SAA are useful for clinical monitoring of activity in Crohn’s
disease and UC, although these tests cannot be used to distinguish
the 2 conditions.25 CRP levels are elevated in active CIBD compared
with inactive disease26 and fall with 5-aminosalicylic acid and steroid
therapy in Crohn’s disease.27
• Children and adults with CIBD have abnormal coagulation factors and
fibrinogen. AT III levels are low,28 while fibrinogen is increased in 45%
of CIBD, and levels are typically higher in Crohn’s disease than in UC
(as part of the intense APR).29 Among patients with Crohn’s disease,
fibrinogen levels are higher in active than in “inactive” disease,
48
although levels are still above normal in “inactive” disease, indicating
that subclinical inflammation is present.30 Levels are also high at 3
to 12 months postsurgery for Crohn’s disease, suggesting that the
elevated level is due to a systemic inflammatory condition rather
than local bowel disease alone.31 The changes may be involved in the
development of thromboembolism and the pathogenesis of mucosal
inflammation.30
• Higher levels of α1-acid glycoprotein after steroid/prednisone
therapy in IBD and in quiescent Crohn’s disease are associated with
increased risk for relapse.32 Total parenteral nutrition (TPN) may
cause an isolated elevation of α1-acid glycoprotein; thus its
measurement has limited value for monitoring disease activity in
Crohn’s patients on TPN.33
• Retinol-binding protein (RBP) levels are low in CIBD; this is
associated with decreased retinol/vitamin A levels.35
LABORATORY TESTING IN CIBD
Monitoring
Relapse
Risk Factor Evaluation
CRP
Alb
SAA
AAG*
FIB
AT III
*Among patients not on total parenteral nutrition.
REFERENCES
1. Ritzmann SE, Daniels JC, eds. Serum Protein Abnormalities: Diagnostic and Clinical
Aspects. Little, Brown and Co., Boston, 1975. P.197-203.
2. Kelly AM, Feldt RH, Driscoll DJ, Danielson GK. Use of heparin in the treatment
of protein-losing enteropathy after fontan operation for complex congenital
heart disease. Mayo Clin Proc. 1998;73:777-779.
3. Brasitus TA, Bissonnette BM. Protein-losing gastroenteropathy. In: Feldman M,
Scharschmidt BF, Sleisenger MH, eds. Sleisenger and Fordtran’s Gastrointestinal and
Liver Disease. 6th ed. Philadelphia, PA:WB Saunders Company; 1998;1:369-370.
4. McPherson RA. Specific Proteins. In: Henry, JB, ed. Clinical Diagnosis and
Management by Laboratory Methods. 19th ed. Philadelphia, PA:WB Saunders
Company, 1996:250.
5. Molina JF, Brown RF, Gedalia A, Espinoza LR. Protein losing enteropathy as the
initial manifestation of childhood systemic lupus erythematosus. J Rheumatol.
1996;23:1269-1271.
6. Yuceyar S, Erturk S, Dirican A, Cengiz A, Saner H.The role of acute phase
reactant proteins, carcinoembryonic antigen and CA 19-9 as a marker in the
preoperative staging of colorectal cancer: a prospective clinical study. Int Surg.
1996;81:136-139.
49
Section I.B.
• Low albumin may be due both to the APR and to malabsorption/
protein losing gastroenteropathy. It is also a good marker of endoscopically visual activity in Crohn’s colitis and UC.34
7. Stamatiadis AP, Manouras AJ,Triantos GN, Kateregiannakis VA, Apostolidis NS.
Combination of serum carcino-embryonic antigen and C-reactive protein - a
useful test in preoperative staging of colorectal cancer. Eur J Surg Oncol.
1992;18:41-43.
8. Nozoe T, Matsumata T, Kitamura M, Sugimachi K. Significance of preoperative
elevation of serum C-reactive protein as an indicator for prognosis in
colorectal cancer. Am J Surg. 1998;176:335-338.
9. McMillan DC,Wotherspoon HA, Fearon KC, Sturgeon C, Cooke TG, McArdle
CS. A prospective study of tumor recurrence and the acute phase response
after apparently curative colorectal cancer surgery. Am J Surg. 1995;170:
319-322.
Section I.B.
10. McMillan DC, Leen E, Smith J, et al. Effect of extended ibuprofen administration
on the acute phase protein response in colorectal cancer patients. Eur J Surg
Oncol. 1995;21:531-534.
11. Bernacka K, Kuryliszyn-Moskal A, Klimiuk PA. Serum α1-antitrypsin and
α1-antichymotrypsin after surgical treatment and during postoperative clinical
course of human gastric cancer. Neoplasma. 1993;40:111-116.
12. Ogoshi T,Tajima T, Mitomi T,Tsuda M,Yamamura M.Acute-phase plasma proteins
in gastric cancer: association with metastatic potential and prognosis. Tumour
Biol. 1996;17:281-289.
13.Agroyannis B, Dalamangas A, Dardouphas K, et al. Serum transferrin and ceruloplasmin in patients with cancer of the gastrointestinal and other systems.
Anticancer Research. 1994;14:2201-2203.
14. Nicholls S, Smith V, Davies R, Doig C,Thomas A, Miller V. Diffuse juvenile nonadenomatous polyposis: a rare cause of severe hypoalbuminemia in childhood.
Acta Paediatrica. 1995;84:1447-1448.
15. Steinberg J, Erlichman C, Gadalla T, Fine S,Wong A. Prognostic factors in
patients with metastatic colorectal cancer receiving 5-fluorouracil and folinic
acid. Eur J Cancer. 1992;28A:1817-1820.
16.Tsavaris N,Tsigalacis D, Kosmas C, et al. Preliminary evaluation of the potential prognostic value of serum levels of immunoglobulins (IgA, IgM, IgG, IgE) in
patients with gastric cancer. Int J Biol Markers. 1998;13:87-91.
17.Tsavaris N,Tsigalakis D, Bobota A, et al. Prognostic value of serum levels of
immunoglobulins (IgA, IgM, IgG, IgE) in patients with colorectal cancer. Eur J
Surg Oncol. 1992;18:31-36.
18. Jones DV Jr, Levin B, Salem P. Intestinal lymphoma, including immunoproliferative small intestinal disease. In: Feldman M, Scharschmidt BF, Sleisenger MH,
eds. Sleisenger and Fordtran’s Gastrointestinal and Liver disease. 6th ed.
Philadelphia, PA:WB Saunders Company; 1998;2:1849.
19. Jones DV Jr, Levin B, Salem P. Intestinal lymphoma, including immunoproliferative small intestinal disease. In: Feldman M, Scharschmidt BF, Sleisenger MH,
eds. Sleisenger and Fordtran’s Gastrointestinal and Liver disease. 6th ed.
Philadelphia, PA:WB Saunders Company;1998.Vol. 2. p.1853.
20.Aviles A, Narvaez BR. β2-microglobulin and lactate dehydrogenase levels are
useful prognostic markers in early stage primary gastric lymphoma. Clin Lab
Haematol. 1998;20:297-302.
50
21.Aviles A, Diaz-Maqueo JC, Rodriguez L, Garcia EL, Guzman R,Talavera A.
Prognostic value of serum β2-microglobulin in primary gastric lymphoma.
Hematol Oncol. 1991;9:115-121.
22. Kato I, Dnistrian AM, Schwartz M, et al. Iron intake, body iron stores and
colorectal cancer risk in women: a nested case control study. Int J Cancer.
1999;80:693-698.
23.Akiba S, Neriishi K, Blot WJ, et al. Serum ferritin and stomach cancer risk
among a Japanese population. Cancer. 1991;67:1707-1712.
24. Kishida T, Sato J, Fujimori S, et al. Clinical significance of serum iron and ferritin
in patients with colorectal cancer. J Gastroenterol. 1994;29:19-23.
25. Niederau C, Backmerhoff F, Schumacher B, Niederau C. Inflammatory mediators and acute phase proteins in patients with Crohn’s disease and ulcerative
colitis. Hepatogastroenterology. 1997;44:90-107.
27. Ricci G, D’Ambrosi A, Resca D, Masotti M, Alvisi V. Comparison of total sialic
acid, C-reactive protein, α1-acid glycoprotein, and β2-microglobulin in patients
with non-malignant bowel diseases. Biomed Pharmacother. 1995;49:259-262.
28. Heneghan MA, Cleary B, Murray M, O’Gorman TA, McCarthy CF. Activated
protein C resistance, thrombophilia, and inflammatory bowel disease. Dig Dis
Sci. 1998;43:1356-1361.
29.Weber P, Husemann S,Vielhaber H, Zimmer KP, Nowak-Gottl U. Coagulation
and fibrinolysis in children, adolescents, and young adults with inflammatory
bowel disease. J Pediatric Gastroenterol Nutr. 1999;28:418-422.
30. Novacek G,Vogelsang H, Genser D, et al. Changes in blood rheology caused
by Crohn’s disease. Eur J Gastroenterol Hepatol. 1996;8:1089-1093.
31. Chiarantini E,Valanzano R, Liotta AA, et al. Persistence of hemostatic
alterations in patients affected by Crohn’s diseases after bowel surgery.
Thromb Res. 1997;87:539-546.
32. Kjeldsen J, Lauritsen K, De Muckadell OB. Serum concentrations of
orosomucoid: improved decision-making for tapering prednisolone therapy
in patients with active inflammatory bowel disease? Scand J Gastroenterol.
1997;32:933-941.
33. Carlson GL, Gray P, Barber D, Shaffer JL, Mughal M, Irving MH.Total parenteral
nutrition modifies the acute phase response to Crohn’s disease. J Royal Coll
Surg Edinb. 1994;39:360-364.
34. Moran A, Jones A, Asquith P. Laboratory markers of colonoscopic activity in
ulcerative colitis and Crohn’s colitis. Scand J Gastroenterol. 1995;30:356-360.
35. Janczewska I, Bartnik W, Butruk E,Tomecki R, Kazik E, Ostrowski J. Metabolism
of vitamin A in inflammatory bowel disease. Hepatogastroenterol. 1991;38:
391-395.
51
Section I.B.
26. Cellier C, Sahmoud T, Froguel E, et al. Correlations between clinical activity,
endoscopic severity, and biological parameters in colonic or ileocolonic Crohn’s
disease. A prospective, multicenter study of 121 cases.The Groupe d’Etudes
Therapeutiques des Affections Inflammatoires Digestives. Gut. 1994;35:231-235.
HEMATOLOGIC DISEASE
Monoclonal gammopathy
Anemia
Section I.B.
MONOCLONAL GAMMOPATHY
Monoclonal gammopathy is a disorder of immunoglobulin synthesis,
due to proliferation of a single B-cell. The monoclonal immunoglobulin
(M-component) is detected by SPE and its corresponding heavy and light
chain classes are characterized by immunofixation. Serum protein analysis
usually demonstrates elevated levels of the involved immunoglobulin class,
with decreased levels of normal immunoglobulins.1 M-components may be
IgG,A, M, D, or E (decreasing order of frequency), as well as immunoglobulin light-chain (LC; Bence-Jones protein) or heavy-chain.2 Two percent to
3% of patients with M-components have biclonal gammopathies.3,4 In 75%
of all subjects with an M-component and 98% of patients with multiple
myeloma, the protein is also detectable in urine. Some M-components
only appear as urine light-chain, without a serum abnormality.5,6
CLINICAL ASSOCIATIONS OF MONOCLONAL GAMMOPATHY
M-components may be benign, as in monoclonal gammopathy of
unknown significance (MGUS, ~67% of M-components), or due to Bcell malignancy as in multiple myeloma (14%) and Waldenström’s
macroglobulinemia (2%) (below). They may also occur in lymphoproliferative diseases such as chronic lymphocytic leukemia (2%) and nonHodgkin’s lymphoma (5%). Monogammopathy may also be seen in
other cancers (1 to 2%) and in primary amyloidosis (9%).1,6 Although
monogammopathy does not typically resolve spontaneously, transient
M-components have been recorded in infections, in passive neonatal
transfer from mother, during bone marrow reconstitution or blood
transfusion, in cancer, and in drug hypersensitivity.2,7 They disappear
with resolution of the primary condition.
M-COMPONENT PROPERTIES WITH CLINICAL IMPLICATIONS
A given M-component may have none, one, or more of the following
properties:1
• Cold precipitation (5% to 10% of multiple myeloma patients have
cryoglobulins);
• Cold agglutination of erythrocytes;
• Formation of amyloid fibrils, usually monoclonal light chains.
(See Amyloidosis);
• High viscosity (most common for IgM); and
• Ability to complex with other proteins and interfere with their function.
For example, hemorrhagic problems may occur if M-components interact with clotting factors V,VII, or VIII and with prothrombin or fibrinogen.
52
Monoclonal gammopathy of unknown significance (MGUS)
IgG
-/++
IgA
-/++
IgM
-/++
IgD
-/++
IgE
N/++
LC
N
CRP
N
B2M
N
Up to 67% of patients presenting with an M-component have MGUS, as
defined by:8
• Serum M-component level <30 g/L;
• Urine M-component excretion <1 g/day;
• Bone marrow plasma cell content <5%;
• Normal immunoglobulin levels;
• Stability of clinical and laboratory findings over time.
The frequency of MGUS increases with age (~3% over 70 years9),
although the disease may be seen in patients 20 years old or, very rarely,
younger patients.10 MGUS is seen in chronic infection (tuberculosis,
hepatitis C), autoimmune disease, immune deficiency, hematologic
malignancies, other malignancies, neurologic disorders, dermatologic
disorders (eg, pyoderma gangrenosum), and as a complication of
chemotherapy for other malignancies.1,3,6,11 Incidence is high in HIV
positive patients and is seen in 13% of AIDS patients and 89% of AIDS
patients with Kaposi’s sarcoma.12
At present, there is no laboratory test to distinguish between benign
MGUS and incipient malignant disease8 (~2% convert to malignancy per
year). The risk for transformation increases with higher M component
levels, development of detectable light chain proteinuria, and increased
bone marrow plasma cell content.13,14
LABORATORY TESTING IN MGUS
Detection and monitoring*
EP**
IgG, IgA, IgM
Immunofixation**
CRYO
* Repeat at 6 months and then annually.3
** Serum and urine
Note: Many M-components may also be detected by measuring the mass ratio of
kappa:lambda light chains. In extreme cases, deviation from the normal 2:1
ratio may suggest the presence of an M-component.
53
Section I.B.
• Absence of skeletal lesions or other clinical signs of multiple myeloma
(anemia, hypercalcemia, renal insufficiency); and
MULTIPLE MYELOMA
IgG
---/+++
IgA
---/+++
IgM
---/+++
IgD
N/+++
IgE
N/+++
LC
+/++
B2M
+/++
CRP
+/++
C3/C4
-
Section I.B.
Multiple myeloma is most common in older patients (often males), who
may present with anemia, weakness, weight loss, fatigue, back pain, bone
pain, osteoporosis, recurrent infections, renal insufficiency, immunoglobulin deficiency, and sensorimotor peripheral neuropathy. Diagnostic
criteria are the converse of those for MGUS (above).3,6,8
ACUTE PHASE RESPONSE IN MULTIPLE MYELOMA
• Low albumin and elevated positive acute phase proteins, especially
CRP, are typical in multiple myeloma.6
• Fibronectin levels are increased in multiple myeloma; levels do not
correlate with the concentration of paraprotein.15
IMMUNE RESPONSE IN MULTIPLE MYELOMA
• M-components can cause immune deficiency by suppressing levels
of the normal polyclonal immunoglobulins, due to marrow infiltration
by monoclonal plasma cells. Immunoglobulin levels (with the
exception of the M-component class) may be low (<20% of normal
in ~15% of patients with multiple myeloma).6
• Unlike levels of the other normal polyclonal immunoglobulins, IgE
levels are usually normal.16
• C3/C4 are low, but levels are not related to disease severity or
clinical manifestations.17
PROTEINS ASSOCIATED WITH PROGNOSIS IN MULTIPLE MYELOMA
• M-component concentration >30 g/L, IgA type, and Bence Jones
protein excretion >50 mg/d are predictive of poor outcome/rapid
progression.18 Bence Jones proteinuria may cause “myeloma kidney,”
where tubular cells are packed with hyaline deposits, causing renal
failure.19
• An APR (including elevated CRP) in the absence of overt inflammation suggests cytokine synthesis by tumor cells and a resultant poor
prognosis.20,21 Thus, CRP may be useful to stage and monitor multiple
myeloma.22
• B2M levels depend on tumor mass and renal function and can be
used for staging of multiple myeloma.6,22 Elevated B2M does not
differentiate multiple myeloma and MGUS and is not diagnostic, since
the same pattern is seen in other lymphoproliferative disorders,
but it is very useful to assess prognosis and response to therapy in
multiple myeloma.23-25
54
• Low and decreasing albumin26,27 and apo B levels are associated with
worsening prognosis.28
IMMUNOGLOBULIN CLASS IMPLICATIONS IN MULTIPLE MYELOMA
• IgG myeloma6 (60% of cases) causes greater reduction in normal
immunoglobulin levels, more frequent infections, higher M-component
level, slower tumor growth, and less hypercalcemia and amyloidosis
than other classes. IgG myelomas may cause hyperviscosity at high
concentrations (>50 g/L) and many cryoglobulins are IgG M-components.
• IgA myeloma6 (25% of cases) is associated with hypercalcemia;
hyperviscosity is common as the IgA clones tend to polymerize.
There are fewer infections, but amyloidosis is not uncommon.
• IgD myeloma6 (2% of cases) results in a shorter survival than many
myelomas. The M-component is often low in concentration and hard
to detect. Bence Jones protein is common. There may be severe
Bence Jones proteinuria, renal failure, hypercalcemia and anemia.
• IgE myeloma29 prevalence is 0.01% of all plasmacytomas, but it has a
very malignant course, with a high frequency of Bence Jones proteinuria and plasma cell leukemia.
• Bence-Jones proteinemia (light chain excretion) is seen in up to
80% of patients with multiple myeloma.5 Light chains are a common
cause of renal disease,19,30 but not all are nephrotoxic.31 In light
chain disease (17% of multiple myelomas), these are the only M-components produced.32 There is a malignant clinical course and shorter
survival (similar to IgD multiple myeloma), with increased frequency
of renal failure, lytic bone disease, hypercalcemia and amyloidosis.33 In
multiple myeloma, except for IgD myeloma, ~60% of M-components
are associated with kappa light chain.34
LABORATORY TESTING IN MULTIPLE MYELOMA**
Detection
Monitoring
EP*
IgG
EP*
IgG
Immunofixation*
IgA
IgM
CPR
IgA
Immunofixation*
IgM
B2M
* Serum and urine.34
** In addition to hematologic, chemistry, renal, and radiologic testing
(see diagnostic criteria for MGUS).
Waldenström’s Macroglobulinemia
IgM
+++
IgA
--
IgG
--
IgE
N
B2M
++
CRP
++
55
Section I.B.
• IgM myeloma6 (<1% of multiple myeloma cases). All patients with
Waldenström’s macroglobulinemia have IgM M-components.
Waldenström’s macroglobulinemia is a plasma cell malignancy producing
19S IgM that accounts for 2% of hematologic malignancies.The clinical
picture is similar to chronic lymphocytic leukemia or lymphoma, and
symptoms are typically due to the properties of the M-component
(hyperviscosity, cryoprotein, and interaction with other proteins).34,35
Patients present with fatigue, weakness, and anemia,8 together with
CNS symptoms, nephritis, bleeding, in vivo hemolysis4, and congestive
heart failure. Recurrent infections and weight loss may also occur, but
lytic bone lesions, renal disease, and amyloidosis are rare.34,36,37
• 80% of patients have detectable light chain in urine11; 75% of light
chains in Waldenström’s macroglobulinemia are kappa.37
Section I.B.
• B2M and CRP are elevated38;
• RF levels may be elevated.39
LABORATORY TESTING IN WALDENSTRÖM’S MACROGLOBULINEMIA**
Detection
Monitoring
EP* IgG
IgA
Immunofixation*
IgM
CRYO
EP*
IgG
IgA
Immunofixation* B2M
IgM
CRP
** In addition to hematologic, renal, radiologic, and chemistry testing
(see MGUS diagnostic criteria).
Primary Amyloidosis
IgG
---/+++
IgA
---/+++
IgM
---/+++
IgD
---/+++
IgE
N/+++
LC
+++
B2M
+/++
CRP
+/++
Amyloidosis is characterized by the tissue deposition of insoluble
protein fibrils, resulting in damage to and dysfunction of the affected
organ(s). Clinical symptoms are varied and include presentations such
as kidney failure and amyloidotic cardiomyopathy. In hereditary
amyloidosis, the fibrils are formed by polymerization of an abnormal
protein variant (such as prealbumin). In nonhereditary amyloidosis,
80% to 90% of patients have an M-component. The fibrils are formed
by the deposition of immunoglobulin light chain (lambda in 70% of
cases). Amyloidosis is seen in ~10% of patients with multiple myeloma
when sufficiently sensitive detection methods are used.6
56
LABORATORY TESTING IN PRIMARY AMYLOIDOSIS**
Detection
Monitoring
EP*
IgG
IgA
IgM
Immunofixation*
CRYO
EP*
IgG
IgA
Immunofixation* B2M
IgM
CRYO
** In addition to histologic studies of bone marrow and affected organs.
Heavy chain disease
IgG
-
IgA
-
HC(α, y, or υ)
++
IgM
-
• α-HC disease is most common in the Middle East, the Mediterranean,
and Africa; it is an abdominal lymphoma that may develop from
immunoproliferative small intestinal disease. Symptoms include severe
malabsorption with diarrhea, steatorrhea, and weight loss due to
plasma cell infiltration of the jejunal mucosa.40
• γ-HC disease is seen in all age groups and may be associated with
lymphoma.8 Clinical and laboratory features may be similar to chronic
lymphocytic leukemia or lymphoma, with lymphadenopathy,
splenomegaly and hepatomegaly, recurrent bacterial infections, and
anemia. Different organs are affected depending on where the
proliferation predominates.34,40
• µ-HC disease has a similar presentation to chronic lymphocytic
leukemia with progressive hepatosplenomegaly.2
LABORATORY TESTING IN HEAVY CHAIN DISEASE**
Detection and Monitoring
EP
IgG
IgA
IgM
Immunofixation*
* EP does not detect HC in 40% of patients, if it migrates in the β1/β2
region and is obscured by other protein bands, and immunofixation
is necessary if HC disease is suspected.34,40 On immunofixation, sera
react to the anti-intact Ig (usually faster mobility than normal Ig), but
not to kappa or lambda light chain.40
** In addition to hematologic and chemistry testing.
57
Section I.B.
Heavy chain (HC) disease is a lymphocyte/plasma cell dyscrasia with
clinical symptoms more like lymphoma than multiple myeloma. IgA HC
causes α-HC disease; IgG HC causes γ-HC disease; and IgM HC causes
µ-HC disease. In HC disease, levels of all normal polyclonal
immunoglobulins are suppressed.
ANEMIA
Anemia is a common clinical presentation in any practice. It may be
due to many different causes, including blood loss, nutritional deficiency,
hemolysis, hereditary conditions, chronic illness, or malignancy. The
present discussion focuses on serum protein analysis in iron deficiency
anemia and anemia of chronic disease.
IRON DEFICIENCY ANEMIA
Section I.B.
Tf
++
%TS
--
Fe
--
FER
--
Hb
--
sTfR
--
The signs and symptoms of iron deficiency anemia are pallor, weakness,
fatigue, headache, increased cold sensitivity, inability to concentrate,
restlessness, poor exercise tolerance, and decreased work performance.41
• Elevated transferrin level and an associated low value (<10% to 15%)
for percent transferrin saturation (%TS) are characteristic of
iron deficiency.42 Levels normalize with successful therapy. Transferrin
measurement gives information equivalent to the chemistry measurement of total iron binding capacity (TIBC).
• Serum ferritin estimates the amount of available stored iron, except
in the presence of inflammation43,44 (see Inflammation). Low ferritin
levels (<100 µg/L44) indicate iron deficiency,42 and increasing levels
indicate successful iron supplementation.45,46
• Soluble transferrin receptor (sTfR) levels vary according to the
degree of erythropoiesis and the amount of body iron stores.47,48 In
the absence of enhanced erythropoiesis (see below), elevated sTfR is
a quantitative measure of functional iron deficiency.49 sTfR levels are
not altered by the APR and are therefore useful to distinguish iron
deficiency anemia from the anemia of chronic disease.50 sTfR can
detect iron deficiency in pregnancy as levels are not changed by
gestational effects.51 sTfR levels normalize with successful iron
replacement therapy.52
• The sTfR/FER index (sTfR/log FER) is a useful measure of iron
deficiency,53 since both analytes contribute independently to the
prediction of marrow iron status.54
FACTORS CONFOUNDING THE DETECTION OF IRON DEFICIENCY ANEMIA:*
• Pregnancy: Increased levels of transferrin (and also low hemoglobin and some microcytosis/hypochromia without iron deficiency) are
seen in pregnancy and estrogen therapy.55 Use sTfR51 or ferritin56
to detect iron deficiency in pregnancy.
58
• Inflammation: Decreased transferrin and increased ferritin occur
in inflammation, and this may mask iron deficiency. Use sTfR to
detect iron deficiency in these cases.50,57,58
• Malnutrition: In malnutrition, transferrin levels may be low or
normal even in the presence of iron deficiency.59,60
• Liver disease: Ferritin levels are disproportionately elevated in relation to iron stores in patients with liver disease. This may confound
the diagnosis of iron overload disorders, as well as anemia.50
• Vigorous exercise: Low hemoglobin, haptoglobin, iron, and
ferritin may be seen in athletes due to mechanical hemolysis, intestinal bleeding, hematuria, sweating, and poor intestinal absorption.63
These findings do not necessarily reflect iron deficiency.
• Erythropoiesis: Enhanced erythropoiesis can increase sTfR levels
independently of the effects of iron deficiency. Thus, conditions
associated with increased, but ineffective, erythropoiesis64-67
(eg, thalassemia, megaloblastic anemia) can confound the use of
sTfR measurement for the detection of iron deficiency. If iron
deficiency is excluded, sTfR provides a quantitative measure of
total erythropoiesis.49,68
* See also Preanalytical Concerns in the Introduction.
ANEMIA OF CHRONIC DISEASE
Tf
--
%TS
--
Fe
--
FER
N/++
sTfR
N/+
CPR
+/++
Anemia of chronic disease is seen in patients with infections, inflammation, or neoplastic diseases persisting longer than 1 to 2 months41,69,70
and is characterized by low serum iron in the face of adequate iron
stores.42 It is caused by a defect in iron recycling. Iron is diverted from
sites of erythropoiesis to storage in the reticulo-endothelial system,
and tissue iron release to transferrin is blocked.41,71,72 The only treatment is correcting the underlying disorder.41
• Increased ferritin levels reflect body iron stores and the effect of the
APR. Changes parallel the increase in CRP levels in inflammation.73
This reduces the sensitivity of ferritin to detect iron deficiency.
59
Section I.B.
• Renal Failure: Anemia in chronic renal failure is due to decreased
erythropoietin production and iron deficiency; iron deficiency may be
exacerbated by r-huEPO therapy. The percentage of TS is not a reliable measure of iron deficiency in stable chronic failure; ferritin may
be better.61 During maintenance r-huEPO therapy, sTfR loses its
specificity for detecting tissue iron deficiency, due to the effect of
increased erythropoiesis (see Erythropoiesis).62
In anemia of chronic disease, serum ferritin <100 µg/L is 65% sensitive
to detect iron deficiency,44 compared with 92% sensitivity for ferritin
<30 µg/L in iron deficiency alone.74
• sTfR measurement can both distinguish between iron deficiency
anemia and the anemia of chronic disease and detect iron deficiency
concurrent with anemia of chronic disease. sTfR is slightly, but not
significantly, elevated in anemia of chronic disease without iron deficiency. If the patient has anemia of chronic disease plus iron deficiency
anemia, then sTfR is elevated.50,75,76
Section I.B.
• A panel of CRP (more sensitive and specific inflammation marker
than ESR77,78), ferritin, and sTfR is useful to distinguish anemia of
chronic disease from iron deficiency anemia.79
LABORATORY TESTING IN ANEMIA*
Etiology
CRP
FER
Tf
Iron
sTfR
%TS
Etiology
Iron deficiency anemia
Monitoring
Anemia of chronic disease
FER
%TS
CRP
FER
sTrR
CRP
sTfR
* In addition to standard hematologic studies.
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30. Picken MM, Shen S. Immunoglobulin light chains and the kidney: an overview.
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31. Sanders PW, Herrera GA, Chen A, Booker BB, Galla JH. Differential nephrotoxicity of low molecular weight proteins including Bence Jones proteins in
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32. Ameis A, Ko HS, Pruzanski W. M components-a review of 1242 cases.
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33. Bladé J, Lust JA, Kyle RA. Immunoglobulin D multiple myeloma: presenting features, response to therapy, and survival in a series of 53 cases. J Clin Oncol.
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34. Keren DF. Clinical indications for electrophoresis and immunofixation. In: Rose
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44. Kis AM, Carnes M. Detecting iron deficiency in anemic patients with concomitant medical problems. J Gen Intern Med. 1998;13:455-461.
45. Hallak M, Sharon AS, Diukman R, Auslender R, Abramovici H. Supplementing
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46.Vychytil A, Haag-Weber M. Iron status and iron supplementation in peritoneal
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47. Baynes RD. Refining the assessment of body iron status. Am J Clin Nutr.
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58.Ahluwalia N. Diagnostic utility of serum transferrin receptors measurement in
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64
LIVER DISEASE
Inherited liver diseases
Viral hepatitis
Chronic liver disease
The term “liver disease” encompasses a wide range of conditions, both
primary and secondary, with effects that reflect the many functions of
the liver. Presenting symptoms are diverse and will not be a focus of
this discussion.
INHERITED LIVER DISEASES
AAT
--
Cp
--
FER
+++
AAT deficiency should be considered in any adult or child with unexplained liver disease or emphysema.3 Serum AAT measurement alone
is insufficient to diagnose AAT deficiency (particularly in pediatric liver
disease), because the presence of an APR may confound the measurement3 and also low levels may be secondary to loss or consumption, as
in infant respiratory distress syndrome. Thus, AAT phenotyping is
also necessary.
WILSON’S DISEASE (HEPATOLENTICULAR DEGENERATION)
Wilson’s Disease (WD) is a rare (1:30,000) autosomal recessive disorder of copper overload, due to a defective intracellular transmembrane
copper transport protein.4-6 Decreased incorporation of copper into
ceruloplasmin results in decreased ceruloplasmin synthesis and low
serum ceruloplasmin levels.7
WD may present as chronic or fulminant liver disease, progressive
neurologic disorder, isolated acute hemolysis, or psychiatric illness.
In children, hepatic presentation is most common and WD should
be considered in those with unexplained liver disease.7 Also,WD
may be clinically indistinguishable from autoimmune hepatitis,
65
Section I.B.
α1-ANTITRYPSIN (AAT) DEFICIENCY
AAT deficiency is the most common genetic cause of liver disease
(homozygous frequency 1:1750 in Caucasians; rare in Blacks and absent
in Asians. Inheritance is autosomal recessive with codominant expression). Pi*ZZ is the most common deficient phenotype and is associated
with AAT levels 10 to 15% of normal (Pi*Z heterozygotes have levels
50% to 70% of expected).1 AAT deficiency has a variable clinical presentation. Most patients with primary deficiency suffer from early-onset
emphysema, regardless of phenotype 1 but only subjects with certain
phenotypes (most frequently Pi*ZZ) develop liver disease. Patients
with Pi*ZZ or Pi*Z have an increased risk of hepatic carcinoma.2
with fatigue, malaise, rashes, arthropathy, elevated IgG, antinuclear
antibodies (ANA), and anti-smooth muscle antibodies and should
be considered in these cases.7
A low serum level of ceruloplasmin is considered diagnostic* for WD
(95%).8 This test is not useful for screening an unselected presymptomatic population,9 since ceruloplasmin levels can also be low in acute viral
hepatitis, malabsorption, nephrosis, and alcohol-induced liver disease7 and
may even be normal or high in WD when there is a concurrent APR.
Ceruloplasmin is lowest in WD patients with Kayser-Fleischer rings or
with neurologic problems.10
Section I.B.
* Other diagnostic criteria: elevated 24-hour urine copper excretion; ocular findings.
HEREDITARY HEMOCHROMATOSIS (HH)
HH is a common autosomal recessive disorder (prevalence 1:200-1:400
among persons of Northern European ancestry) in which excess
amounts of iron are absorbed from the gut, causing iron deposition in
the liver, heart, pancreas, pituitary gland, skin and joints.11-13 Consider
HH in subjects ages 40 to 60 years, presenting with skin pigmentation,
unexplained chronic arthritis, jaundice, mildly elevated liver enzymes,
cirrhosis, or unexplained liver failure. If undetected, individuals are at
risk for cirrhosis and primary hepatoma, as well as diabetes, arthritis,
and myocardial disease. Disease expression is exacerbated by male
gender, alcohol abuse, and hepatitis.14
• Transferrin and iron measurements are used to calculate transferrin saturation, which is the primary biochemical screening test
for hemochromatosis.12,15,16
• Elevated ferritin is used to assess the degree of iron overload.12,15,16
• Ceruloplasmin testing may be useful to rule out primary deficiency,
which causes a clinical syndrome similar to HH.17
Because an APR causes decreased transferrin, iron, and percent transferrin saturation and increased ferritin, it is important to measure CRP
as part of an iron status profile to identify potentially false positive
ferritin results. False negative results for percent transferrin saturation
due to the APR may occur in early iron overload disease, before significant iron has accumulated. Data may also be confounded if iron is
increased by sample hemolysis, diurnal variation, nonfasting, or dietary
supplements (see Preanalytical Variables in the Introduction). Genetic
testing may be considered in some circumstances if hemochromatosis
is suspected on the basis of family history and/or the results of biochemical testing.16,18,19
66
VIRAL HEPATITIS
CRP Alb
+/++ -
Hp
N/-
AT III
-
FER
+
ACT
-
C3/C4
N/-
IgG
+
IgA
N/-
IgM
+
RF
B2M
N/++ ++
Seventy-five percent of acute hepatitis cases are due to viral insult; of
these, 90% present with malaise, anorexia, arthritis, nausea, hepatic tenderness, jaundice, and/or hepatomegaly. All viral hepatitides, except for
hepatitis A (HAV) and Epstein-Barr Virus-associated hepatitis, can cause
chronic liver disease*, cirrhosis, and possibly hepatocellular carcinoma.20
* See Chronic Liver Disease.
• While a normal APR may be seen in early infection, later disharmonic
changes in many acute phase proteins are due to the inhibitory
effects of viral insult on hepatic protein synthesis. Thus, albumin,
haptoglobin,22 antithrombin III (AT III),23 α1-antichymotrypsin24
and C1-esterase inhibitor25 levels decrease. AT III levels decline in
direct proportion to the degree of hepatic necrosis;26 low C1esterase inhibitor may cause acquired angioedema in HCV;25 and low
α-ACT is an independent predictor of progression to cirrhosis in
HCV.24 Low haptoglobin may be due to the effects of hemolysis.
IMMUNOLOGIC RESPONSE IN VIRAL HEPATITIS
• Type II cryoglobulinemia is the most common immunologic
disorder in chronic HCV infection.27,28
• C4 levels are low in HCV with cryoglobulins and can be used to
predict the presence of these unstable proteins.27
• Rheumatoid factor (RF) is often increased in early pre-jaundice
viral hepatitis.29 Levels return to normal late in resolution phase.
• β2-Microglobulin (B2M) is elevated in HCV due to cell necrosis
and levels correlate with the duration and extent of disease.30
• Viral hepatitis has variable effects on the immunoglobulins. IgA is
often low in HCV,31 while IgG and IgM are increased in acute viral
hepatitis32 and IgM is increased in acute EBV. The changes occur
early, before the onset of icterus, and resolve in 2 to 3 months.33
Persistence of elevated immunoglobulins may indicate subacute or
chronic hepatitis.
• Antibodies against the specific viral antigen are increased.
• ANA may be present.34,35
67
Section I.B.
ACUTE PHASE RESPONSE IN VIRAL HEPATITIS
• CRP and ferritin14,21 levels are typically high; CRP correlates with
disease progression in chronic HBV, but not in chronic HCV.2
ENZYME STUDIES IN VIRAL HEPATITIS
Aspartate aminotransferase is increased 100 times, and alkaline
phosphatase is increased 3 times.32
LABORATORY TESTING IN VIRAL HEPATITIS
Diagnosis/etiology
Monitoring
Aspartate aminotransferase
Alkaline phosphatase
Specific anti-viral antibodies
Albumin
SPE
CRP (in HBV)
B2M (in HCV)
(chronic disease)
AT III
Fibrinogen
Apo B
CHRONIC LIVER DISEASE
Section I.B.
Alb
-FIB
N/--
PAL
-PMG
-/--
Tf
-AT III
-/--
RBP
Lp(a)
-
CRP
N/++
Apo A-I
--
AAT
+++/Apo B
+/-
AAG
-/--IgG
++
Cp
+/IgA
+/+++
Hp
++
IgM
++
FN
+/-C3
+/--
FER
-C4
--
A2M
N/+
RF
N/++
In the primary evaluation of chronic liver disease, protein measurements are typically secondary to measuring enzyme and autoantibody
levels, viral serology, and radiologic studies.36 Proteins are, however,
useful in clinical evaluation and disease monitoring and if taken in
proper perspective can provide specific diagnostic information.
Regardless of cause, immunoglobulin levels are significantly increased
in advanced hepatic parenchymal disease.32 Type III cryoglobulin35,37 and
RF35,38 are also often present. In contrast, the effects of liver disease on
proteins synthesized by the liver are variable and depend on the oftenopposing effects of inflammation and decreased synthetic capacity.32,33,39,40
DISEASE-SPECIFIC PATTERNS
ADVANCED HEPATIC CIRRHOSIS39,40
CRP
+/++
a
a
b
AAT
IgA
++/+++ +++
IgG
+
IgM
++
c
Alb
-/--
Tf
-/--
C3/C4
-/--
Hp
---
PAL
---
Cp
--
Apo B
--
Key Finding in cirrhosis; marked increase in balcoholic cirrhosis41,42 and cviral
cirrhosis.32 Enzyme markers of hepatocellular and parenchymal damage are high
(aspartate aminotransferase, 10x normal), with lesser increases in enzyme
markers of biliary obstruction (alkaline phosphatase, 5x normal).
68
BILIARY OBSTRUCTION39
Apo B
+++
C3
++
Hp
++
CRP
N
Alb
N
PAL
N
TF
N
BILIARY CIRRHOSIS (PRIMARY OR SECONDARY)32,43
Alb
Early disease:
N/Plus hepatocellular damage: --
IgG IgA
N/+ N/+
++ ++
IgM Apo B
++ +++
+++ +++
C3
+++
N/--
C4
--
Hp CP CRP
++ N
-/--- -- N/+
Fulminant Hepatic Failure
CRP Alb
+/++ -
AAT
-
C3/C4
---
FN
-
FIB
-
AT III
-
PMG
-
IgG*
++
IgA*
++
IgM*
++
Enzyme markers of hepatocellular and parenchymal damage are high.
PROTEIN MEASUREMENTS RELATED TO DISEASE SEVERITY
• Low prealbumin is a more sensitive indicator of dysfunction than
low albumin.44
• Increased IgA is seen in alcoholic cirrhosis,41,42 but not viral cirrhosis.32
• Levels of Apo B, Apo AI, and Lp(a) are low in cirrhosis and chronic
liver failure.45-47
• Complement C3 and C4 levels decrease with disease severity in
hepatitis, cirrhosis, and PBC.48-50 C3 is the first of all proteins to
decrease as liver damage progresses.39
• Albumin is low. In severe disease, this is due to loss of hepatocyte
mass; in earlier disease, this reflects the APR and a response to the
oncotic effects of elevated immunoglobulins.51
• Plasminogen, fibrinogen, and AT III are low in cirrhosis and
fulminant hepatic failure.52,53 The low AT III levels have a complex
relationship with hemostasis.54 Serial changes in AT III levels
correlate with bleeding risk,23,55 but low AT III may also predispose
patients to the thrombotic events seen sporadically in cirrhosis.56
69
Section I.B.
Enzyme markers of biliary obstruction are elevated (alkaline phosphatase, 20 times
normal), with milder increases in enzyme markers of hepatocellular and parenchymal damage (aspartate aminotransferase, 5 times normal). Also, primary biliary
cirrhosis is characterized by the presence of anti-M2 mitochondrial antibodies.
PROTEIN MEASUREMENTS RELATED TO PROGNOSIS
• Low albumin levels correlate with worse survival in cirrhosis.57
• In cirrhosis32 and hepatitis, lower IgG levels indicate improvement,
while higher levels indicate worsening.33
• Fibrinogen: In fulminant hepatic failure, a relatively high fibrinogen
level indicates a better survival rate.58
• In alcoholic hepatitis, large increases in CRP indicate high risk for liver
failure, while levels returning to normal suggest recovery.59
Section I.B.
• In cirrhosis, fulminant hepatic failure, and subacute hepatic failure,
persistently low fibronectin levels predict a poor prognosis and are
associated with an increased incidence of infection and associated
mortality.60,61
PROTEIN INTERPRETATIONS CONFOUNDED IN CHRONIC LIVER DISEASE
• Evaluation of the APR: A typical APR is rarely seen in chronic liver
disease, since changes in the serum levels of the acute phase proteins
are confounded by the liver’s altered synthetic capacity and by the
effects of malnutrition. Albumin, prealbumin, transferrin, and
retinol binding protein are low in chronic liver disease, due not only
to APR but also to decreased liver synthetic capacity, the toxic effects
of alcohol, malnutrition, or (in the case of albumin) redistribution
(ascites). Most proteins that increase in the APR are usually decreased
in liver disease, including α1-acid glycoprotein, haptoglobin,
fibrinogen, AT III, plasminogen, ceruloplasmin, fibronectin, and
complement C3 and C4. Exceptions are CRP, which is increased in
severe liver disease, such as fulminant hepatic failure58 and α1-antitrypsin (AAT), which is elevated in cirrhosis,62 although levels may be
low in fulminant hepatic failure.58 The increase in AAT in cirrhosis
may be due to the liver’s inability to conjugate estrogen, leading to
stimulation of AAT synthesis by unconjugated estrogen.
• Evaluation of Iron Status: Ferritin is the most powerful noninvasive test for the diagnosis of iron deficiency anemia in patients with
and without liver cirrhosis,63 except in alcoholic liver disease. Ferritin
is frequently increased in alcoholic liver disease due to the APR,
although levels normalize with abstinence.64
• Evaluation of Nutritional Status: In liver disease, it is difficult to
interpret serum protein changes in terms of nutritional status, as levels may be decreased for other reasons. Retinol-binding protein is
considered to be the most sensitive marker of protein-calorie malnutrition in cirrhotic patients, even in mild (Child A) disease, but this
effect may actually reflect liver failure or inflammation/necrosis as
much as protein-calorie malnutrition.65
70
LABORATORY TESTING IN CHRONIC LIVER DISEASE
Differential diagnosis
Monitoring*
AAT
CER
Hp
Alb
CRP
C3/C4
IgG,
Fibrinogen
Apo B
FER
AAT phenotype
SPE
Apo B
PAL
SPE
Hp
IgA,
AT III
Apo AI
IgM
* Choice depends on specific condition; see text for details.
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3. Norman MR, Mowat AP, Hutchison DC. Molecular basis, clinical consequences
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4. Chowrimootoo GF, Ahmed HA, Seymour CA. New insights into the
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5. Bull PC,Thomas GR, Rommens JM, Forbes JR, Cox DW.The Wilson disease
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6. Schaefer M, Roelofsen H,Wolters H, et al. Localization of the Wilson’s disease
protein in human liver. Gastroenterology. 1999;117:1380-1385.
7. Stolz A. Liver physiology and metabolic function. In: Feldman M, Scharschmidt
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9. Cauza E, Maier-Dobersberger T, Polli C, Kaserer K, Kramer L, Ferenci P.
Screening for Wilson’s disease in patients with liver diseases by serum
ceruloplasmin. J Hepatol. 1997;27:358-362.
10. Steindl P, Ferenci P, Dienes HP, et al.Wilson’s disease in patients presenting
with liver disease: a diagnostic challenge. Gastroenterology. 1997;113:212-218.
11. Maher JJ. Inherited, infiltrative, and metabolic disorders involving the liver;
1:785-786; Fairbanks VF, Baldus WP. Iron Overload;2:1132-1135. In: Cecil
Textbook of Medicine. JC Bennett and F Plum, eds. 20th ed.WB Saunders Co,
Philadelphia, 1996.
12. Edwards CQ, Kushner JP. Screening for hemochromatosis. N Engl J Med.
1993;328:1616-1620.
13. Bothwell TH, Charlton RW, Motulsky AG. Hemochromatosis. In: Scriver CR,
Beaudet AL, Sly WS,Valle D, eds. The Metabolic and Molecular Bases of Inherited
Disease. 7th ed. New York, NY: McGraw-Hill; 1995;II:2237-2269.
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2. Zhou H, Fischer HP. Liver carcinoma in PiZ alpha-1-antitrypsin deficiency.
Am J Surg Pathol. 1998;22:742-748.
14. Piperno A,Vergani A, Malosio I, et al. Hepatic iron overload in patients with
chronic viral hepatitis: role of HFE gene mutations. Hepatology.
1998;28:1105-1109.
15.Witte DL, Crosby WH, Edwards CQ, Fairbanks VF, Mitros FA. Practice guideline development task force of the College of American Pathologists.
Hereditary hemochromatosis. Clin Chim Acta. 1996;245:139-200.
16. Cogswell ME, McDonnell SM, Khoury MJ, Franks AL, Burke W, Brittenham G.
Iron overload, public health, and genetics: evaluating the evidence for
hemochromatosis screening. Ann Int Med. 1998;129:971-979.
Section I.B.
17. Cox DW, Roberts EA.Wilson Disease. In: Feldman M, Scharschmidt BF,
Sleisenger MH, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver disease.
6th ed. Philadelphia, PA;WB Saunders Co, 1998;2:1106.
18. Burke W,Thomson E, Khoury MJ, et al. Hereditary hemochromatosis: gene
discovery and its implications for population-based screening. JAMA.
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19. Davis JG. Population screening for hemochromatosis: the evolving role of
genetic analysis. Ann Intern Med. 1998;129:905-908.
20. Chitkara YK, Fontes MD. Guidelines for serological testing in the diagnosis of
acute hepatitis A and B. Diag Microbiol Infect Dis. 1999;33:241-245.
21. Shima M, Nakao K, Kato Y, Nakata K, Ishii N, Nagataki S. Comparative study
of C-reactive protein in chronic hepatitis B and chronic hepatitis C. Tohoku J
Exp Med. 1996;178:287-297.
22. Louagie HK, Brouwer JT, Delanghe JR, De Buyzere ML, Leroux-Roels GG.
Haptoglobin polymorphism and chronic hepatitis C. J Hepatol. 1996;25:
10-14.
23. Pramoolsinsap C, Busagorn N, Kurathong S. Haemostatic abnormalities in
patients with liver disease associated with viral hepatitis. J Med Assoc Thai.
1996;79:681-688.
24.Verbaan H,Widell A, Bondeson L, Andersson K, Eriksson S. Factors associated
with cirrhosis development in chronic hepatitis C patients from an area of low
prevalence. J Viral Hepat. 1998;5:43-51.
25. Farkas H, Csepregi A, Nemesanszky E, et al. Acquired angioedema associated
with chronic hepatitis C. J Allergy Clin Immunol. 1999;103:711-712.
26. Sundar S, Mall RK, Dube B, Singh VP. Antithrombin III in liver disorders. J Assoc
Phys India. 1991;39:522-524.27. Hwang SJ, Lee SD, Li CP, Lu RH, Chan CY,Wu
JC. Clinical study of cryoglobulinaemia in Chinese patients with chronic
hepatitis C. J Gastroenterol Hepatol. 1997;12:513-517.
27. Hwang SJ, Lee SD, Li CP, Lu RH, Chan CY, Wu JC. Clinical study of cryoglobulinaemia in Chinese patients with chronic hepatitis C. J Gastroenterol Hepatol.
1997;12:513-517.
28. Lunel F, Musset L. Hepatitis C virus infection and cryoglobulinaemia. Forum.
1998;8:95-103.
29.Werner M, Soule J. In: Ritchie RF, Navolotskaia O, eds. Serum Proteins in Clinical
Medicine. Scarborough, ME: Foundation for Blood Research; 1999;2:112.00.4.4.
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30. Malaguarnera M, Restuccia S, DiFazio I, Zoccolo AM,Trovato BA, Pistone G.
Serum beta2-microglobulin in chronic hepatitis C. Digestive Dis Sci.
1997;42:762-766.
31. Ilan Y, Shouval D, Ashur Y, Manns M, Naparstek Y. IgA deficiency associated with
chronic hepatitis C virus infection. A cause or an effect? Arch Intern Med.
1993;153:1588-1592.
32.Werner M, Soule J. In: Ritchie RF, Navolotskaia O, eds. Serum Proteins in Clinical
Medicine. Scarborough, ME: Foundation for Blood Research; 1999;2:112.00.4.1.
Aspects. Boston, MA: Little, Brown and Co; 1975:409-413.
34. Pawlotsky JM, Roudot-Thoraval F, Simmonds P, et al. Extrahepatic immunologic
manifestations in chronic hepatitis C and hepatitis C virus serotypes. Ann
Intern Med. 1995;122:169-173.
36. Keren DF. Clinical indications for electrophoresis and immunofixation. In: Rose
NR, Conway de Macario E, Folds JD, Lane HC, Nakamura RM, eds. Manual of
Clinical Laboratory Immunology. 5th ed.Washington, DC: American Society for
Microbiology Press; 1997:67.
37. Foerster J. Cryoglobulins and cryoglobulinemia. In: Lee GR, Foerster J, Lukens
J, Paraskevas F, Greer JP, Rodgers GM, eds. Wintrobe’s Clinical Hematology.
eds. Rheumatology. 2nd ed. London, UK: Mosby; 1998;1:2.10.4-2.10.5.
39. Johnson AM. Plasma protein assays in clinical diagnosis and management.
Bulletin 6215. Brea, CA: Beckman Instruments Inc.
Aspects. Little, Boston, MA; Brown and Co; 1975;528-535.
41. Meillet D, Labrousse F, Benoit MO, Hernvann A, Musset L, van Amerongen G.
Increased serum concentration of IgA2 subclass and IgA2/IgA1 ratio: specific
markers of chronic alcoholic abuse? Eur J Clin Chem Clin Biochem.
1997;35:275-279.
42. Deviere J, Content J, Denys C, et al. Immunoglobulin A and interleukin 6 form
a positive secretory feedback loop: a study of normal subjects and alcoholic
cirrhotics. Gastroenterology. 1992;103:1296-1301.
43. Lindor KD. Primary Biliary Cirrhosis. In: Feldman M, Scharschmidt BF,
Sleisenger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease.
6th ed. Philadelphia, PA:WB Saunders Co; 1998;2:1275-1283.
44.Yasmin MY, Aziz B, Nazim M, Madhavan RK. Prealbumin rather than albumin
is a more sensitive indicator of acute liver disease. Malays J Pathol.
1993;15:147-150.
45. Malaguarnera M, Giugno I,Trovato BA, Panebianco MP, Restuccia N, Ruello P.
Lipoprotein(a) in cirrhosis. A new index of liver functions? Curr Med Res Opin.
1996;13:479-485.
73
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35. Lee YH, Ji JD,Yeon JE, Byun KS, Lee CH, Song GG. Cryoglobulinaemia and
rheumatic manifestations in patients with hepatitis C virus infection. Ann
Rheum Dis. 1998;57:728-731.
46. Cimminiello C, Soncini M, Gerosa MC, Toschi V, Motta A, Bonfardeci G.
Lipoprotein(a) and fibrinolytic system in liver cirrhosis. Coagulation
Abnormalities in Liver Cirrhosis (CALC) Study Group. Biomed Pharmacother.
1995;49:364-368.
47. Sposito AC,Vinagre CG, Pandullo FL, Mies S, Raia S, Ramires JA.
Apolipoprotein and lipid abnormalities in chronic liver failure. Braz J Med
Biol Res. 1997;30:1287-1290.
48. Ritzmann SE, Daniels JC, eds. Serum Protein Abnormalities: Diagnostic and
Clinical Aspects. Boston, MA: Little, Brown and Co; 1975:285.
49. Gardinali M, Conciato L, Cafaro C, et al. Complement system is not activated
in primary biliary cirrhosis. Clin Immunol Immunopathol. 1998;87:297-303.
Section I.B.
50. Sopena B, Martinez-Vazquez C, Fernandez-Rodriguez CM, et al. Serum
angiotensin converting enzyme and C4 protein of complement as a combined
diagnostic index in alcoholic liver disease. Liver. 1996;16:303-308.
51. Ritzmann SE, Daniels JC, eds. Serum Protein Abnormalities: Diagnostic and
Clinical Aspects. Boston, MA: Little, Brown and Co; 1975. p. 180.
52. Pasqualetti P, Festuccia V, Acitelli P, Natali L, Collacciani A, Casale R. Circadian
rhythms of fibrinogen, antithrombin III, and plasminogen in chronic liver diseases of increasing severity. Haemostasis. 1997;27:140-148.
53. Rodriguez Cuartero A. Plasminogen in patients with liver cirrhosis. Revista
Espanola de Enfermedades Digestivas. 1997;89:457-462.
54. Castelino DJ, Salem HH. Natural anticoagulants and the liver. J Gastroenterol
Hepatol. 1997;12:77-83.
55.Vukovich T,Teufelsbauer H, Fritzer M, Kreuzer S, Knoflach P. Hemostasis
activation in patients with liver cirrhosis. Thromb Res. 1995;77:271-278.
56. Dumitrascu DL, Radu D,Vonica A.The significance of low antithrombin III
levels in cirrhosis. Roman J Intern Med. 1991;29:151-154.
57. Sugimura T,Tsuji Y, Sakamoto M, et al. Long-term prognosis and prognostic
factors of liver cirrhosis in the 1980s. J Gastroenterol Hepatol. 1994;9:154-161.
58. Izumi S, Hughes RD, Langley PG, Pernambuco JR,Williams R. Extent of the
acute phase response in fulminant hepatic failure. Gut. 1994;35:982-986.
59. Gupta S, Slaughter S, Akriviadis EA,Valenzuela R, Deodhar SD. Serial measurement of serum C-reactive protein facilitates evaluation in alcoholic hepatitis.
Hepatogastroenterology. 1995;42:516-521.
60.Acharya SK, Dasarathy S, Irshad M. Prospective study of plasma fibronectin in
fulminant hepatitis: association with infection and mortality. J Hepatol.
1995;23:8-13.
61. Irshad M, Acharya SK, Joshi YK, Tandon BN. Role of fibronectin and
complement in immunopathogenesis of acute and subacute hepatic failure.
J Gastroenterol Hepatol. 1994;9:355-360.
62. Dabrowska M, Mantur M, Panasiuk A, Prokopowicz J. Does the concentration
of alpha 1-proteinase inhibitor reflect the transformation of liver cirrhosis to
liver carcinoma? Neoplasma. 1997;44:305-307.
74
63. Intragumtornchai T, Rojnukkarin P, Swasdikul D, Israsena S.The role of serum
ferritin in the diagnosis of iron deficiency anaemia in patients with liver
cirrhosis. J Intern Med. 1998;243:233-241.
64. Bell H, Skinningsrud A, Raknerud N, Try K. Serum ferritin and transferrin
saturation in patients with chronic alcoholic and non-alcoholic liver diseases.
J Intern Med. 1994;236:315-322.
65. Calamita A, Dichi I, Papini-Berto SJ, et al. Plasma levels of transthyretin and
retinol-binding protein in Child-A cirrhotic patients in relation to proteincalorie status and plasma amino acids, zinc, vitamin A and plasma thyroid
hormones. Arquivos de Gastroenterologia. 1997;34:139-147.
NEUROLOGIC DISEASE
MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is a progressive, demyelinating neuropathy
affecting the brain, optic nerves, and spinal cord, usually presenting at
15 to 50 years, and is more frequent among women.1 Characterized
typically by a relapsing/remitting disease course, the etiology of MS is
unknown but may involve immune-mediated inflammation following
exposure of a genetically susceptible individual to an environmental
trigger such as viral infection.
IMMUNOLOGIC RESPONSE IN MS
IgG oligoclonal banding
CSF
+
Serum
-
IgG Index
CSF/serum
++
C3
serum
N/-
• IgG oligoclonal banding is the finding of multiple, restricted bands
in the γ-region of CSF protein electrophoresis, due to the limited
number of intrathecal B-cell clones. Oligoclonal banding is characteristic (but not diagnostic) of MS. It is seen in cerebrospinal fluid but
not in serum.2
• An elevated IgG index (normal, ≤0.63) is seen in 90% of MS
patients; as with oligoclonal banding in CSF, it is a measure of
intrathecally synthesized IgG.3
IgG index= CSF IgG/Serum IgG
CSF Alb/Serum Alb
• Complement C3 is decreased in acute MS attack due to classical
pathway activation and consumption by immune complexes. Low
serum C3 levels and high levels of circulating immune complexes
may be a marker for severity in MS.4
75
Section I.B.
Multiple sclerosis
Paraproteinemic neuropathy
OTHER CSF PROTEIN MARKERS IN MS
• In acute episodes of MS, myelin basic protein, which is released during
demyelination, may be elevated in CSF.5
LABORATORY TESTING IN MS
Diagnosis
Monitoring
EP (CSF+serum) IgG index
Immunofixation using α-IgG
C3 (serum)
Section I.B.
PARAPROTEINEMIC NEUROPATHY
Ten percent of peripheral neuropathies of unknown etiology have an
associated monoclonal gammopathy (MG), malignant or benign. These
neuropathies are heterogenous, and the MG may be coincident or pathogenic. Amyloidosis or cryoglobulinemic neuropathy can also occur
with MG. Thus, MG of unknown significance (MGUS), multiple myeloma,
and Waldenström’s macroglobulinemia are included in the differential
diagnosis of sensorimotor peripheral neuropathy in adults.6
MONOCLONAL PROTEINS IN PARAPROTEINEMIC NEUROPATHY
IgG
-/+++
IgA
-/+++
IgM
-/+++
The relationship between peripheral neuropathy and the reactivity of
IgM MG toward neuronal antigens has been studied extensively. IgM
anti-myelin-associated glycoprotein (α-MAG) is associated with
demyelinating peripheral neuropathy, IgM α-GM1 with motor neuropathy,
and IgM α-sulfatide with sensory neuropathy.7
• In IgM MG, serum IgM levels are elevated, levels of normal (polyclonal) immunoglobulins are suppressed, and SPE/immunofixation
demonstrates a monoclonal protein.
• Compared with IgA/IgG MG neuropathy, IgM MG neuropathy has
higher frequency of sensory loss and ataxia. Higher frequency of
nerve conduction abnormalities; and higher frequency of dispersion of
the compound muscle action potential.8
• Neither the amount of monoclonal IgM nor the presence of identified
antigenic reactivity such as αMAG is associated with the severity of
neuropathy.8
IgA/IgG MGs are associated with neuropathy among patients with
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,
myeloma, and skin changes).6
76
• As for IgM MG, serum levels of IgG or IgA will be elevated, with
suppression of the normal (polyclonal) immunoglobulins.
SPE/immunofixation detects an M-component.
LABORATORY TESTING IN PARAPROTEINEMIC NEUROPATHY
Diagnosis and Monitoring
IgG, IgA, IgM
SPE
Immunofixation
Specific serologic testing (αMAG; αGM1; αsulfatide)
REFERENCES
1. Rudick RA. Multiple sclerosis and related conditions. In: Bennett JC, Plum F, eds.
Cecil Textbook of Medicine. 20th ed. Philadelphia, PA:WB Saunders Co;
1996;2:2106-2110.
3. Blennow K, Fredman P,Wallin A, et al. Protein analysis in cerebrospinal fluid. II.
Reference values derived from healthy individuals 18-88 years of age. Eur
Neurol. 1993;33:129-133.
4. Cojocaru M, Serbanescu A, Cojocaru IM. Changes of serum complement and of
circulating immune complexes in patients with multiple sclerosis. Rom J Int Med.
1993;31:131-137.
5. Martin-Mondiere C, Jacque C, Delassalle A, Cesaro P, Carydakis C, Degos JD.
Cerebrospinal myelin basic protein in multiple sclerosis. Identification of two
groups of patients with acute exacerbation. Arch Neurol. 1987;44:276-278.
6. Latov N. Pathogenesis and therapy of neuropathies associated with monoclonal
gammopathies. Ann Neurol. 1995;37(suppl 1):S32-42.
7. Steck AJ, Erne B, Gabriel JM, Schaeren-Wiemers N. Paraproteinaemic
neuropathies. Brain Pathol. 1999;9:361-368.
8. Gosselin S, Kyle RA, Dyck PJ. Neuropathy associated with monoclonal gammopathies of undetermined significance. Ann Neurol. 1991;30:54-61.
77
Section I.B.
2. Keshgegian AA, Coblentz J, Lisak RP. Oligoclonal immunoglobulins in cerebrospinal fluid in multiple sclerosis. Clin Chem. 1980;26:1340-1345.
PULMONARY DISEASE
Chronic obstructive pulmonary disease
Asthma
Lung cancer
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Chronic obstructive pulmonary disease (COPD) is characterized by
chronic, progressive, and irreversible decrease of airflow within the
passages of the lungs. The term includes chronic bronchitis and
emphysema, asthma with chronic, variable airflow obstruction,
bronchiectasis, and upper airway obstructions.1
Section I.B.
GENETIC CONSIDERATIONS IN COPD
AAT
-
α1-Antitrypsin (AAT) deficiency is most often due to the presence of
the Pi Z allele (see Liver Disease). As AAT levels increase in the APR,
the diagnosis requires AAT phenotyping in addition to measuring AAT
levels.2 Pi ZZ and Pi SZ are the most common genotypic associations
with early onset emphysema in adults.3 An AAT concentration of
~80 mg/dL (~60% of normal) marks a threshold below which COPD
risk may increase.4 Risk is further increased by cigarette smoke.5,6
The frequency of Pi ZZ is 3% among COPD patients, compared with
1/3,500 to 1/1,670 in persons of northern European ancestry.7 The
Pi Z allele is rare in African and absent in Asian populations.1
ACUTE PHASE RESPONSE IN COPD
CRP
N/+
FIB
+
C4
+/-
• COPD exacerbation is often associated with infection. In these cases,
CRP is elevated.8
• Fibrinogen levels may also be elevated, increasing the risk for
thrombosis.9
• Complement C4 levels are typically elevated in the APR; however, in
COPD due to chronic bronchitis, decreased C4 levels correlate with
the degree of emphysema.10
IMMUNOLOGIC RESPONSE IN COPD
• IgA and IgG may be elevated.11
78
• In COPD, there is an inverse association between total IgE and lung
function, which is assessed by one-second forced expiratory volume
(FEV1) or forced vital capacity.12
LABORATORY STUDIES IN COPD*
Etiology
Monitoring
AAT/AAT phenotyping
CPR
FIB
* In addition to pulmonary function studies.
ASTHMA
Asthma is a chronic disorder that involves airway inflammation and
causes wheezing, breathlessness, chest tightness, and cough.
Section I.B.
ACUTE PHASE RESPONSE IN ASTHMA
C3
++
Hp
+/++
• Complement C3 is disproportionally elevated in uncomplicated
asthma, and levels are higher than in bacterial infection.13
• Haptoglobin is elevated in children and adults with asthma.
Haptoglobin level is higher in acute exacerbation than in remission
in children with asthma, and may reflect the degree of airway
inflammation.14 In adults, haptoglobin level is inversely related to
FEV1 and is higher among those with bronchial hyperresponsiveness.15
IMMUNOLOGIC RESPONSE IN ASTHMA
IgE
++
IgG
+
IgM
+
• IgE, IgG, and IgM are elevated in asthma.16,17 Wheezing and early
sensitization are associated with high total IgE, even in infants.7
In adults with undiagnosed asthma, IgE predicts the extent of
bronchospasm.17
• In asthma due to allergy, allergen-specific IgE is elevated.
LABORATORY STUDIES IN ASTHMA*
Etiology
IgE (total and allergen-specific)
* In addition to pulmonary function studies.
79
LUNG CANCER
Serum protein changes in lung cancer are mostly due to the APR and
are relatively nonspecific and nondiagnostic. In established disease,
certain measurements may be useful to evaluate prognosis and monitor
disease progress.
ACUTE PHASE RESPONSE IN LUNG CANCER
CRP
++
Alb
-
FER
+
FIB
+/-
Section I.B.
• CRP is increased in many types of lung cancer.19 Elevated and rising
CRP is an adverse prognostic factor.20
• Low serum albumin implies a systemic effect of the malignancy.
Return to normal levels after treatment correlates with survival while
the converse indicates poor prognosis. In all types of lung cancer,
normal albumin is associated with better survival.21
• Both ferritin and fibrinogen may be elevated due to tumor-related
inflammation. A ferritin level >400 µg/L is associated with shortened
survival.22 In small cell carcinoma of the lung, higher pretreatment
fibrinogen is associated with more advanced disease and a lower
probability of disease regression with chemotherapy.23 Conversely,
low fibrinogen levels may be seen in adenocarcinoma of the lung,
leading to bleeding disorders.24
IMMUNOLOGIC RESPONSE IN LUNG CANCER
Monoclonal gammopathy may be seen in lung cancer.11
LABORATORY STUDIES IN LUNG CANCER
Prognosis*
CRP
FIB
Monitoring
FER
Alb
CRP
* See text for specific applications.
REFERENCES
1. Jeppson J-O. Chronic obstructive pulmonary disease. In: Ritchie RF, Navolotskaia
O, eds. Serum Proteins in Clinical Medicine. Scarborough, ME: Foundation for
Blood Research; 1999:110.00.
2.Wiechmann DA, Balistreri WF. Inherited metabolic disorders of the liver. In:
Feldman M, Scharschmidt BF, Sleisenger MH, eds. Sleisenger and Fordtran’s
Gastrointestinal and Liver Disease. 6th ed. Philadelphia, PA:WB Saunders Co;
1998:1083.
3. Cox DW. (1-Antitrypsin deficiency. In: Scriver CR, Beaudet AL, Sly WS,Valle D,
eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York,
NY: McGraw Hill, Inc; 1995;3:4137-4140.
80
4.Wiedemann HP, Stoller JK. Lung disease due to alpha 1-antitrypsin deficiency.
Curr Opin Pulm Med. 1996;2:155-160.
5. Silverman EK, Speizer FE. Risk factors for the development of chronic obstructive pulmonary disease. Med Clin North Am. 1996;80:501-522.
6. Larsson C. Natural history and life expectancy in severe α1-antitrypsin
deficiency PiZ. Acta Med Scand. 1978;204:345-351.
7. Buist AS. Alpha-1-antitrypsin deficiency in lung and liver disease. Hosp Pract.
1989;51-59.
8. Dev D,Wallace E, Sankaran R, et al.Value of C-reactive protein measurements
in exacerbations of chronic obstructive pulmonary disease. Respir Med.
1998;92:664-667.
10. Kosmas EN, Zorpidou D,Vassilareas V, Roussou T, Michaelides S. Decreased
C4 complement component serum levels correlate with the degree of
emphysema in patients with chronic bronchitis. Chest. 1997;112:341-347.
11. Ritzmann SE. Immunoglobulin abnormalities. In: Ritzmann SE, Daniels JC.
Brown and Co; 1975:351-486.
12. Sherrill DL, Lebowitz MD, Halonen M, Barbee RA, Burrows B. Longitudinal
evaluation of the association between pulmonary function and total serum IgE.
Am J Resp Crit Care Med. 1995;152:98-102.
13. Lin RY, Caveliere LF, Lorenzana FG, Go EF, Altman KA. Pattern of C3, iC3b, and
C3d in patients hospitalized for acute asthma. Ann Allergy. 1992;68:324-330.
14. Koh YY, Kim YW, Park JD, Oh JW. A comparison of serum haptoglobin levels
between acute exacerbation and clinical remission in asthma. Clin Exper Allergy.
1996;26:1202-1209.
15. Kauffmann F, Frette C, Annesi I, Oryszczyn MP, Dore MF, Neukirch F.
Relationships of haptoglobin level to FEV1, wheezing, bronchial hyperresponsiveness and allergy. Clin & Exper Allergy. 1991;21:669-674.
16. Garg S, Gupta S, Prakash K, Bhatnagar P. Clinical ventilatory functions and
immunological studies in bronchial asthma. J Indian Med Assoc. 1991;89:6-9.
17. Lebowitz MD, Bronnimann S, Camilli AE. Asthmatic risk factors and bronchial
reactivity in non-diagnosed asthmatic adults. Eur J Epidemiol. 1995;11:541-548.
18. Pastorello EA, Incorvaia C, Ortolani C, et al. Studies on the relationship
between the level of specific IgE antibodies and the clinical expression of allergy:
I. Definition of levels distinguishing patients with symptomatic from patients
with asymptomatic allergy to common aeroantigens. J Allergy Clin Immunol.
1995;96:580-587.
19. Sattar N, Scott HR, McMillan DC, Talwar D, O’Reilly DS, Fell GS. Acute-phase
reactants and plasma trace element concentrations in non-small cell lung
cancer patients and controls. Nutr Cancer. 1997;28:308-312.
81
Section I.B.
9.Alessandri C, Basili S,Violi F, Ferroni P, Gazzaniga PP, Cordova C.
Hypercoagulability state in patients with chronic obstructive pulmonary
disease. Chronic Obstructive Bronchitis and Haemostasis Group. Thromb
Haemost. 1994;72:343-346.
20.Wojciechowska-Lacka A, Adamiak E, Stryczynska G, Lacki JK. Prognostic value
of serial serum interleukin-6 level estimation in patients with lung cancer: a
preliminary report. Yale J Biol Med. 1997;70:139-148.
21. Espinosa E, Feliu J, Zamora P, et al. Serum albumin and other prognostic factors related to response and survival in patients with advanced non-small cell
lung cancer. Lung Cancer. 1995;12:67-76.
22. Milman N, Sengelov H, Dombernowsky P. Iron status markers in patients
with small cell carcinoma of the lung. Relation to survival. Br J Cancer.
1991;64:895-898.
Section I.B.
23. Meehan KR, Zacharski LR, Moritz TE, Rickles FR. Pretreatment fibrinogen levels are associated with response to chemotherapy in patients with small cell
carcinoma of the lung: Department of Veterans Affairs Cooperative Study 188.
Am J Hematol. 1995;49:143-148.
24. Meijer K, Smid WM, Geerards S, van der Meer J. Hyperfibrinogenolysis in
disseminated adenocarcinoma. Blood Coag Fibrinol. 1998;9:279-283.
RENAL DISEASE
Nephrotic syndrome
Chronic renal failure
Glomerulonephritis
Hemostatic balance in renal disease
NEPHROTIC SYNDROME
A2M FIB ApoB Lp(a) FN
+++ +++ +++ ++
+
Alb
---
Tf
---
AAT C3/C4
---
AT III
-
IgG
--
IgA
N
IgM AAG
+++ ---
Heavy proteinuria, abnormal serum protein profile, and peripheral
edema characterize the nephrotic syndrome (NS). Serum levels of small
to medium-sized proteins decrease in active NS due to loss through
the damaged glomerular membranes, while larger proteins or particles
are retained.1 Hepatic protein synthesis compensates successfully
during early disease, contributing to elevated levels of large and intermediate-sized proteins. Hyperlipidemia is common due to retention
of circulating β lipoprotein.
SERUM PROTEIN CHANGES DUE TO SELECTIVE SIEVING IN NS
• Levels of smaller proteins such as albumin, α1-antitrypsin,2 IgG,3
and transferrin4 are decreased in NS due to glomerular/urinary
losses beyond the synthetic capacity of the liver to compensate. The
losses are size-dependent; decreases in serum levels of the larger IgG
molecule are less than for albumin, α1-antitrypsin, or transferrin.
• Complement C3 and C4 are decreased due either to primary
disease (eg, immune complex fixation in SLE) or secondary to
glomerular loss.5
82
• Low antithrombin III* (AT III) levels are due both to urinary loss
and to intravascular consumption as Thrombin-AT III complex.6 AT III
levels are increased by steroid therapy.7
• Serum levels of larger proteins such as α2-macroglobulin,
fibrinogen, IgM, fibronectin, apo B, and apo(a)/Lp(a)2,8,9 are
increased due to increased synthesis and/or glomerular retention.
* See Hemostatic Balance in Renal Disease for further information.
CLINICAL CONSEQUENCES OF PROTEIN CHANGES IN NS
• Decreases in fibrinogen are a marker for decreased renal function in
lupus nephritis with NS.10 Levels are increased by steroid therapy7 and
elevated levels are associated with coagulopathy.6,9
• Decreased transferrin may interfere with iron processing.
• Decreased serum levels of oncotically active proteins, particularly
albumin, cause peripheral edema.1
LABORATORY TESTING IN NS
Prognosis
SPE
AAT
FIB
FIB
Lp(a)
A2M
Tf
Alb
AT III
Protein S
Apo B*
Protein C
* As part of a lipoprotein profile.
CHRONIC RENAL FAILURE
Alb PAL Tf FER Cp AT III FIB CysC CRP AAG B2M MYO
- + +
++
+
+
+
Apo B Apo A-1 Lp(a)
++
+
Chronic renal failure (CRF) of any etiology is characterized by
decreased glomerular filtration rate (GFR), azotemia, and acidosis.
Unlike in NS, serum levels of low MW proteins increase due to
decreased GFR and decreased catabolism in the proximal tubule.
Superimposed on these renal-associated effects, the chronic inflammation
of CRF may be associated with characteristic changes in the acute phase
proteins.There is generalized hypoproteinemia as a result of malnutrition
(secondary to hypercatabolism, decreased calorie intake, fluid retention,
or the catabolic effects of the primary disease), and the toxic effects of
CRF on hepatic protein synthesis.13 Similar changes in serum protein
levels are seen in hemodialysis (HD) as in CRF.
83
Section I.B.
• Elevated Lp(a)11 and apo B12 may contribute to increased CVD risk
in renal disease.
THE ACUTE PHASE RESPONSE IN CRF
• CRP,14 fibrinogen,15 and α1-acid glycoprotein16 levels are increased
in dialyzed and untreated patients due both to the APR and
decreased GFR. CRP levels predict morbidity and mortality in both
HD and continuous ambulatory peritoneal dialysis (CAPD).17 High
fibrinogen predicts CVD events in CRF and is associated with
shorter functional survival of vascular access in HD.18
Section I.B.
• Low albumin is a prominent feature of azotemia and is correlated
with morbidity due to CAPD and HD.19 It is a long-term poor
prognostic factor in CRF.20 In HD, low albumin is due to decreased
synthesis (APR and poor nutrition).21 In CAPD, low albumin is also
secondary to loss in urine and across the peritoneal membrane21
when ascites are present.
PROTEIN MARKERS OF GFR
• Cystatin C is a low MW protein produced by all nucleated cells; it is
freely filtered by the glomerulus and catabolized in the tubules.22,23,24
Thus, GFR is the major determinant of cystatin C levels in serum.
Levels are independent of gender and muscle mass and are thus
easier to interpret than creatinine.25
• High retinol-binding protein,26 α1-microglobulin,27 and
β2-microglobulin28 levels are markers for decreased GFR in both
children and adults. Their performance is inferior to cystatin C.
PROTEINS ASSOCIATED WITH CLINICAL COMPLICATIONS OF CRF
• Atherosclerosis: High Lp(a)29 and high apo B30 levels may be
associated with increased risk for atherosclerosis.
• Thrombosis: Low AT III and high fibrinogen levels may contribute to
increased thrombotic risk in CRF.31 See Hemostatic Balance in Renal
Disease for further information.
• Malnutrition: Low Prealbumin is seen in malnutrition and the APR.
Prealbumin has a rapid turnover and a relatively small circulating pool
and is both a reliable measure for identifying dialysis patients in need
of nutritional supplementation32 and a predictor of survival.33 Low
transferrin and albumin may also be seen due to the APR and/or
malnutrition.
• Anemia: In CRF with normal serum protein levels, percent transferrin saturation (TS) is 100% sensitive and 80% specific as a measure of iron deficiency; however, in CRF with hypoproteinemia, measurement of TS plus ferritin gives the best sensitivity and specificity.34
Elevated soluble transferrin receptor (sTfR) can also be used to
detect iron deficiency anemia in HD patients, except during recombinant human erythropoietin (r-huEPO) therapy as this agent increases
sTfR levels.35 Children with renal failure taking r-huEPO should have
84
ferritin levels monitored, as low levels are the best predictor of
developing iron deficiency in this group36 (ferritin =60 µg/L suggest a
need for oral iron supplementation). Low levels of sTfR predict a
hemoglobin response when initiating r-huEPO therapy in anemic HD
patients.37
• Amyloidosis: Polyclonal free light chains (predominantly lambda
type)38 and β2-microglobulin39 are increased in the serum of HD
patients and may contribute to HD amyloidosis. In light chain deposition disease, monoclonal light chains accumulate in the mesangium,
and patients often present with renal symptoms.40,41
• Elevated myoglobin is seen in HD patients.42
• Complement C3 is low in HD,43 most likely due to persistent
complement activation.44
• Ceruloplasmin levels are low in both HD and CAPD. Dialysis may
cause a moderate copper deficiency when copper-based membranes
are not used.45
LABORATORY TESTING IN CRF
Etiology
GFR
Nutritional status
Anemia
C3/C4 IgG, IgA, IgM
SPE
CRYO
CysC
Alb
PAL
Tf FER
sTfR
AT III FIB
CRP
Apo B Apo A-I Lp(a)
GLOMERULONEPHRITIS
CRP
N/+
C3/C4
N/--
IgG
N/++
IgA
N/++
IgM
N/++
Glomerulonephritis (GN) is characterized by glomerular inflammation
and membrane damage leading to proteinuria, hematuria (when damage
is severe), decreased GFR, hypertension, and peripheral edema. The
disease has many histologic variations, most of which (except for poststreptococcal GN) progress to CRF and ESRD. GN is immune-mediated,
demonstrating immune complex deposition on the glomerular basement
membrane, immune complexes in the γ region on SPE, and functional
and quantitative abnormalities of the complement system. Virtually all
types of GN may be complicated by NS; thus it is important to evaluate
the proteins discussed above (see Renal Disease). If NS develops, the
GN-related protein changes discussed below will be modulated by the
superimposed effect of NS.
85
Section I.B.
EFFECTS OF HEMODIALYSIS ON SERUM PROTEINS
In addition to the changes described below, HD itself may decrease
serum protein levels due to their adhesion to the dialysis membrane.
ACUTE PHASE RESPONSE IN GN
The APR is evident in GN secondary to chronic pyelonephritis and GN
secondary to chronic infection.
• CRP is useful as a screening test to distinguish pyelonephritis or
other inflammatory renal diseases from simple, uncomplicated
hydronephrosis as causes of GN.46
Section I.B.
IMMUNE RESPONSE IN GN
• Complement C3 and C4 are the most practical complement
components to measure in the evaluation of GN. Levels are typically
decreased in acute/active disease, but decreased C3 may persist in
chronic disease as well.47,48,49 Note: if there is a concurrent APR,
C3 may be normal.
50
Membranoproliferative GN
Membranous GN
SLE nephritis*
Cryoglobulinemic nephritis
Idiopathic focal glomerulosclerosis***
Mesangial proliferative GN****
IgA nephropathy
C3
N
-**
N
N/N
50
C4
N/++
N
* There may also be a polyclonal increase in IgG and evidence of an APR.51
An APR is uncommon in SLE unless bacterial complications are present.
** The presence of low C3 early in the course of SLE indicates a poor prognosis,52
and levels are inversely correlated with disease severity by biopsy.53
*** C3 level is inversely correlated with degree of loss of renal function and the
severity of histologic changes.54 Low C3 is a result, rather than a direct cause
of poor renal function.
**** In mesangial proliferative GN (with COPD), IgG and IgA are elevated.55
• Immunoglobulin measurements are important when GN may be
secondary to infection.
GN in chronic pyelonephritis
Acute post-streptococcal GN
GN post S. Aureus
GN secondary to chronic infection***
Infection***
IgG
N/+++
++
++
N
IgA
N/+++
N
++
N
IgM
N/+++
++
N
++
* Levels depend on type/duration of infection.56
** Acute post-streptococcal GN presents with very low C3 levels which may
persist for up to 6 weeks or longer and then resolve (if levels remain low,
suspect other conditions).50
*** In GN secondary to chronic infection (eg, SBE), cryoglobulins57 and RF58 are
often seen; C3 and C4 are decreased59 indicating classical pathway activation.
86
SERUM PROTEINS ASSOCIATED WITH ETIOLOGY
• Although changes in α1-antitrypsin (AAT) levels are not specifically
associated with GN, severe genetic AAT deficiency may be associated
with GN and NS. Thus, AAT deficiency should be considered as a
rare causative factor in adults with abnormal renal function and
chronic liver disease.60
• IgA nephropathy is the most common form of GN.61 Among
Caucasians, 50% have elevated IgA levels62,63 while in Blacks the disease is rarely seen.64 No serum protein measurements are sufficiently
diagnostic for this condition.64 Henoch-Schönlein (H-S) purpura
nephropathy has glomerular and serum protein changes similar to IgA
nephropathy, suggesting a common pathogenesis.65
• In C3 deficiency 15% to 20% of subjects have GN69,70, mostly resembling type I membranoproliferative GN.71
LABORATORY TESTING IN GN
Etiology
IgG, IgA, IgM
CRP
C3/C4
AAT
SPE
CRYO
Nephrotic Syndrome
Infection/Inflammation
A2M
Alb
ApoB
CRP
IgG, IgA, IgM
C3/C4
AAT
Tf
SPE
C3/C4
HEMOSTATIC BALANCE IN RENAL DISEASE
FIB
+
AT III
+/-
PSM
+/-
Protein C
+
Protein S
+/-
NEPHROTIC SYNDROME (NS)
There is a precarious hemostatic balance in NS. It is important to
review the coagulation profile in all patients with NS to identify those
at increased risk for thromboembolism.72
• Children with NS appear to be relatively protected against thromboembolism. AT III level is low, but the anticoagulants protein S and
C become elevated.73 Thromboembolism in children is characterized
by very low levels of AT III, and low protein C and albumin (<20
g/L).72 Steroid therapy causes elevated protein C, protein S, AT III,
and fibrinogen. AT III decreases in patients in relapse with or without steroid treatment and in those in early remission. AT III level is
normal in late remission and in steroid-resistant patients.7,72
• In adults with NS, very low AT III is generally associated with thrombotic events.2,9
87
Section I.B.
• A C4 gene deletion may be a risk factor for SLE,66 as well as
IgA nephropathy and H-S purpura nephritis.67 The presence of C4
deficiency in IgA nephropathy is associated with poor outcome.68
CHRONIC RENAL FAILURE (CRF)
Patients with ESRD are at risk for vascular thrombosis due to numerous coagulation factor abnormalities.
• In CRF there is increased fibrinogen and decreased AT III, protein S,
tPA, and plasminogen.31
• In HD, r-huEPO causes decreased plasminogen and AT III. This does
not occur when patients are not on dialysis. Thus, r-huEPO may
cause increased extracorporeal dialyzer clotting and consumption
coagulopathy.74
LABORATORY TESTING: HEMOSTATIC BALANCE IN RENAL DISEASE*
Section I.B.
Evaluation of thrombotic risk
FIB
AT III
Protein C
Protein S
* In addition to standard functional coagulation tests such as partial
thromboplastin time.
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Medicine. Scarborough, ME: Foundation for Blood Research; 1999;2:116.02.
51. Cameron JS, Lessof MH, Ogg CS, Williams BD, Williams DG. Disease activity
in the nephritis of systemic lupus erythematosus in relation to serum
complement concentrations, DNA-binding capacity, and precipitating antiDNA antibody. Clin Exp Immunol. 1976;25:418-427.
52. Xie SK, Feng SF, Fu H. Long term follow-up of patients with systemic lupus
erythematosus. J Dermatol. 1998;25:367-373.
53. Houssiau FA, D’Cruz D,Vianna J, Hughes GR. Lupus nephritis: the
significance of serological tests at the time of biopsy. Clin Exp Rheumatol.
1991;9:345-349.
54. Cosio FG, Hernandez RA. Favorable prognostic significance of raised serum
C3 concentration in patients with idiopathic focal glomerulosclerosis.
Clin Nephrol. 1996;45:146-152.
55. Dasgupta DJ, Garg ID, Kaushal SS, Chauhan S, Sharma A, Goyal A. Mesangial
proliferative glomerulonephritis in chronic obstructive pulmonary disease.
J Ind Med Assoc. 1998;96:338-340.
56. Ritzmann SE, Daniels SE, eds. Serum Protein Abnormalities: Diagnostic And Clinical
Aspects. Boston, MA: Little, Brown and Co; 1975:414.
57. Hurwitz D, Quismoria FP, Friou GJ. Cryoglobulinaemia in patients with infectious endocarditis. Clin Exp Immunol. 1975;19:131-141.
58. Sheagren JN,Tuazon CU, Griffin C, Padmore N. Rheumatoid factor in acute
bacterial endocarditis. Arthritis Rheum. 1976;19:887-890.
59.West CD.The complement profile in clinical medicine: Inherited and acquired
conditions lowering the serum concentrations of complement component and
control proteins. Complement Inflamm. 1989;6:49-64.
91
Section I.B.
49.Vallota EH, Forristal J, Davis NC,West CD.The C3 nephritic factor and membranoproliferative nephritis: correlation of serum levels of the nephritic factor
with C3 levels, with therapy, and with progression of the disease. J Pediatr.
1972;80:947-959.
60. Stauber RE, Horina JH, Trauner M, Krejs GJ, Ratschek M, Klimpfinger M.
Glomerulonephritis as late manifestation of severe alpha-1 antitrypsin
deficiency. Clin Investig. 1994;72:404-408.
61. Endo Y. IgA nephropathy: human disease and animal model. Ren Fail.
1997;19:347-371.
62. Clarkson AR,Woodroffe AJ, Aarons I. IgA nephropathy and Henoch-Schönlein
purpura. In: Schrier RW, Gottschalk CW, eds. Diseases of the Kidney. Boston,
MA: Little, Brown & Company; 1988:2061-2089.
63. Layward L, Allen AC, Hattersley JM, Harper SJ, Feehally J. Elevation of IgA in
IgA nephropathy is localized in the serum and not saliva and is restricted to
the IgA1 subclass. Nephrol, Dial,Transplant. 1993;8:25-28.
Section I.B.
64. Galla JH. IgA nephropathy. Kidney Int. 1995;47:377-387.
65. Silverstein DM, Greifer I, Folkert V, Bennett B, Corey HE, Spitzer A. Sequential
occurrence of IgA nephropathy and Henoch-Schönlein purpura: support for
common pathogenesis. Pediatr Nephrol. 1994;8:752-753.
66. Gallin JI, Goldstein IM, and Snyderman R, eds. Inflammation: Basic Principles and
Clinical Correlates. 2nd ed. New York, NY:Raven Press; 1992:89.
67. Jin DK, Kohsaka T, Koo JW, Ha IS, Cheong HI, Choi Y. Complement 4 locus II
gene deletion and DQA1*0301 gene: genetic risk factors for IgA nephropathy
and Henoch-Schönlein nephritis. Nephron. 1996;73:390-395.
68.Wopenka U,Thysell H, Sjoholm AG,Truedsson L. C4 phenotypes in IgA
nephropathy: disease progression associated with C4A deficiency but not with
C4 isotype concentrations. Clin Nephrol. 1996;45:141-145.
69. Frank MM, Austen KF, Claman HN, Unanue ER, eds. Samter’s Immunologic
Disease. 5th ed. Boston, MA: Little Brown and Co; 1995:492.
70. Colten HR, Rosen FC. Complement deficiencies. Ann Rev Immunol.
1992;10:809-834.
71. Rose NR, Conway de Macario E, Folds JD, Lane HC, Nakamura RM, eds.
Manual of Clinical Laboratory Immunology. 5th ed. American Society for
Washington, DC: Microbiology Press; 1997:848.
72.Anand NK, Chand G,Talib VH, Chellani H, Pande J. Hemostatic profile in
nephrotic syndrome. Ind Pediatr. 1996;33:1005-1012.
73.Al-Mugeiren MM, Gader AM, al-Rasheed SA, Bahakim HM, al-Momen AK,
al-Salloum A. Coagulopathy of childhood nephrotic syndrome - a reappraisal
of the role of natural anticoagulants and fibrinolysis. Haemostasis.
1996;26:304-310.
74.Tsao CJ, Kao RH, Cheng TY, Huang CC, Chang SL, Lee FN.The effect of
recombinant human erythropoietin on hemostatic status in chronic uremic
patients. In J Hematol. 1992;55:197-203.
92
RHEUMATIC DISEASE
Ankylosing spondylitis
Juvenile rheumatoid arthritis
Mixed connective tissue disease
Osteoarthritis
Polymyalgia rheumatica/giant cell arteritis
Polymyositis/dermatomyositis
Rheumatoid arthritis (active)
Sjögren’s syndrome
Systemic lupus erythematosus
Systemic sclerosis/scleroderma
The systemic rheumatic diseases comprise a diverse group of disorders,
having in common clinical and laboratory findings related to autoimmunity and inflammation. Rheumatologic symptoms such as arthropathy may
also be secondary to other diseases, such as neoplastic or neurologic
disease, hemochromatosis, or infection. Serum protein analysis is often
useful in the diagnostic differentiation and monitoring of these conditions and in detecting “migration” between diseases.
CRP
+
AAG
+
IgA
+
RF
-
Ankylosing spondylitis (AS) is a chronic inflammatory disease principally
of the axial skeleton, most common in males, characterized by pain and
progressive immobility and stiffening. Peripheral joints and other
organs (eyes, lungs, heart) may also be involved. The diagnosis of AS
is often one of exclusion.
ACUTE PHASE RESPONSE IN AS
An APR is evident in active AS.
• CRP is increased 1; levels may correlate with disease activity.2
• α1-Acid glycoprotein levels predict an increase in the radiologic
lumbar spine score in AS over 12 months.3
IMMUNE RESPONSE IN AS
• Increased IgA levels correlate with disease activity in AS.4
LABORATORY TESTING IN AS
Diagnosis
Monitoring
As for RA
CRP AAG SPE IgG, IgA, IgM
JUVENILE RHEUMATOID ARTHRITIS
CRP
+++
RF
+/-
IgG, IgA, IgM
+/-
C3/C4
+/-
93
Section I.B.
ANKYLOSING SPONDYLITIS
Juvenile rheumatoid arthritis (JRA) occurs in young patients and is a
heterogenous group of diseases that includes systemic-onset JRA (Still’s
disease), pauciarticular-onset JRA, and polyarticular-onset JRA.5 There
is much overlap of clinical presentation and age of onset between JRA
and adult RA. It is important to differentiate JRA from conditions with
similar presentations, such as rubella, as the outcome and treatment
are very different.
ACUTE PHASE RESPONSE IN JRA
Section I.B.
• CRP is usually elevated in active JRA and levels correlate with
disease activity.6 Most other acute phase protein levels change as
expected for an APR.1,7
• Complement C3 and C4 levels may be normal, due to coincident
APR-related increases and consumption by immune complex activation.8
• Elevated ferritin level (>3 mg/L) in a young patient suggests Still’s
disease when there is an acute febrile illness with no evidence of
infection.9,10 These levels are higher than expected for a simple
inflammatory state.
IMMUNE RESPONSE IN JRA
• Serum immunoglobulins are elevated in most patients with active
JRA.11,12 Increased IgA is associated with cartilage erosions.12,13
Hypogammaglobulinemia14 and selective IgA deficiency15 have also
been reported in JRA.
• ANA are uncommon in systemic-onset disease, but are seen in >50%
of those with pauciarticular disease,1,16 in which they are associated
with increased risk for chronic anterior uveitis.16,17
• Rheumatoid factor is seen in JRA in up to 35% of cases, especially
those with polyarticular disease.18,19
LABORATORY TESTING IN JRA
Diagnosis
Monitoring
As for RA
ANA-speckled
CRP
SPE
FER
C3, C4
MIXED CONNECTIVE TISSUE DISEASE
CRP
+
Alb
N/-
IgG, IgA, IgM
++
RF
N/++
ANA
++
C3/C4
N/-
Mixed connective tissue disease (MCTD) is a generalized connective
tissue disorder, most common among females, with clinical features of
SLE, scleroderma, and polymyositis. Subjects may have striking laboratory abnormalities for years yet few clinical complaints.
94
ACUTE PHASE RESPONSE IN MCTD
• CRP is elevated in MCTD, but to a lesser extent than in RA.20
• Low albumin suggests progression to more serious illness.21
IMMUNE RESPONSE IN MCTD
• Immunoglobulins may be markedly elevated (not diagnostic).20,21
• Antinuclear antibody (ANA) titer is usually high, with specificity
to ribonucleoprotein (RNP).22-24
• Rheumatoid factor is often very high, with little joint or lung
involvement.25
LABORATORY TESTING IN MCTD
Diagnosis
Monitoring
As for RA
Plus: ENA (RNP)
ANA
CRP
SPE
C3, C4
OSTEOARTHRITIS
CRP
+
SAA
+
C3/C4
N
Osteoarthritis (OA) occurs later in life and involves joints affected by
day-to-day trauma. Because classical rheumatic diseases can present
with similar symptoms, OA is often a diagnosis of exclusion, based on
the results of laboratory data.
ACUTE PHASE RESPONSE IN OA
• Low level increases in CRP are present in early OA of the knee and
predict progressive disease.26,27 Very modest CRP elevation (but not
ESR) is associated with clinical severity in OA of the knee or hip.28
This suggests that low-grade inflammation or necrosis is important
in OA. Long-term monitoring of CRP may be useful.27 Interpretation
of CRP data must take into account the possibility of coincident
inflammatory illnesses.
• Serum amyloid A is elevated in OA, but less so than in RA.27
• Complement C3 and C4 are normal in OA.8 Should changes be
found, the diagnosis must be re-evaluated.
95
Section I.B.
• Complement C3 and C4 are typically normal in MCTD; if levels are
low, this suggests either conversion to another rheumatic disease,
such as SLE, or that the true diagnosis is SLE.21
LABORATORY TESTING IN OA
Diagnosis
Monitoring
As for RA
CRP
POLYMYALGIA RHEUMATICA/GIANT CELL ARTERITIS
CRP
++
SAA
++
ACT
+
Section I.B.
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA, temporal
arteritis) are related disorders, each expressing vasculitic features and
typically seen at >50 years of age. In both, the APR is prominent.
ACUTE PHASE RESPONSE IN PMR/GCA
• CRP is increased 29, and levels may be extreme.25 The initial CRP
response to corticosteroids predicts therapeutic response.30
• Serum Amyloid A (SAA)31 and α1-antichymotrypsin (ACT)32
are also high in PMR/GCA; levels correlate with disease activity.14
LABORATORY TESTING IN PMR/GCA
Diagnosis
Monitoring
As for RA
CRP
SAA
ACT
POLYMYOSITIS/DERMATOMYOSITIS
CRP
+
AAT
+
AAG
+
Hp
+
C3/C4
N
Alb
-
PAL
-
Tf
-
IgG,A,M
+++
ANA
+
MYO
++
Polymyositis (PM) and dermatomyositis (DM) are rare idiopathic inflammatory myopathies with immunological features. In dermatomyositis,
there are also skin and nail changes. Patients are typically female,
presenting at 40 to 50 years of age with symmetric, proximal muscle
weakness. Histologic studies of involved muscle biopsy material
demonstrate characteristic changes of inflammation, mononuclear
infiltrates, and muscle cell necrosis.
ACUTE PHASE RESPONSE IN PM and DM
Serum protein changes characteristic of the APR (see pp. 1-9) are often
seen33,34, reflecting acute inflammation and myonecrosis.
• Albumin, prealbumin, and transferrin may be decreased.
• Haptoglobin, α1-antitrypsin, and CRP may be increased.
• Complement C3 and C4 are usually normal, unless an overlap
syndrome is developing.33
96
IMMUNE RESPONSE IN PM and DM
• One or more immunoglobulins may be extremely elevated.33
• There is a high frequency (90%) of ANA and anticytoplasmic
antibodies (anti-Jo-1 is the most common).35,36
• Immune complexes may be seen on SPE.33
OTHER FINDINGS IN PM and DM
• Muscle damage causes myoglobinemia (and myoglobulinuria).33
LABORATORY TESTING IN PM and DM*
Diagnosis
Monitoring
As for RA + ENA + Myoglobin
Urine myoglobin SPE Acute phase panel
Section I.B.
*In addition to serum enzyme testing (transaminase, creatine kinase, lactate
dehydrogenase, aldolase, carbonic anhydrase III).
RHEUMATOID ARTHRITIS (active)
RF
CRP
+++/- ++
SAA
++
AAG
+
ACT
+
AAT
+
CER
+
IgG,A,M
+
FN
+
C3/C4
+/-
FER
+/-
Alb
-
Rheumatoid arthritis (RA) is usually a symmetric, inflammatory, intermittently active polyarthritis that leads to deformity and destruction/erosion
of cartilage and bone.An autoimmune disorder (frequency 0.5 to 1.0%),
RF most often presents at ages 30 to 55 years.
ACUTE PHASE RESPONSE IN RA
Many of the serum protein changes associated with active RA are
related to inflammation (see pp. 1-9) and the APR.
• α1-Acid glycoprotein, α1-antichymotrypsin, α1-antitrypsin,
fibrinogen, and ceruloplasmin are elevated.37-39
• Albumin is decreased (levels are lower in RA than in SLE).40,41
• CRP and SAA are high in active RA.42,43 Suppression of elevated
CRP by anti-inflammatory therapy is associated with improvement
in functional score,43,44 while persistent CRP elevation suggests
progression and deterioration.45
• Fibronectin levels are frequently elevated in RA with extraarticular
manifestations, particularly vasculitis.46
• Complement C3 and C4 are typically increased in the APR;
however, levels may be normal or even low, due to coincident
activation and immune complex complement consumption.41,47
97
IMMUNE RESPONSE IN RA
• Polyclonal gammopathy is frequent in active RA and high, low,
or normal levels may be seen in the absence of clinical activity.41,48,49
IgM and IgA are often elevated.50,51 Elevated IgG is a prospective risk
factor for RF-positive RA.52 Rheumatoid factor (RF) and ANA are
common in RA.41,53 RF can fix complement and induce joint inflammation as the result of intraarticular immune complex formation.54,55
Very high RF values can cause hyperviscosity,56 and the pulmonary
complications of extreme elevations in RF can be dramatic.
Section I.B.
MEASUREMENTS RELATED TO DISEASE SEVERITY IN RA
• High titers of RF indicate more severe RA, with likely progression
of radiologic damage, and the development of vasculitis and other
systemic symptoms. The converse, however, is not true.54,57-59
• CRP and SAA levels correlate with disease activity.60 CRP predicts
both radiologic progression in RA42,43 and the response to therapy,30,61
and is useful in assessing the degree of inflammatory activity and
extent of synovial tissue injury.
• Complement C3 and C4 levels are low in severe, active disease.
They indicate the development of vasculitis as a complication.62
MEASUREMENTS CONFOUNDED IN RA
• In adult Still’s disease, serum ferritin levels are higher than expected
for a simple inflammatory state (>3.5 mg/L).63 Levels reflect disease
activity and can be used to guide therapy and to monitor treatment,
as they decrease with successful therapy.9
LABORATORY TESTING IN RA
Diagnosis
Monitoring
CRP
ANA
RF
AAG
Alb
IgG, IgA, IgM SPE
FER C3/C4
CRP ANA FER*
RF SPE C3/C4
* See text for details specific clinical circumstances.
SJÖGREN’S SYNDROME
IgG, IgA, IgM
++
ANA
N/+
RF
N/+
B2M
N/+
Sjögren’s syndrome (SjS) is a connective tissue disease marked by
inflammation and destruction of the salivary and lacrimal glands, causing
sicca symptoms (dry eyes, dry mouth); it may also involve exocrine
glands such as the pancreas. The disease may be primary (restricted to
salivary and lacrimal glands) or secondary to other rheumatic disease
(often RA). The serum protein profile in secondary SjS is consistent
with the changes associated with the primary disorder.
98
IMMUNE RESPONSE IN SjS
• Hypergammaglobulinemia is common in SjS and may precipitate
recurrent purpuric lesions,64 due to venous stasis secondary to
hyperviscosity. IgA is often elevated,65 and elevated IgG is seen in
children with primary SjS.66 Elevated IgG predicts development
of SjS in subjects with sicca symptoms.67
• Elevated ANA titers (speckled pattern) are typically seen and are
usually specific for Ro/SSA and/or La/SSB.68
• RF is elevated in ~70% of patients with juvenile SjS,69 and in a lower
percentage of patients diagnosed as adults.70
• β2-Microglobulin is elevated; high levels are associated with the
development of SjS among patients with sicca syndrome.66
Section I.B.
LABORATORY TESTING IN SjS
Diagnosis
As for RA
Monitoring
+ ENA
IgG, A, M
ENA (SSA, SSB)
SYSTEMIC LUPUS ERYTHEMATOSUS
Active
Inactive
CRP
Alb
C3/C4
Apo B
A2M
N
N
N/N
N/N
N/+
N
N/+
N
IgG,A,M
+/N
Hp
N/N
ANA
+++
+++
Systemic lupus erythematosus (SLE) is the classic autoimmune disease
and can affect any or all organs. The disease occurs most frequently in
women (M/F ratio of ~1/7) and presents most often in the 3rd and 4th
decades. Patients present in many ways reflecting the involvement of
the entire body in this process. Most frequent are arthralgia (often
periarticular), renal disease, rashes, alopecia areata, anemia, and
leukopenia.
ACUTE PHASE RESPONSE IN SLE
• Elevated CRP in SLE indicates infection, not inflammation.71 CRP
may be significantly suppressed by administered steroids; as a result
marked elevation is rare and given the name of Jacoud’s arthropathy.25
A marked elevation should prompt review of the diagnostic
possibilities, including infection.
IMMUNE RESPONSE IN SLE
• Hypergammaglobulinemia is frequent (cathodal IgG on SPE),
and the increases are correlated with disease severity; however,
hypogammaglobulinemia may occur with intense immune
complex deposition or the nephrotic syndrome.41,72
99
• Elevated IgM with low IgG and IgA suggests the nephrotic syndrome
(see Nephrotic Syndrome).
• Monoclonal gammopathy of unknown significance is seen
occasionally in SLE,73 as is cryoglobulinemia.74 The latter is a
marker for difficult therapeutic management.25
Section I.B.
• The key laboratory finding in SLE is the presence of multiple
autoantibodies, including ANA, anti-dsDNA, and specific ENAs.
The absence of elevated levels of ANA seriously questions the
diagnosis, the exception being during very active disease, C3
consumption, and primary C4 deficiency.75
• Complement C3 and C4 are decreased in SLE with active nephritis
due to active immune complex deposition;41,76 thus, C3 and C4 are
used to assess disease activity.8 Total C4 deficiency is rare and is
associated with an SLE-like syndrome.77
PROTEIN CHANGES DUE TO DISEASE COMPLICATIONS IN SLE
• α2-Macroglobulin, IgM, haptoglobin, if phenotype is 2-1 or 2-2,
and apo B are elevated in SLE-associated nephrotic syndrome
(see Renal Disease).78
• Albumin levels may be decreased due to inflammation, malnutrition,
nephrotic syndrome, or protein-losing gastroenteropathy (increased
mucosal permeability).78
• Low haptoglobin indicates intravascular hemolysis. Autoimmune
hemolytic anemia may occur in SLE due to the presence of IgG
autoantibodies against erythrocyte surface antigens.79,80
LABORATORY TESTING IN SLE
Diagnosis
Monitoring
ANA
dsDNA
ENA
ANA
dsDNA
C3, C4
SPE
Alb
IgG,A,M*
FER*
CRP*
Apo B*
Hp*
A2M*
CRYO*
* See text for details of specific circumstances.
SYSTEMIC SCLEROSIS/SCLERODERMA
IgG,A,M
+/+++
ANA
+/-
RF
+/-
Systemic sclerosis/scleroderma (SSc) comprises a heterogenous group
of disorders, typically characterized by the presence of smooth, thickened, leathery skin, most frequently occurring among women 40 to 50
years of age. The disease may be localized, primarily affecting the skin,
or systemic, with variable degrees of visceral and vascular involvement.
100
IMMUNE RESPONSE IN SSc
• Immunoglobulin levels show mild to massive increases.25,81
• Most patients have ANA82,83 (nucleolar and centromere patterns are
common.83 Centromere pattern may indicate CREST syndrome—
calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly,
and telangiectasia84,85). Specific ENA against Scl-70 are seen in 75% of
patients with diffuse scleroderma and lung involvement.86
• Rheumatoid factor (RF) may be elevated, especially among those
with overlap syndromes.81
• NOTE: There may be no laboratory evidence of autoimmunity
despite severe and progressive dermal involvement.25
Section I.B.
ACUTE PHASE RESPONSE IN SSc
There is often little or no laboratory evidence of inflammation.81
LABORATORY TESTING IN SSc
Diagnosis
As for RA
Monitoring
+ ENA
ANA
SPE
ENA
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37. Lacki JK, Klama K, Porawska W, Mackiewicz SH, Muller W,Wiktorowicz K.
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41. Fye KH, Sack KE. Rheumatic Diseases. In: Stites DP,Terr AI, eds. Basic and
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outcome. J Rheumatol. 1997;24:9-13.
43. Blackburn WD Jr.Validity of acute phase proteins as markers of disease
activity. J Rheumatol. 1994;42 (suppl):9-13.
44. Dawes PT, Fowler PD, Clarke S, Fisher J, Lawton A, Shadforth MF. Rheumatoid
arthritis: treatment which controls the C-reactive protein and erythrocyte
sedimentation rate reduces radiologic progression. Br J Rheumatol. 1986;25:
44-49.
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45. Otterness IG.The value of C-reactive protein measurement in rheumatoid
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47. Franco AE, Schur PH. Hypocomplementemia in rheumatoid arthritis. Arth
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49.Adhya S, Chakraborty G, Hajra B, et al. Serology and immunoglobulin profile in
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50. Jorgensen C, Anaya JM, Cognot C, Sany J. Rheumatoid arthritis associated with
high levels of immunoglobulin A: clinical and biological characteristics. Clin Exp
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51. Kloppenburg M, Dijkmans BA,Verweij CL, Breedveld FC. Inflammatory and
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54. Moore TL, Dorner RW. Rheumatoid factors. Clin Biochem. 1993;26:75-84.
55. Mannik M. Rheumatoid factors in the pathogenesis of rheumatoid arthritis.
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58. Paimela L, Palosuo T, Leirisalo-Repo M, Helve T, Aho K. Prognostic value of
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106
Section II: General Information on Serum Proteins
ALBUMIN (ALB)
Function: Alb is the predominant plasma protein, comprising more than half
of the total protein in normal serum. It has numerous functions including:
• maintaining the colloidal osmotic pressure within the vasculature;
• providing a source of amino acid for protein synthesis;
• serving as a transport protein for many metallic ions, drugs, vitamins,
hormones, and bilirubin; and
• functioning as an antioxidant.
Clinical Significance: Alb has long been used as an indicator of general
protein status; however, its reliability as a marker of nutritional status
is compromised due to its long half-life (19 days) and its diminished
synthesis in most inflammatory processes.
Reference Range1,2:
Age (yrs.)
Males
0 to 1
2 to 30
31 to 50
>50
35.5
36.6
36.1
33.4
to
to
to
to
50.0
55.2
53.6
50.9
Females
g/L
g/L
g/L
g/L
36.3
35.0
35.1
33.0
to
to
to
to
50.0
54.0
51.4
49.7
g/L
g/L
g/L
g/L
Decreased Levels:
• APR (inflammation,
infection, trauma,
surgery, malignancy)
• Severe liver disease
• Nephrotic syndrome
• Other renal disease
•
•
•
•
Malnutrition
Pregnancy
Genetic analbuminemia (rare)
Premature infants
Indications for Quantification: Perhaps the most important role of
Alb is that of prognostication. Alb is used in long-term chronic care
settings to detect changes in nutritional status and to monitor progress
during therapy (see prealbumin/transthyretin); monitoring liver disease;
adding perspective in the evaluation of local central nervous system
synthesis of IgG (with serum: CSF IgG ratio).
Genetic Variants: More than 80 alleles have been described.
Homozygous deficiency is rare and is associated with minimal edema
due to equilibration, as well as compensatory hyperglobulinemia.
Indications for Phenotyping: Population genetics and linkage studies
in families with variants.
Alb References:
Whicher J, Johnson AM. Hypoproteinemia. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
Scarborough, ME: Foundation for Blood Research; 1998:103.00.1-103.00.15.
Podolsky DK, Isselbacher KJ. Evaluation of liver function. In: Fauci AS, Braunwald E, Isselbacher
K, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York, NY; McGraw-Hill Co;
1998:1663-1667.
Mr: 66.3 kDa
EP Zone: Albumin
107
Section II
Increased Levels: Rare, usually associated with hemoconcentration.
ALPHA-1-ACID GLYCOPROTEIN (Orosomucoid) (AAG)
Function: Although its physiologic role is uncertain, AAG (like albumin)
binds and transports many basic drugs and hormones, particularly
compounds such as quinidine, propranolol, and certain antibiotics and
steroids. AAG aids in maintaining the negative charge of the glomerular
basement membrane. In vitro, AAG modifies platelet adhesive capacity
and has apparent immunoregulatory functions.
Clinical Significance: AAG is especially useful in monitoring early acute
phase responses. Levels are also helpful in distinguishing inflammatory
processes (elevated levels) from estrogen effects (normal or depressed
levels), since both processes affect most other reactants similarly.
In uncomplicated acute phase response, AAG levels should rise in
concordance with changes in the other acute phase proteins.
Reference Range3:
Age (yrs.)
Section II
0 to 1
2 to 10
11 to 50
>50
Males and Females
0.11
0.45
0.45
0.55
to
to
to
to
1.49
1.48
1.28
1.42
g/L
g/L
g/L
g/L
Increased Levels:
• ~2 to 4 fold
increase in the
APR (inflammation,
infection, trauma,
surgery, malignancy)
• Rheumatoid arthritis
• Pneumonia
• Recurrence of
many tumors (kidney,
adrenal, lung, etc.)
• Chronic renal failure
• Androgen use
• Corticosteroid therapy
• Estrogen therapy
• Newborns
• Severe hepatic damage
• Malnutrition
Decreased Levels:
• Pregnancy
Indications for Quantification: Confirmation of acute phase response
(use in conjunction with haptoglobin to detect in vitro hemolysis), since
both processes affect most other reactants similarly. Differentiation
of acute phase response from estrogen effects and monitoring tumor
recurrence. A lack of agreement among protein levels can indicate in vivo
hemolysis or immune complex consumption of anti-inflammatory drugs.
AAG References:
Whicher J, Bienvenu J. Orosomucoid. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
Dinarello CA.The acute phase response. In: Bennett JC, Plum F, eds. Cecil Textbook of Medicine.
20th edition. Philadelphia, PA:W.B. Saunders Co;1996:1535-1537.
108
Mr: 40 kDa
EP Zone: α1
ALPHA- 1- ANTICHYROMOTRYPSIN (ACT)
Function: ACT is one of a family of antiproteases that also includes
AAT. Physiologically, its major function is the inhibition of cathepsin G
enzyme found in the azurophilic granules of leukocytes and secreted
during phagocytosis.
Clinical Significance: ACT is one of the earliest responding acute
phase reactants; thus, it may be assayed to determine the presence of
inflammation or tissue necrosis. A deficiency state has been described
which may predispose to obstructive lung disease and influence the
course of liver disease.
Reference Range4:
Adult: 0.3 to 0.6 g/L
Increased Levels:
• Acute phase response (inflammation,
infection, trauma, surgery, malignancy)
• Rheumatic diseases
• Liver disease
• Ulcerative colitis
• Crohn’s disease
Decreased Levels:
• Status asthmaticus
• Cold urticaria
• Newborns and infants
Section II
Indications for Quantification: Confirmation of the acute phase
response; evaluation of liver disease complications.
ACT References:
Whicher J.The acute phase response. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
Dinarello CA.The acute phase response. In: Bennett JC, Plum F, eds. Cecil Textbook of Medicine.
Mr: 68 kDa
EP Zone: slow α1 to α2 interzone
109
ALPHA-1-ANTITRYPSIN (AAT)
Function: AAT inhibits all serine proteases; however, its main function
is to inhibit neutrophil elastase.
Clinical Significance: Severe inherited deficiency of AAT is associated
with increased risk for development of liver disease in children (neonatal hepatitis syndrome, infantile cirrhosis) and chronic lung disease in
adults aged 30 to 50 years (emphysema, chronic bronchitis). Among
AAT deficient subjects of Northern European origin, there is an
increased incidence of hepatoma.
Reference Range5:
Age (yrs.)
0 to 1
2 to 10
11 to 50
>50
Males
0.84
0.88
0.84
0.88
to
to
to
to
1.67
1.71
1.63
1.85
Females
g/L
g/L
g/L
g/L
0.86
0.89
0.89
0.89
to
to
to
to
1.76
1.86
1.87
1.90
g/L
g/L
g/L
g/L
Increased Levels:
Section II
• ~4-fold in the APR
• Pregnancy
• Estrogen or androgen therapy
• Acute hepatitis
• Active liver disease including
alcoholism
• Malignant tumors
Decreased Levels:
• Inherited deficiency
• Idiopathic respiratory distress syndrome
• End-stage pancreatic
or liver disease
• Malnutrition and cachexia
Indications for Quantification: Decreased AAT band on electrophoresis;
neonatal hepatitis syndrome; chronic obstructive pulmonary disease;
unexplained cirrhosis (in all age groups); assessment of acute phase
response; study of at-risk family members.
Genetic Variants: Approximately 75 inherited variants of AAT have
been reported, but only a few (null, Z, S, and P) are associated with
serum levels low enough to be associated with disease, especially if
homozygous or present in certain heterozygous combinations.
Indications for Phenotyping: Marked reduction in serum level (~1/2
the normal mean concentration in the absence of the acute phase
response or estrogen effects), family studies, and population genetics.
AAT References:
Jeppsson J-O. α1-Antitrypsin. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine. Scarborough,
ME: Foundation for Blood Research; 1998:8.01.1-8.01.8.
Cox DW. α1-Antitrypsin Deficiency. In: Scriver CR, Beaudet AL, Sly WS,Valle D, eds.
The Metabolic and Molecular Basis of Inherited Disease, 7th ed. New York, NY: McGraw-Hill Co;
1995:4125-4158.
110
Mr: 52 kDa
EP Zone: α1
ALPHA-1-MICROGLOBULIN (Protein HC) (A1M)
Function: A1M is a member of the lipocalin superfamily that carries
hydrophobic prosthetic groups. It exists in three forms (free, bound
to IgA, and bound to albumin) each differing in structure. Although
its precise function is unclear, A1M has been shown to exert an
immunosuppressive effect in vivo on chemotaxis and on lymphocyte
response to antigen.
Clinical Significance: Serum A1M has a higher diagnostic sensitivity
than creatinine for detecting a decrease in glomerular filtration rate,
particularly in the so-called blind region of decrease of glomerular
function rate. As a small, stable urinary protein, A1M is an indicator
of acute and chronic dysfunction of the proximal renal tubule.
Measurement of the urinary A1M/Albumin ratio permits differentiation
of primary and secondary forms of glomerular disease.
Reference Range6,7:
Adult, serum (free A1M): 14 to 36 mg/L
Adult, urine (2nd morning void): 1.58 g/mol creatinine
Increased Levels:
• Behçet’s syndrome
• Severe burns (A1M is not
an acute phase protein)
• Pregnancy
• Interstitial nephritis
• Combined nephritides (glomerular
basement membrane and proximal
renal tubule disease)
Decreased Levels:
Serum:
• Severe liver disease (decompensated cirrhosis and fulminant hepatitis).
Urine:
• Similar as for serum.
Indications for Quantification: Detection and quantification of A1M in
nephritides, advanced diabetic nephropathy, exposure to heavy metals,
or post administration of nephrotoxic drugs, indicate tubular damage.
A1M References:
Guder WC, Johnson AM. a1-Microglobulin. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
Weber MH,Verwiebe R. Alpha-1-Microglobulin (Protein HC): Features of a Promising Indicator
of Proximal Tubular Dysfunction. Eur J Clin Chem Clin Biochem. 1992:30:683-692.
Mr: 31 kDa
EP Zone: α1 (free protein)
111
Section II
Serum:
• End-stage renal disease (up to 10-fold)
• IgA myeloma
• IgA nephropathy
• Decreased glomerular filtration rate
Urine:
• Renal tubular disease
• Non-renal causes of fever and urinary
tract infections including
acute pyelonephritis
• Cadmium poisoning
ALPHA-2-MACROGLOBULIN (A2M)
Function: A2M is a relatively nonspecific inhibitor of most endoproteases, including enzymes involved in blood coagulation, clot lysis, complement “cascades,” collagenases from white blood cells, and lysosomal
cathepsins. It also serves as a transport protein for cytokines, certain
hormones, and metals, particularly zinc.
Clinical Significance: A2M is important in the rapid control and
removal of active proteases from the circulation. A2M is distributed
intravascularly (due to its large molecular size) and is an indicator of
membrane permeability in serum and fluids (eg, CSF). Recent studies
suggest that A2M may have a role in the modulation of local inflammatory reactions and tissue repair in glomerular disease.
Reference Range8:
Age (yrs.)
0 to 1
2 to 10
11 to 30
>30
Males
1.72
2.74
1.28
1.10
to
to
to
to
5.52
5.59
5.00
3.13
Females
g/L
g/L
g/L
g/L
1.72
2.58
1.52
1.40
to
to
to
to
5.16
4.95
4.48
3.67
g/L
g/L
g/L
g/L
Section II
Increased Levels:
• Nephrotic syndrome (marked increase)
• Diabetes mellitus
• Liver cirrhosis (moderate increase)
• Pregnancy
Decreased Levels:
• Final days of life in the critically ill
(marked decrease)
• Acute pancreatitis
• Fibrinolysis and DIC
(moderate decrease)
• Stress
• Post-surgery
• Liver disease
• Onset of puberty
(marked decrease)
Indications for Quantification: Single values not useful in differential
diagnosis. Sequential A2M values helpful in clinical monitoring of
nephrotic syndrome and assessment of various proteolytic conditions
(eg, pancreatitis).
A2M References:
Davis AE. a2-Macroglobulin. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine. Scarborough,
112
Mr: 725 kDa
EP Zone: α2
ANTITHROMBIN III (AT III)
Function: AT III is the main glycoprotein and inhibitor of thrombin and
clotting factors IXa, Xa, XIa, and XIIa.
Clinical Significance: AT III is essential for the control of thrombin
activity, as evidenced by the markedly increased tendency of individuals
who are genetically deficient, pregnant, or taking estrogen therapy
toward development of thrombotic and embolic disease. The heparin
effect as measured by in vitro tests depends upon the presence of AT
III-heparin complexes.
Reference Range9:
Adult: 0.21 to 0.30 g/L
Increased Levels:
• Acute phase response (inflammation,
infection, trauma, surgery, malignancy)
• Vitamin K deficiency
• Heparin therapy, functional increase
Decreased Levels:
• Acute thrombosis
• DIC
• Other consumptive
coagulopathies
• Infancy (markedly
decreased in hyaline
membrane disease)
Indications for Quantification: Evaluation of patients at risk for
thrombotic-embolic disease (in suspected genetic deficiency, assay when
clinically well and test other family members). Assessment of thrombotic risk of contraceptive or other estrogen therapy (levels should be
assayed before and after onset of therapy), and in surgical patients
receiving heparin.
Genetic Variants: Deficiency is inherited as an autosomal codominant
trait. In Type I deficiency, individuals have immunological and functional
levels that are reduced by 30% to 60% of normal mean levels. In type II
deficiency, functional activity is significantly reduced, whereas immunologic activity remains unchanged. Assays using AT III-heparin cofactor
indicates that the frequency of AT III deficiency is ~1 in 350 in the general population. Complete homozygosity (estimated to be 1 in 2500)
has not been described and is presumed to be lethal during fetal life.
AT III References:
Mosher DF. Disorders of blood coagulation. In: Bennett JC, Plum F, eds. Cecil Textbook of
Medicine. 20th edition. Philadelphia, PA:W.B. Saunders Co;1996:997-998.
Cosgriff TM, Bishop DT, Hershgold EJ, et al. Familial atithrombin III deficiency: Its natural
history, genetics, diagnosis and treatment. Medicine. 1983;62:09-220.
Mr: 58 kDa
EP Zone: Inter α to α2
113
Section II
• Some contraceptive
medications
• Heparin therapy
• Chemotherapeutic drugs
(acute or chronic)
APOLIPOPROTEIN A-1 (Apo A-1)
Function: Apo A-I, the major structural protein component of
high-density lipoprotein, serves as a cofactor for lecithin-cholesterol
acyltransferase, the enzyme that catalyzes the esterification of cholesterol. In addition, Apo A-I contributes to the antiatherogenic role of
high-density lipoprotein by enhancing reverse cholesterol transport.
Clinical Significance: Apo A-I is an independent risk factor for
coronary artery disease (possibly more important in women than in
men). Low levels are associated with an increased risk for coronary
artery disease, whereas high levels are protective.
Reference Range10:
Age (yrs.)
Males
Females
0 to 1
2 to 60
>60
0.61 to 1.64 g/L
0.89 to 1.86 g/L
0.73 to 1.86 g/L
0.59 to 1.69 g/L
0.86 to 2.23 g/L
0.91 to 2.24 g/L
Increased Levels:
Section II
• Familial hyper-alphalipoproteinemia
• Modest alcohol intake
• Estrogen use
• Exercise
• Some drugs
• Thyroid hormones
Decreased Levels:
• Familial lecithin-cholesterol • Familial and non-familial
• Smoking
acyl-transferase deficiency
hypoalphalipoproteinemia • Chronic renal failure
• Tangier disease
• Diabetes
• Liver disease
• Hypertriglyceridemia
• Androgen use
Indications for Quantification: Total cholesterol in upper quartile
for age and sex, coronary artery disease risk profiling, and personal or
family history suggestive of arteriosclerotic vascular disease.
Genetic Variants: At least 7 variants described. Markedly decreased
HDL and Apo A-I levels are seen in Tangier disease, a rare autosomal
recessive disorder associated with corneal opacity and xanthomata
with splenomegaly or hepatomegaly, but with no apparent increased
risk for coronary artery disease.
Apo A-I References:
Ginsberg HN, Goldberg IJ. Disorders of lipoprotein metabolism. In: Fauci AS, Braunwald E,
Isselbacher K, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York, NY;
McGraw-Hill Co; 1998:2138-2148.
Craig WY, Stein E. Apolipoprotein A-I. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
114
Mr: 28.3 kDa
EP Zone: α1 interzone
APOLIPROTEIN B (Apo B)
Function: Apo B exists as Apo B100 and Apo B48. Both have roles
in cholesterol metabolism. Apo B100, synthesized by the liver, is the
ligand that binds low-density lipoprotein (LDL) to receptors on cells,
facilitating the transport of cholesterol from LDL into various tissues.
Apo B48 (synthesized by the intestine) is involved in the metabolism of
chylomicron remnants by the liver.
Clinical Significance: Since each LDL particle contains one Apo B100
molecule, Apo B, it is a good marker of LDL levels. Elevated Apo B
levels are associated with atherosclerosis (coronary artery disease,
myocardial infarction, stroke).
Reference Range11:
Age (yrs.)
0 to 1
2 to 20
21 to 50
>50
Males
0.16
0.48
0.53
0.54
to
to
to
to
1.24
1.29
1.73
1.69
Females
g/L
g/L
g/L
g/L
0.17
0.52
0.55
0.64
to
to
to
to
1.20
1.35
1.72
1.82
g/L
g/L
g/L
g/L
Increased Levels:
• Corneal arcus
• Hepatosplenomegaly
• Apolipoprotein E4
phenotype
• Chronic renal disease
• Tangier disease
• Hypothyroidism
• Acute inflammation
• Exercise
• Liver disease
• Moderate alcohol
intake
• Apolipoprotein
E2 phenotype
• Neurologic disease
• Certain medications
Decreased Levels:
• Familial
hypobetalipoproteinemia
• Abetalipoproteinemia
• Neuromuscular degeneration
• Chronic anemia
Indications for Quantification: Family history of coronary artery
disease, premature cardiovascular disease, xanthelasma, tendon
xanthoma, cardiac profiling, and coronary artery disease patients
with LDL-C >1.3 g/L.
Genetic Variants: At least 25 variants associated with hypobetalipoproteinemia.
Indications for Phenotyping: Population genetics, linkage studies.
Apo B References:
McGraw-Hill Co; 1998:2138-2148.
Craig WY. Apolipoprotein B. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine. Scarborough,
Mr: Apo B100 - 540 kDa; Apo B48 - 241 kDa
EP Zone: β1 to β2 interzone 115
Section II
• Premature atherosclerosis
• Familial defective Apo B100
• Familial hypercholesterolemia
• Hyperapobetalipoproteinemia
• Tendon xanthomata
BETA-2-MICROGLOBULIN (B2M)
Function: B2M is a transmembrane protein found on all cells that
carry HLA antigens; however, its precise immunological function is
unknown. It is cytotoxic to lymphocytes in the presence of complement and may be involved in the recognition phase of the immune
response.
Clinical Significance: Free B2M is a product of cell breakdown. After
filtration through the glomeruli B2M is reabsorbed and catabolized by
the proximal tubular cells. Decreased glomerular filtration is associated
with high serum levels of B2M, whereas tubular insufficiency is associated with normal serum and high urine levels. In multiple myeloma and
leukemia, B2M is an important prognostic factor as increased levels of
this protein are associated with a worse outcome.
Reference Range12:
Age (yrs.)
Males and Females
<60
>60
8 to 24 mg/L
8 to 30 mg/L
Section II
Increased Levels:
Serum:
• Decreased glomerular
filtration
• Lymphoproliferative
disorders
• Myeloma
• Other malignancies
• Sjögren’s syndrome
• Viral infections
(eg, AIDS, CMV)
• Dialysis related
amyloidosis
• Anti-cancer drugs
• Certain anti-inflammatory
compounds (especially
corticosteroids)
• End-stage renal disease
• Newborns
Urine: Tubular proteinurias (eg, cadmium nephrotoxicity), renal transplant rejection.
Synovial fluid: Active rheumatoid arthritis; Saliva: Severe Sjögren’s syndrome
CSF: Some malignant tumors, following subarchnoidal bleeding, multiple sclerosis
patients with severe neurologic dysfunction
Decreased Levels:
Serum/Urine: None reported.
Indications for Quantification: Differentiation of glomerular and
tubular nephropathies, as well as early detection of renal transplant
rejection. Useful in the clinical evaluation of patients with neoplastic
diseases, wherein B2M is related to prognosis and disease activity.
Monitoring the therapeutic response of patients with nonsecretory
myeloma or light chain disease.
B2M References:
Davis AE. Genito-urinary protein loss. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
Cooper DL:Tumor markers. In: Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th
edition. Philadelphia, PA:W.B. Saunders Co;1996:1023-1024.
116
Mr: 11.8 kDa
EP Zone: β1 to β2 interzone
CERULOPLASMIN (Cp)
Function: Cp is a copper oxidase enzyme that serves as a ferroxidase
and in the maintenance of hepatic copper homeostasis.
Clinical Significance: Cp levels are decreased in hepatolenticular
degeneration (Wilson’s disease), which is characterized by an inability
to incorporate copper into Cp and other proteins, and in Menke’s
disease (kinky hair syndrome) due to poor uptake and utilization of
dietary copper. There is a rare congenital deficiency of Cp which
presents as a hereditary hemochromatosis-like syndrome.
Reference Range13,14:
Age (yrs.)
Males and Females
0.5 to 3
4 to 12
13 to 19
>19
0.26
0.25
0.15
0.20
to
to
to
to
0.90
0.46
0.50
0.60
g/L
g/L
g/L
g/L
Increased Levels:
•
•
•
•
Bile duct obstruction
• APR (inflammation, infection, • Physical exercise
Primary biliary cirrhosis trauma, surgery, malignancy) • Pregnancy (late)
Hypoplastic anemia
Leukemia
• Wilson’s disease
(if no inflammation)
• ~10% of asymptomatic
heterozygote carriers of
the Wilson’s disease gene
•
•
•
•
Menke’s disease
Nephrotic syndrome
Severe liver disease
Primary sclerosing
cholangitis
• Acute viral hepatitis
• Gastroenteropathies
• Malnutrition
(hypochromic anemia)
Indications for Quantification: Unexplained hepatitis; liver cirrhosis
or neurologic manifestations of unknown origin, especially in young
adults (Wilson’s disease); chronic or recurring lack of coordination
(Wilson’s disease); presence of Kayser-Fleischer rings (Wilson’s disease);
malnutrition with “kinky” hair (Menke’s disease); and monitoring of
the acute phase response. Evaluation of hypochromic anemia and
patients with hereditary hemochromatosis-like symptoms if not true
hemochromatosis.
Genetic Variants: Two rare variants (A and C); however, all reported
variants function normally.
Indications for Phenotyping: Population genetics, forensic (paternity
and identity testing).
Cp References:
Johnson AM. Ceruloplasmin. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine. Scarborough,
Scheinberg IH.Wilson’s disease. In: Fauci AS, Braunwald E, Isselbacher K, et al, eds. Harrison’s
Principles of Internal Medicine. 14th ed. New York, NY; McGraw-Hill Co; 1998:2166-2169.
Mr: 132 kDa
EP Zone: Inter-α to α2
117
Section II
Decreased Levels:
COMPLEMENT COMPONENT (C3)
Function: C3 is the rate-limiting factor for both the classic and the
alternative complement pathways. In addition, C3 is necessary for
activation of the late-reacting factors (C5-9) which may result in lysis
of red cells, bacteria, and viruses.
Clinical Significance: Decreased levels of C3 (and C4) indicate
evidence of complement activation, decreased synthesis, protein loss,
or consumption. Deficiency (total or partial) of C3 is associated with
severe, recurrent infections and with increased risk of SLE. C3 fixation
on red cells and in tissue may result in an autoimmune hemolytic
disorder or severe tissue damage, respectively. C3 is consumed in
many autoimmune diseases.
Reference Range15:
Age (yrs.)
0 to 1
2 to 30
31 to 50
>50
Males
0.58
0.80
0.84
0.76
to
to
to
to
1.49
1.56
1.64
1.64
Females
g/L
g/L
g/L
g/L
0.58
0.84
0.84
0.76
to
to
to
to
1.51
1.68
1.75
1.81
g/L
g/L
g/L
g/L
Section II
Increased Levels:
• APR (inflammation, infection, trauma,
surgery, malignancy); response is
usually delayed 3 to 7 days
• Biliary obstruction
•
•
•
•
Obstructive jaundice
Diabetes mellitus
Gout
Some connective tissue diseases
(excluding SLE)
Decreased Levels:
• Autoimmune diseases
• Immune complex
diseases (eg, acute
glomerulonephritis and
lupus erythematosus
with renal involvement
•
•
•
•
•
Mixed cryoglobulinemia
Serum sickness
Late stage liver disease
Familial hemolytic
uremic syndrome
• Thrombotic
thrombocytopenic
purpura
• Neonatal respiratory
distress syndrome
• Genetic deficiency
(rare)
Indications for Quantification: Severe, recurrent bacterial infections;
suspected autoimmune renal disease; monitoring progression or clinical
activity of acute glomerulonephritis; SLE; assessment of the subacute
phase response.
Genetic Variants: Many variants (autosomal codominant inheritance),
some with disease implications.
C3 References:
Whicher J. Complement component C3. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
Haynes B, Fauci A. Disorders of the immune system, connective tissue, and joints. In: Fauci AS,
Braunwald E, Isselbacher K, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York,
NY; McGraw-Hill Co; 1998:1753-1776.
118
Mr: 185 kDa
EP Zone: β1 to β2
COMPLEMENT COMPONENT (C4)
Function: C4 is activated in the classic complement pathway. It is
cleaved by C1 esterase into C4a and C4b. This reaction enables
C4b to bind covalently to groups of cells, proteins, other biologic
membranes, and certain drugs.
Clinical Significance: C4 is essential for activation of the classic
complement pathway. Levels may be markedly reduced in the presence
of classic pathway activation or in incomplete genetic deficiency. The
latter may be associated with a high prevalence of systemic lupus
erythematosus and recurrent infections.
Reference Range16:
Age (yrs.)
0 to 1
2 to 20
21 to 50
>50
Males
0.07
0.12
0.15
0.16
to
to
to
to
Females
0.40
0.43
0.48
0.49
g/L
g/L
g/L
g/L
0.07
0.13
0.15
0.14
to
to
to
to
0.41
0.44
0.50
0.52
g/L
g/L
g/L
g/L
Increased Levels:
• Temporal arteritis
• Acute viral hepatitis
• Myocardial infarction
• Malignancies
• Thyroiditis
• Irritable bowel
disease
• Pneumonia
• Pregnancy
Decreased Levels: Acquired deficiencies resulting from:
Hypercatabolism:
• Any disease in which circulating
immune complexes are likely to lead
to acquired hypocomplementemia
(eg, SLE, RA, auto-immune hemolytic
anemia); subacute bacterial endocarditis;
essential mixed cryoglobulinemia;
progressive glomerulonephritis; and
hereditary angioneuroticedema
(see C1-esterase inhibitor)
Hyposynthesis:
• Protein-calorie malnutrition
• Liver disease
Congenital deficiencies:
• Associated with increased frequency
of scleroderma
• C4a deficiency predisposes to
development of end-stage renal
failure in IgA nephropathy; chronic
hepatitis; Henoch-Schönlein purpura;
and, auto-immune hepatitis
Indications for Quantification: Whenever a complement-activating
disease is suspected or diminished synthesis due to inherited deficiency
is a possibility (assay along with C3). Screening for hereditary
angioneurotic edema and evaluation of SLE, post-strep glomerulonephritis, and autoimmune hemolytic anemia.
C4 References:
Johnson AM. Complement component C4. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
Haynes B, Fauci A: Disorders of the immune system, connective tissue, and joints. In: Fauci AS,
NY; McGraw-Hill Co; 1998: 1753-1776.
Mr: 206 kDa
EP Zone: β1
119
Section II
• Acute phase response
• Systemic lupus erythematosus
• Rheumatic fever
• Ankylosing spondylitis
C1 ESTERASE INHIBITOR (C1 INH)
Function: C1 INH is a primary regulator of complement activation.
It also inhibits the fibrinolytic enzyme plasmin, the kinin-forming system
enzyme kallikrein, and the coagulation system enzymes (factors XI
and XII).
Clinical Significance: Inherited deficiency and nonfunctional variants
are associated with hereditary angioneurotic edema, an infrequent (1 in
2000) but potentially fatal condition associated with recurring swelling
of the subepithelial tissues of the skin, larynx, peritoneal lining, and the
gastrointestinal tracts. Abrupt onset of laryngeal edema can be fatal.
Onset of symptoms is usually late teens to early 20s and commonly
triggered by surgery, trauma, or stress.
Reference Range17:
Adult: 8 to 19.5 mg/L
Increased Levels:
• Acute phase response (inflammation, infection, trauma, surgery, malignancy)
• Some dysfunctional genetic variants
Section II
Decreased Levels:
• 80% to 85% of individuals with hereditary angioneurotic edema. Acquired
deficiency of C1 INH associated with either an autoantibody to C1 INH or
by excessive utilization as in lymphoma.
Indications for Quantification: Family history suggestive of hereditary
angioneurotic edema. If only immunoassay is done in screening, C4
should also be assayed, since 15% to 20% of patients have normal or
elevated levels of nonfunctional inhibitor. If C4 is depressed and
history suggests hereditary angioneurotic edema, functional assay of
the inhibitor should be performed. Most functional and nonfunctional
variants have altered electrophoretic mobility and can be detected
by immunofixation.
Genetic Variants: There are 2 forms of hereditary angioneurotic
edema variants, each inherited with autosomal dominant characteristics: one characterized by a deficiency of C1 esterase in serum (quantitative variant) and the other is a structural variant that is inactive and
results in normal levels when measured immunochemically and can
lead to hereditary angioneurotic edema.
Indications for Phenotyping: Evaluation of potential nonfunctional
variants by immunofixation.
C1 INH References:
Whicher J. C1-esterase inhibitor. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
Austen KF. Disorders of immediate type hypersensitivity. In: Fauci AS, Braunwald E, Isselbacher
1998:1660-1668.
120
Mr: 105 kDa
EP Zone: α2
C-REACTIVE PROTEIN (CRP)
Function: In the presence of calcium ions, CRP promotes phagocytosis
of many bacteria, immune complexes, and other foreign substances by
activating the classic complement pathway in the absence of specific
antibody. Recently, CRP has been shown to activate monocytes, causing the expression of tissue factor, an initiator of coagulation.
Clinical Significance: CRP is the archetypal acute phase protein and
plays an important role in early defense of certain infections. It is one
of the most consistently elevated (levels may rise more than 1000-fold
during an acute phase response) and fastest reacting acute phase proteins and is therefore a useful marker for disorders with inflammation
or tissue necrosis. Sequential analysis is preferred for therapeutic
monitoring.
Reference Range13:
Adults and children: <5 mg/L (assay dependent)
Increased Levels:
• Malignancies with
widespread metastases
• Renal transplant
failure
• Early pregnancy
• Intrauterine devices
• Viral infection does
not of itself induce
increased levels
of CRP
Decreased Levels:
• No known deficiency states described.
Indications for Quantification: Assessment of the activity, extent,
and course of inflammatory processes; differentiation of viral/bacterial
infections; monitoring for post-surgical complications and antimicrobial
therapy; monitoring patients who are immunosuppressed either from
chemotherapy or from disease for potential bacterial infection; late
stages of high-risk pregnancy; and as a prognostic marker for coronary
heart disease in patients with unstable angina. Nonsteroidal antiinflammatory drugs as well as corticosteroids cause elevated levels
to return to normal.
CRP References:
Bienvenu J,Whicher J, Aguzzi F. C-reactive protein. In: Ritchie RF, ed. Serum Proteins in Clinical
Medicine. Scarborough, ME: Foundation for Blood Research; 1996:7.01.1-7.01.6.
Dinarello CA: The acute phase response. In: Bennett JC, Plum F, eds. Cecil Textbook of Medicine.
Mr: 118 kDa
EP Zone: β to γ2 (Ca2+ dependent)
121
Section II
• Bacterial infections
• Rheumatic fever
• Active rheumatoid arthritis
• Vascular disorders
CYSTATIN C (Cys C)
Function: As a member of the cystatin superfamily, Cys C inhibits
most cysteine proteases of the papain type and other peptidases that
have a sulfhydryl group at the active site.
Clinical Significance: Due to its low molecular weight and relatively
constant rate of production (unaffected by inflammation or diet), serum
or plasma levels of Cys C are more closely correlated with glomerular
filtration rate than is serum creatinine, B2M, or A1M concentration.
Age (yrs.)
0.1 to 1
1 to 14
20 to 50
>50
Males and Females
0.21
0.48
0.70
0.84
to
to
to
to
0.57
0.96
1.20
1.55
mg/L
mg/L
mg/L
mg/L
Increased Levels:
Section II
•
•
•
•
Progressive primary metastatic melanomas
Colorectal cancer
HIV infection
Decreased Levels:
CSF: Hereditary cystatin C amyloid angiopathy (HCCAA)
Indications for Quantification: As a marker of glomerular filtration
rate in patients with acute or chronic renal disease and in patients
undergoing hemodialysis or renal transplantation.
Genetic Variants: HCCAA is a fatal disorder transmitted as an autosomal dominant trait with almost complete penetrance. The disease
results from the deposition of a Cystatin C variant as amyloid fibrils
in cerebral arteries. Low levels (quantitative) of CSF Cystatin C are
characteristic of HCCAA.
Cys C References:
Randers E, Kristensen JH, Erlandsen EJ, Danielsen J. Serum cystatin C as a marker of the renal
function. Scan J Clin Lab Invest. 58:585-592, 1998.
Kos J, Stabuc B, Cimerman N, Brunner N. Serum cystatin C as a new marker of glomerular
filtration rate is increased during malignant progression. Clin Chem. 1998;44:2556-2557.
122
Mr: 13.3 kDa
EP Zone: Post-γ
FERRITIN (FER)
Function: FER is the major soluble iron storage protein (found in
the liver, spleen, and marrow as well as serum) from which iron is
mobilized for the synthesis of hemoglobin, myoglobin and other iron
containing proteins. In the absence of inflammation, ferritin levels
correlate closely with total body iron stores.
Clinical Significance: Low serum FER indicates depletion of iron
stores. Levels are depressed prior to the exhaustion of mobilizable
iron stores and the development of anemia (FER <10 µg/L indicates
iron deficiency). High serum levels are seen in patients with some
forms of iron overload, liver disease, and in the acute phase response.
Reference Range20:
Age (yrs.)
Males
Females
0.5 to 15
>15
7 to 140 µg/L
20 to 250 µg/L
7 to 140 µg/L
10 to 120 µg/L
Increased Levels:
• Various neoplastic diseases
• Anemia of chronic disease
• Thalassemia
• Sideroblastic anemia
• Hereditary hemochromatosis
Decreased Levels:
•
•
•
•
•
Iron deficiency
Pregnancy
Chronic blood loss
Frequent blood donations
Existence of colonic polyps
Indications for Quantification: Detection of iron deficiency or
overload and monitoring treatment thereof.
FER References:
Hillman RS. iron deficiency and other hypoproliferative anemias. In: Fauci AS, Braunwald E,
McGraw-Hill Co; 1998:638-645.
Lee GR. Anemia. A diagnostic strategy. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP,
Rodgers GM, eds. Wintraube’s Clinical Hematology. 10th ed. Maryland:Williams & Wilkins;
1999:908-940.
Mr: 450 kDa
EP Zone: undetectable
123
Section II
• Liver disease, alcoholic and nonalcoholic
• Cirrhosis
• Acute phase response (infection,
surgery, inflammation)
• Adult Still’s disease
• Chronic viral hepatitis
FIBRINOGEN (FIB)
Function: FIB is converted to a fibrin monomer by thrombin cleavage
of fibrinopeptides A and B. The monomers polymerize to form a
fibrin clot.
Clinical Significance: FIB is an acute phase protein (primary factor
in erythrocyte sedimentation rate) and an essential component of
blood clotting. In comparison with hemophiliacs, however, individuals
with inherited FIB deficiency or nonfunctional variants have relatively
few clinical problems in the absence of trauma or surgery. FIB is
valuable in the detection, diagnosis, and prognosis of diseases involving
tissue damage due to inflammation. It is also an independent prospective risk factor for coronary artery and cerebrovascular disease.
Levels predict cardiovascular death in stroke survivors.
Reference Range21:
Newborn: 1.2 to 3.0 g/L
Increased Levels:
Section II
• APR (inflammation,
infection, trauma, surgery,
and malignancy)
• Nephrotic syndrome • Estrogen therapy
• Hemodialysis patients • Contraceptives
• Pregnancy (normal)
• Acromegaly
Decreased Levels:
• Consumption
coagulopathies
• Recurrent pulmonary
embolism
• Recurrent stroke
• DIC
• Incompatible blood
transfusion reactions
• Obstetrical complications
(eg, abruptio placentae,
amniotic fluid embolism)
(and dysfibrinogenemia,
by functional assays)
• Prostatic carcinoma
• Liver disease
• Certain drugs (eg,
tamoxifen, anabolic
steroids, fibrate drugs,
nicotinic acid)
Indications for Quantification: Effective in coagulation workups
when all three stages of functional assays are abnormal, coagulopathies
as listed above, selective fibrinolysis (acquired coagulopathy with
normal factor VIII levels), assessment of patients with end-stage renal
disease who are at risk for cardiovascular complications, assessment of
the acute phase response (also measured indirectly as the erythrocyte
sedimentation rate). Plasma levels predict cardiovascular disease;
however, due to high diurnal variability, measurements should be
obtained on several occasions.
Genetic Variants: Rare.
FIB References:
Handin R. Disorders of coagulation and thrombosis In: Fauci AS, Braunwald E, Isselbacher K, et
al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York, NY; McGraw-Hill Co;
1998:736-743.
Chung DW, Ichinose A. Hereditary disorders of fibrinogen and factor XIII In: Fauci AS,
124
Mr: 340 kDa
EP Zone: β2 to γ1
FIBRONECTIN (FN)
Function: FN is a glycoprotein, present on cell surfaces, that plays
an active role in tissue remodeling and repair through the promotion of
cell to cell adhesion and retraction of fibrin clots by cross-linking.
FN will bind to gelatin, fibrin, heparin, DNA, and C1q component and
is common in immune complexes.
Clinical Significance: FN has been implicated in the formation of
cryoprecipitates in various rheumatic diseases and in various diseases
where immune complexes are observed (eg, fibrillary glomerulonephritis). FN fragments are found in synovial fluid of osteoarthritis patients
and may contribute to pathogenesis in the late stages of this disease.
FN has a high specificity and a good predictive value in distinguishing
normals and patients with liver disorders other than cirrhosis. Levels
are increased in rheumatoid arthritis, particularly among patients with
vasculitis. Levels are also useful in predicting the onset of preeclampsia.
Reference Range22:
Adult: 300 ± 100 mg/L
Increased Levels:
• Systemic lupus
erythematosus
• Coronary artery disease
• Pregnancy
• Aging
Decreased Levels:
(inflammation, infection,
trauma, septic shock)
• Meningococcal disease
• DIC
• Acute leukemia
• Cirrhosis
• Fulminant hepatic failure
• Splenomegaly
• Hypothyroidism
• Mixed connective tissue
diseases
• Immune complex disorders
• Hereditary deficiency
Indications for Quantification: Rule out risk for preeclampsia.
Genetic Variants: Multiple isoforms have been identified. Although
most cases of fibrillary glomerulonephritis are familial, the genetic
defect in FN is unknown.
Indications for Phenotyping: Predominantly for research applications
in the study of chronologic aging and related pathologies.
FN References:
Gordon DA: Musculoskeletal and connective tissue diseases. In: Bennett JC, Plum F, eds. Cecil
Textbook of Medicine. 20th edition. Philadelphia, PA:W.B. Saunders Co;1996:1444-1445.
Mr: 440 kDa
EP Zone: α2 to β1 interzone
125
Section II
Serum:
• Chronic active hepatitis • Various cancers (breast,
lung, and colon)
• Spondylarthropathy
• Hyperthyroidism
• Multiple myeloma
• Preeclampsia
• Neonatal sepsis
Synovial fluid: Rheumatoid arthritis
HAPTOGLOBIN (Hp)
Function: Hp binds to dimers of hemoglobin as they are released into
the circulation during intravascular hemolysis. These large complexes
exceed the renal threshold for excretion and are removed by the liver,
allowing the iron to be recycled. The complex is a potent peroxidase
which may play a role in the regulation of inflammation.
Clinical Significance: Ineffective erythropoiesis or minimal degrees of
intravascular hemolysis results in a rapid decline of Hp concentration.
Since coexistence of an APR and hemolysis may confound interpretation, Hp and AAG levels should be measured together since only
hemolysis and glomerular protein loss cause divergent effects on
their levels.
Section II
Reference Range23:
Age (yrs.)
Males
Females
0 to 1
2 to 10
11 to 20
21 to 50
>50
~0.00 to 3.00 g/L
0.03 to 2.70 g/L
0.08 to 2.34 g/L
0.27 to 2.46 g/L
0.40 to 2.68 g/L
~0.00 to 2.35 g/L
0.11 to 2.35 g/L
0.27 to 2.13 g/L
0.45 to 2.37 g/L
0.62 to 2.73 g/L
Increased Levels:
• Biliary obstruction
• Nephritis
• Aplastic anemia
• Major depression
• Corticosteroid therapy
• Androgen use
Decreased Levels:
• Ineffective erythropoiesis, • Intravascular hemolysis:
(eg, sickle cell anemia and including isoimmune
folic acid deficiency)
(transfusion reactions),
autoimmune, mechanical
(artificial heart valves,
contact sports)
• Red cell defects
• Genetic anhaptoglobinemia
• Progressive tumors
of liver and marrow
• Pregnancy
• Newborns
Indications for Quantification: Anemia or other indicators of possible
hemolysis, transfusion reactions (assay pre- and post-transfusion
samples). Hp levels should be interpreted in conjunction with AAG.
Genetic Variants: <2% of American Blacks have genetic anhaptoglobinemia.
Indications for Phenotyping: Population genetics, forensic (paternity
and identity testing), and linkage studies.
Hp References:
Jeppsson J-O. Haptoglobin. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine. Scarborough, ME:
Foundation for Blood Research; 1996:7.04.1-7.04.6.
Rosse W, Bunn F. Hemolytic anemias and acute blood loss In: Fauci AS, Braunwald E, Isselbacher
1998: 659-671.
126
Mr: 85 - >1,000 kDa
EP Zone: α2 or α2-β1 interzone
HEMOPEXIN (HPX)
Function: HPX binds heme released by in vivo hemolysis and transports it to the liver where it is broken down into bilirubin. Free HPX
is returned to the circulation. HPX does not bind with hemoglobin or
cytochrome.
Clinical Significance: In cases such as thalassemia where there is no
decrease in haptoglobin, a decrease in HPX is sometimes significant as
the heme is released from sources other than hemoglobin, and HPX
will complex with it.
Reference Range24:
Increased Levels:
• Acute phase response (inflammation, infection, trauma, surgery, and malignancy)
Decreased Levels:
• Hemolytic diseases (sickle cell anemia, thalassemia major, autoimmune hemolytic
anemia, pernicious anemia)
• Internal bleeding (eg, hemorrhagic pancreatitis)
• Newborns
HPX References:
Deiss A. Destruction of Erythrocytes. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP,
1999:278-280.
Schreiber G. Response of the plasma protein synthesizing system in the liver to trauma and
inflammation. In: Putnam FW, ed. The Plasma Proteins: Structure, Function, and Genetic Control. FL:
Harcourt, Brace & Jovanovich, Academic Press: 1987:302-309.
Mr: 57 kDa
EP Zone: β1
127
Section II
Indications for Quantification: Assessment of severity of hemolysis
(acute and chronic forms) and the evaluation of thalassemia.
IMMUNOGLOBULIN A (IgA)
Function: IgA is the second most abundant immunoglobulin (~10%
of total) and is the major immunoglobulin found in mucosal surfaces.
It is found in lymphoid tissues of the Gl, respiratory, and genitourinary
tracts, where covalent linkage to a secretory component protects it
from proteolytic enzymes. Secretory IgA (2 IgA monomers linked
by the J chain) represents the first line of defense against mucosal
microbial invasions. IgA fixes complement via the alternative pathway;
functions include isoagglutination, antibacterial, and antiviral activity.
Clinical Significance: Chronic inflammatory disease of the GI and
respiratory tracts, including the liver, may cause polyclonal increases in
serum IgA. IgA in colostrum and milk is important in neonatal defense
against GI infections. One-fourth of IgA-deficient patients have anti-IgA
antibodies and are at risk of severe anaphylactic reactions to plasma or
blood transfusions (unless from IgA deficient donors). Approximately
10% to 15% of all myelomas are of the IgA type.
Section II
Age (yrs.)
0 to 1
2 to 10
11 to 60
>60
Males
0.01
0.17
0.57
1.03
to
to
to
to
0.91
3.18
5.43
5.91
Females
g/L
g/L
g/L
g/L
0.01
0.17
0.52
0.90
to
to
to
to
0.91
2.90
4.68
5.32
g/L
g/L
g/L
g/L
Increased Levels:
Polyclonal:
• GI diseases (eg, Crohn’s
• Chronic liver disease
or Whipple’s disease,
• Cirrhosis, alcoholic
ulcerative colitis)
and non-alcoholic
• Some immunodeficiency
• Chronic respiratory
states (eg,Wiskottinfections
Aldrich syndrome)
• Neoplasia of lower GI • Rheumatoid arthritis
• Ankylosing spondylitis;
nephropathy
(~50% of cases)
Oligoclonal:
• May see in electrophoresis
of IgA myeloma serum
Monoclonal:
• Multiple myeloma (IgA type)
Decreased Levels:
• Infancy and early childhood • Protein-losing syndromes • Macroglobulinemia
• Selective IgA deficiency
• Congenital rubella
or Non-IgA
(1/700 live Caucasian births)
multiple myeloma
Indications for Quantification: Chronic infections, particularly of the
respiratory or GI tracts; recurrent otitis media; anaphylactic transfusion
reactions; differential diagnosis of M-components; and monitoring
progression of IgA myeloma.
IgA References:
Bienvenu J,Whicher J, Aguzzi F. Immunoglobulins. In: Ritchie RF, ed. Serum Proteins in Clinical
128
Mr: 160 kDa
EP Zone: β2 to γ1
IMMUNOGLOBULIN D (IgD)
Function: The precise biological function of IgD is undetermined;
however, as a marker of mature B-cells, it is thought to serve as a
triggering receptor as evidenced by IgD antibody activity toward
certain antigens (insulin, penicillin, diphtheria toxoid, nuclear thyroid
antigens). IgD comprises ~0.3% of the total immunoglobulin mass.
Clinical Significance: Unknown. High levels are associated with fever.
Reference Range27:
Newborn: <10 mg/L
Adult: <80 mg/L
Increased Levels:
•
•
•
•
•
•
IgD myeloma (rare)
Chronic infections (pyelonephritis)
Connective tissue disease
Henoch-Schönlein purpura
Hodgkin’s disease
Some forms of liver disease
Decreased Levels:
• Various hereditary and acquired deficiency syndromes.
IgD References:
Mr: 175 kDa
EP Zone: γ1
129
Section II
Indications for Quantification: Monitoring IgD myeloma.
IMMUNOGLOBULIN E (IgE)
Function: IgE comprises ~0.003% of the total immunoglobulin
mass. IgE antibodies are allergic, homocytotropic, anaphylactic, reaginic,
atopic, and skin-sensitizing antibodies. IgE antibodies are the chief
immunoglobulin responsible for immediate hypersensitivity reactions in
humans; however, the relationship between concentration and intensity
of allergic reactions is variable. Upon combination with certain
allergens, IgE antibodies trigger the release of physiologic mediators
responsible for characteristic wheal and flare skin reactions.
Clinical Significance: Present at increased levels in roughly onequarter of normal children and adults, IgE antibodies mediate various
allergic and anti-parasitic responses.
Reference Range28:
Adult: 3 to 423 IU/mL
Section II
Increased Levels:
• IgE myeloma
• Allergic rhinitis
• Atopic dermatitis
• Bronchial asthma
• Hay fever
• Thymic dysplasia
• Selective IgA
immunodeficiency
• Eosinophilic gastroenteritis
(particularly children)
• Wiskott-Aldrich syndrome
• Löffler’s syndrome
• Hyper-IgE syndrome
• Active SLE nephritis
• Certain drugs
(particularly gold
compounds)
Decreased Levels:
• Some progressive neoplastic diseases
• Ataxia-telangiectasia
• Hypogammaglobulinemia
• Hypersensitivity
Indications for Quantification: Assessment of atopic diseases, as well
as various dermatologic and parasitic infections. Although occasionally
useful for screening of cases for bronchopulmonary aspergillosis, the
general lack of specificity limits its routine clinical use. The specific
radioallergosorbitant (RAST) test is preferred.
IgE References:
130
Mr: 190 kDa
EP Zone: γ1
IMMUNOGLOBULIN G (IgG)
Function: IgG is the major serum immunoglobulin, comprising 75% to
85% of the total immunoglobulin mass. It is of particular importance in
the body’s secondary defense against infections, particularly those which
are bloodborne. IgG antibodies contain the majority of antibacterial,
antiviral, and antitoxin antibodies. It is the only immunoglobulin to cross
the placenta and is therefore of special importance in defense against
infection in newborns.
Clinical Significance: Deficiency of IgG is associated with frequent
and occasionally severe pyogenic infections. There are numerous
autoantibodies of the IgG class, including antinuclear, anti-red blood
cell, and antibasement membrane antibodies. Approximately 70% of
all myelomas are of the IgG class.
Age (yrs.)
Males
0 to 0.1
0.2 to 10
11 to 30
>30
4.0
3.5
6.5
6.6
• Autoimmune diseases
(SLE, RA, systemic
sclerosis, Sjögren’s
syndrome, etc.)
• Chronic or
recurrent infections
(eg, tuberculosis)
17.6
16.2
16.2
16.9
Females
g/L
g/L
g/L
g/L
3.9
4.0
6.4
6.5
to
to
to
to
• Sarcoidosis
• Some parasitic infections
• Intrauterine
contraceptive devices
Oligoclonal:
• Lymphoid or
nonlymphoid malignancies
• Various autoimmune
disorders
17.5
15.9
17.0
16.4
g/L
g/L
g/L
g/L
• Infections
Monoclonal:
• IgG myeloma
• Lymphoma
• Monogammopathies
of unknown
significance
Decreased Levels:
• Agammaglobulinemia
• Hypogammaglobulinemia
• Omenn’s syndrome
• X-linked hyper IgM syndrome
•
•
•
•
Nephrotic syndrome
non-IgG myelomas
Infancy
Pregnancy (mild decline)
Indications for Quantification: Recurrent or severe infections,
other clinical suggestions of antibody deficiency (eg,Wiskott-Aldrich
syndrome), evaluation of M-components, and assessment of the
progression and response to treatment of IgG myeloma.
IgG References:
Haynes B, Fauci A. Disorders of the immune system, connective tissue, and joints In: Fauci AS,
Mr: 150 kDa
EP Zone: α2 to γ2
131
Section II
Increased Levels:
Polyclonal:
to
to
to
to
IMMUNOGLOBULIN M (IgM)
Function: IgM comprises approximately 7% to 10% of normal serum
immunoglobulin and are the prominent antibody in initial response to
most antigens. Due to its large molecular weight, IgM is predominantly
restricted to the intravascular space. IgM is an efficient agglutinator of
bacterial antigens, red blood cells and some viruses and can activate
the classical complement pathway.
Clinical Significance: IgM is important in early response to infections.
Cold hemolysins or agglutinins are usually IgM. In Waldenström’s
macroglobulinemia there is a monoclonal increase of IgM. Virus specific
IgM in cord blood or neonatal serum is likely due to a congenital
infection, as IgM does not cross the placenta.
Age (yrs.)
0 to 0.25
0.25 to 1
2 to 30
>30
Males
0.06
0.30
0.30
0.37
to
to
to
to
0.66
1.83
2.65
2.58
Females
g/L
g/L
g/L
g/L
0.06
0.34
0.34
0.39
to
to
to
to
0.66
2.06
3.48
3.38
g/L
g/L
g/L
g/L
Section II
Increased Levels:
Polyclonal
(Hepatitis A,
mycoplasma,
cytomegalovirus,
Coxsackie, Epstein-Barr)
• Parasitic infections
(Filariasis, Malaria)
• Hyper-IgM
dysgammaglobulinemia
• Collagen vascular disease
• Primary biliary cirrhosis
• Primary sclerosing
cholangitis
Monoclonal:
• Waldenström’s
macroglobulinemia
• Malignant lymphoma
• Reticulosis
• Cold agglutinin /
hemolysin disease
Decreased Levels:
•
•
•
•
Immune deficiency states (Wiskott-Aldrich syndrome)
non-IgM myeloma
Infancy and early childhood
Lymphoma (higher incidence with IgM deficiency)
Indications for Quantification: Frequent, chronic, or acute infections;
suspected immunodeficiency; screening for congenital infection; patients
with monoclonal proteins observed on electrophoresis; and monitoring
patients with Waldenström’s macroglobulinemia.
IgM References:
NY; McGraw-Hill Co; 1998.1753-1776.
132
Mr: 971 kDa
EP Zone: γ1 to γ2
IMMUNOGLOBULIN LIGHT CHAINS (kappa/lambda)
Function: The light chain portion of all immunoglobulin molecules is
either kappa or lambda. Light chains can be thermoreactive proteins
(Bence Jones) and in ~10% of cases may precipitate upon heating. They
have no specific function except as a part of intact immunoglobulins.
Clinical Significance: Free light chain proteins are critical in the development of pathologic and clinical signs of plasma cell dyscrasia with
renal manifestations (light chain deposition disease). Among complexed
light chain proteins, a 2:1 kappa to lambda light chain ratio is typical
of polyclonal immunoglobulins. A disturbance in this ratio may indicate
an immunoglobulin abnormality, since monoclonal immunoglobulins
possess only one type of light chain. The presence of one type of
monoclonal light chain in urine suggests a neoplastic process.
Reference Range29:
Adult
Protein
Range
Kappa
Lambda
Kappa to Lambda ratio
0.20 to 0.44 g/L
1.10 to 2.40 g/L
1.35 to 2.65
Abnormal ratios:
Indications for Quantification: Suspected monoclonal gammopathy,
unexplained bands on protein electrophoresis; unexplained renal
disease, congenital immunodeficiency, AIDS; and therapeutic monitoring.
In urine of monogammopathy patients, free light chains are used to
assess tumor proliferation, relapse, and response to therapy. In addition, they are used in the evaluation of patients with suspected renal
tubular dysfunction.
Immunoglobulin Light Chain References:
Aguzzi F,Whicher J. Kappa to lambda light chain ratios. In: Ritchie RF, ed. Serum Proteins in Clinical
Kyle RA: Plasma cell disorders. In: Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th
Mr: monomer ~22 kDa; dimer ~44 kDa
EP Zone: γ1, γ2, α of β if complexed 133
Section II
• Light chain disease
• Waldenström’s macroglobulinemia
• Lymphatic leukemias
• Renal disease
• Some autoimmune disorders
• Multiple myeloma
• Various immunoglobulin deficiencies
• Gastrointestinal and respiratory infections have been reported (rare)
to be associated with an absence of kappa chain synthesis
LIPOPROTEIN(a) [Lp(a)]
Function: The exact function of Lp(a) is unknown; however, it is
thought to promote wound healing. It has been found in atherosclerotic plaques and is associated with endothelial dysfunction. Lp(a)
shares homology with plasminogen and has been shown to inhibit
plasminogen binding with resultant impairment of plasminogen
activation and fibrinolysis.
Clinical Significance: High Lp(a) levels are an independent risk factor
for the development of atherosclerosis and thromboembolic disease.
Elevated levels may identify patients at risk for coronary artery disease
not expressing other major risk factors. In end-stage renal disease,
high Lp(a) levels are an independent predictor of risk of death due to
coronary artery disease.
Reference Range30:
Race
Adult Males
Adult Females
Caucasians
Blacks
0.02 to 0.49 g/L
0.04 to 0.75 g/L
0.02 to 0.57 g/L
0.04 to 0.75 g/L
Section II
Increased Levels:
• Coronary artery disease
• Cerebrovascular disease
• Peripheral vascular
disease
(variable)
• Cancer
• Gout
• Familial hypercholesterolemia
• Acute phase
response
• Pregnancy, transient
increase
Decreased Levels:
• Cirrhosis (particularly, primary biliary cirrhosis)
• Certain drugs (nicotinic acid, oral estrogen, neomycin)
• Some steroids, such as stanozolol
Indications for Quantification: Coronary artery disease risk
assessment, particularly if LDL-C levels are inconclusive. Since Lp(a)
levels are genetically determined, family studies may be useful once
an individual with elevated Lp(a) has been identified.
Genetic Variants: Up to 34 alleles affecting apo(a) size have been
identified in addition to the genetic variation of the nontranslated
region of the gene. Lp(a) concentration is inherited in a Mendelian
co-dominant manner, with variation due to the apolipoprotein (a) gene.
Generally, Lp(a) molecular weight (MR) is inversely related to level.
High MR are associated with decreased Lp(a) levels and vice versa.
Lp(a) References:
McGraw-Hill Co; 1998:2138-2148.
Craig WY: Lipoprotein (a). In: Ritchie RF, ed. Serum Proteins in Clinical Medicine. Scarborough,
134
Mr: 330-700 kDa
EP Zone: pre-β
MANNOSE-BINDING PROTEIN (MBP)
Function: MBP, a collectin and structural analogue of the complement
component C1q, has a high affinity to mannose and N-acetylglucosamine moieties on the surface of various pathogens. It can activate
the classic and alternative complement pathways and functions as
an opsonin with or without complement.
Clinical Significance: MBP is a pattern recognition molecule that
plays an important role in first-line host defense against certain
bacterial, viral, and fungal pathogens. Mutations in the MBP gene are
an important risk factor for infection in children. Patients with low
or undetectable levels of MBP have an increased frequency of infection.
A small percentage of patients with systemic lupus erythematosus
who are homozygous or heterozygous for deficiency alleles are unable
to activate complement under any circumstance and are prone to
earlier and more frequent infections, particularly pneumonia.
Reference Range31:
Adult: 0.30 to 4.10 mg/L
Increased Levels:
Section II
• 2- to 3-fold increase in the acute phase response (inflammation, infection,
trauma, surgery)
• HIV
Decreased Levels:
• Hereditary deficiency
• Infants (6 to 18 months) with recurring bouts of infection
Indications for Quantification: Frequent, unexplained pediatric
infections; chronic diarrhea of infancy; and otitis media in the first year
of life. Adults with recurring infections and monitoring of infection
in patients with chronic lymphocytic leukemia.
Genetic Variants: There are 5 known allelic forms of MBP, 3 of which
are associated with markedly reduced serum MBP levels and increased
susceptibility to infections in early childhood, prior to full development
of their immune system. Homozygosity is common (frequency, ~0.3%)
and may confer a life-long risk of infection and an increased risk of
atherosclerosis.
Indications for Phenotyping: In the investigation of children with
severe or frequent infections. Adults with unusual or severe infections
in whom immunodeficiency has been ruled out.
MBP References:
Sullivan KE.Winkelstein JA. Genetically Determined Deficiency of the Complement System.
In: Ochs HD, Smith CIE, Puck JM, eds. Primary Immunodeficiency Disease. New York: Oxford
University Press; 1999:411.
Reid KB. Lectin Pathway of Non-self Recognition. In: Rother K,Till GO, Hänsch GM, eds.
The Complement System, 2nd ed. New York:Springer Press; 1998:86-92.
Mr: 32 kDa
EP Zone: Undetectable
135
MYOGLOBIN (MYO)
Function: MYO is an oxygen-binding protein present in smooth,
striated, and myocardial muscle. Damage to these tissues results in
myoglobinuria and, acutely, myoglobulinemia.
Clinical Significance: Following injury to skeletal or cardiac muscle,
MYO is released into the circulation and urine due to its small size
and lack of haptoglobin binding. Increased levels in serum are often
evident 2 to 3 hours after myocardial infarction.
Reference Range32:
Adult: <0.09 mg/L (affected by total body muscle mass; 1 g of myoglobin
per Kg of muscle)
Section II
Increased Levels:
Serum:
• Muscular dystrophy
• Renal failure
• Injury to skeletal muscle
• Subclinical myoglobinemia following vigorous exercise
Urine:
• Viral myositis
• Rhabdomyolysis from any cause
• Familial paroxysmal myoglobinuria
Decreased Levels:
• Associated with rheumatoid arthritis and myasthenia gravis
Indications for Quantification: Assessment of myocardial infarction
(generally 2 specimens taken 2 hours apart, in the absence of other
confounding variables), crush injuries, and metabolic diseases with
rhabdomyolysis.
Genetic Variants: At least 5 identified, none associated with
biochemical or physiological dysfunction or deficiency.
MYO References:
Engel AG. Metabolic myopathies. In: Bennett JC, Plum F, eds. Cecil Textbook of Medicine.
136
Mr: 17.8 kDa
PLASMINOGEN (PSM)
Function: PSM is a proenzyme which, upon activation to plasmin by
thrombin, urokinase, and various tissue activators, will cleave fibrin
in blood clots. If uncontrolled, PSM will also cleave fibrinogen. The
resultant fibrinogen split products have anticoagulant activity. Plasmin
activity is regulated by the plasma inhibitors α-2-antiplasmin and
α-2-macroglobulin.
Clinical Significance: Clot lysis, a natural sequel to blood clotting, is
essential for the re-establishment of blood flow. Excessive plasmin
activity, however, results in bleeding disorders such as those seen after
thoracic and prostatic surgery and in obstetrical complications.
Reference Range33:
Adult: 60 to 250 mg/L
Increased Levels:
• Pregnancy
• Contraceptive medications
• Prostatic cancer
Decreased Levels:
Section II
• Streptokinase or other fibrinolytic therapy
• Idiopathic respiratory distress syndrome of infancy
(hyaline membrane disease)
• Liver disease
• DIC
• Venous thrombosis (PSM deficiency)
Indications for Quantification: Evaluation of unexplained bleeding
problems, monitoring fibrinolytic therapy (with fibrinogen assays), and
in suspected deficiency.
Genetic Variants: There are 2 common variants and several rare
ones. PSM deficiency (rare) is associated with severe conjunctivitis
and pseudo-membranous lesions of other mucous membranes.
PSM References:
Greenberg C, Orthner C. Blood Coagulation and Fibrinolysis In: Lee GR, Foerster J, Lukens J,
Paraskevas F, Greer JP, Rodgers GM, eds. Wintraube’s Clinical Hematology. 10th ed. Maryland:
Williams & Wilkins; 1999:727-729.
Vaughan DE, Schager AI, Loscalzo J. Normal Mechanisms of Hemostasis and Fibrinolysis. In:
Loscalzo J, Creager MA, Dzau VJ, eds. Vascular Medicine. Loscalzo J, Creager MA, Dzau VJ, eds.
Massachusetts: Little, Brown & Co; 1992:240-242.
Mr: 91 kDa
EP Zone: β
137
PREALBUMIN (Transthyretin) (PAL)
Function: PAL is a thyroxine-binding protein that also aids in the
transport of vitamin A by forming a complex with retinol-binding
protein, thereby preventing its loss via the kidneys.
Clinical Significance: With a high tryptophan content, short half-life
(2 days), and a small body pool, PAL responds quickly to low energy
intake making it a sensitive indicator of protein deficiency, liver disease,
and acute inflammation.
Age (yrs.)
0 to 1
2 to 10
11 to 30
>30
Males
0.07
0.12
0.15
0.19
to
to
to
to
0.25
0.32
0.44
0.45
Females
g/L
g/L
g/L
g/L
0.08
0.12
0.15
0.18
to
to
to
to
0.25
0.33
0.38
0.39
g/L
g/L
g/L
g/L
Increased Levels:
Section II
• Corticosteroid and anabolic steroid use
• Hodgkin’s disease
• Alcoholism
• Acromegaly
Decreased Levels:
(inflammation; tissue
necrosis, trauma, surgery)
• Renal and hepatic disease
• Poor nutritional status
• Hereditary amyloidosis
• Hyperestrogenism
• Thyrotoxicosis
• Administration of
intravenous fluids
Indications for Quantification: In the absence of an acute phase
response, PAL is:
• a sensitive marker of protein-calorie malnutrition (it should be assayed in
conjunction with at least one other acute phase protein, preferably CRP);
• an indicator of response to nutritional therapy;
• a marker of nutritional inadequacy in premature infants; and
• an index of liver function in hepatobiliary disease.
Genetic Variants: At least 50 identified, many associated with
amyloidosis. Some mutations produce neuropathy, and others lead
to cardiomyopathy or vitreous opacities; however, the vast majority
are neuropathic. The most common inherited condition is familial
amyloidotic polyneuropathy.
PAL References:
Bienvenu J, Jeppsson, J-O, Ingenbleek Y.Transthyretin (prealbumin) & retinol binding protein.
In: Ritchie RF, ed. Serum Proteins in Clinical Medicine. Scarborough, ME: Foundation for Blood
Research; 1996:9.01.1-9.01.7.
Bistrian BR: Nutritional assessment. In: Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th
138
Mr: 55 kDa
EP Zone: Prealbumin
RETINOL-BINDING PROTEIN (RBP)
Function: RBP’s major role is to transport vitamin A in its alcoholic
form, retinol, to target cells requiring the vitamin. RBP in turn is
transported by prealbumin.
Clinical Significance: RBP is a negative acute phase reactant. With a
small body pool size and only a 12-hour half-life, RBP in the absence of
an APR is a useful marker for monitoring short-term nutritional status.
Levels vary directly with PAL levels. Serum levels of RBP are also a
sensitive indicator of early changes in glomerular function.
Reference Range35:
Age (yrs.)
Males
Females
2 to 10
>16
22 to 45 mg/L
34 to 77 mg/L
22 to 45 mg/L
22 to 60 mg/L
Increased Levels:
Serum:
Urine:
• Cadmium induced tubular damage
Decreased Levels:
• Familial secondary
amyloidosis
• Cancerous
• Cachexia
• Proteinuria
• Hyperparathyroidism
Indications for Quantification: Assessment of nutritional status
(levels closely correlate with prealbumin) and in the diagnosis and
evaluation of renal function. As with prealbumin, RBP should be run
in conjunction with another acute phase protein, such as CRP.
RBP References:
Bienvenu J, Jeppsson, J-O, Ingenbleek Y.Transthyretin (prealbumin) & retinol binding protein.
In: Ritchie RF, ed. Serum Proteins in Clinical Medicine. Scarborough, ME: Foundation for Blood
Research; 1996:9.01.1-9.01.7.
Olson JA: Vitamin A, Retinoids and Carotenoids. In: Shils ME, Olson JA, Shike M, eds.
Modern Nutrition in Health and Disease. 8th ed. Pennsylvania: Lea & Febiger Co.;1994:291-293.
Mr: 21 kDa
EP Zone: α2 or prealbumin if complexed
139
Section II
• Malnutrition (kwashiorkor)
• Vitamin A deficiency
• Celiac disease
RHEUMATOID FACTOR (RF)
Function: RF is an autoantibody that binds specifically to the Fc fragment of IgG. It may be IgG, A, M, E (rare), or combinations of these.
Most laboratory tests detect only IgM-RF. Although its exact function
is unknown, RF may enhance the humoral response to invading
microorganisms, complex with and process antigens in immune complexes, and facilitate antigen presentation to T-lymphocytes.
Clinical Significance: High RF titers are common in RA and Sjögren’s
syndrome. Patients who are seropositive usually have a worse prognosis than those who are seronegative. In juvenile rheumatoid arthritis,
RF positivity is associated with rheumatoid nodules, vasculitis, and
poorer prognosis. Occasionally, the presence of RF may help in the
diagnosis of culture-negative bacterial endocarditis, as well as viral
hepatic disease.
Adult: Negative (<30 IU/mL); 95th percentile is ~ 15 IU/mL
Section II
Increased Levels:
Serum:
• Mixed connective
tissue disease
• SLE (slight)
• Systemic sclerosis
• Polymyositis /
dermatomyositis
• Vasculitis (associated
with Hepatitis C or
mixed cryoglobulinemia)
• Pulmonary fibrosis
• Chronic bacterial
infections (tuberculosis,
leprosy, yaws, syphilis,
SBE, salmonellosis)
(hepatitis B and C,
infectious mononucleosis, influenza)
• Parasitic infections
(filariasis, Kala-Azar,
malaria, trypanosomiasis)
• Sarcoidosis
• Age
• Primary biliary cirrhosis
• Chronic hepatocellular
disease
• Waldenström’s
macroglobulinemia
• B-cell lymphoma
• Chronic lymphocytic
leukemia
• Hypergammaglobulinemic
purpura
• Non-Hodgkin’s
lymphoma
Synovial fluid: Rheumatoid arthritis
Decreased Levels: None reported
Indications for Quantification: Evaluation of suspected RA. High
IgM-RF titers are essentially diagnostic of RA; titers correspond to
disease severity at the time of diagnosis. Because RF is a poor
screening test for RA in the general population, its measurement is
most useful in the appropriate clinical context.
RF References:
Tighe H, Carson DA: Rheumatoid Factors. In: Kelley, Harris, Ruddy, Sledge, eds. Textbook of
Rheumatology, 5th Edition. Kelley, Harris, Ruddy, Sledge (eds.),W.B. Saunders Co, Pennsylvania, pp.
241-247, 1997.
Tucker E, Nakamura R. Rheumatoid factors. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
Scarborough, ME: Foundation for Blood Research; 1998:11.06.02.1-11.06.02.4.
140
Mr: ~150 - >1,000 kDa
EP Zone: N/A
SERUM AMYLOID A (SAA)
Function: No specific function for SAA has been identified; however, it
has been shown to have an immunomodulatory effect in the regulation
of the immune response to T-dependent antigens, the production of
prostaglandin-E2, and the fever response. SAA is thought to have a regulatory effect in the metabolism of high-density lipoprotein by impeding
reverse cholesterol transport. SAA is the precursor for Amyloid-A,
which forms the bulk of fibrils in one form of secondary amyloidosis.
Clinical Significance: SAA is an early acute phase reactant. Levels
increase dramatically (500- to 1000-fold) during an acute phase
response, making it a useful protein for monitoring inflammation in
a variety of patient groups. It may respond more rapidly than CRP
in viral disease.
Adult: <9.7 mg/L (levels increase slightly with age)
Increased Levels:
• Viral and bacterial
infections (rubella,
measles, and subacute
panencephalitis)
• Lung inflammation
in cystic fibrosis
• Renal allograft
rejection
• Inflammatory bowel
disease
• Malignancy
Decreased Levels:
• None known (levels drop with antimicrobial therapy)
Indications for Quantification: As an indicator of inflammation,
assessment of a variety of pathologic conditions such as trauma,
bacterial and viral infections, malignant disorders, acute myocardial
infarction, etc. SAA may also predict the risk of a recurrent cardiac
event in stable patients with a prior myocardial infarction.
Genetic Variants: Six main isoforms have been identified.
SAA References:
Whicher J. Serum amyloid A. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine. Scarborough,
Sipe JD, Cohen AS. Amyloidosis. In: Fauci AS, Braunwald E, Isselbacher K, et al, eds. Harrison’s
Principles of Internal Medicine. 14th ed. New York, NY; McGraw-Hill Co; 1998:1856-1860.
Mr: 11.7 kDa
141
Section II
• Chronic inflammatory
diseases which predispose
to amyloidosis
(rheumatoid arthritis,
juvenile rheumatoid
arthritis. ankylosing
spondylitis, progressive
sclerosis)
SOLUBLE TRANSFERRIN RECEPTOR (sTfR)
Function: Transferrin receptor (TfR) is synthesized by all cells when
there is a requirement for iron. TfR is carried to the surface of the
cell membrane, where it specifically binds to iron-laden transferrin and
transports the iron into the cell. In the process, a small amount of
TfR is lost into the circulation as sTfR. sTfR levels are proportional to
the rate of red cell production and are inversely proportional to the
availability of tissue iron.
Clinical Significance: In anemic patients, sTfR is a valuable noninvasive
tool for the diagnosis of iron depletion. Levels rise rapidly in iron
deficient erythropoiesis and/or a proliferative marrow. Levels are
unaffected by inflammation or liver function disorders, estrogen therapy
and pregnancy, and provide a sensitive measure to distinguish iron
deficiency anemia from anemia of chronic inflammation.
Adult: 0.83 to 1.76 mg/L (method dependent)
Section II
Increased Levels:
• Iron deficiency anemia
(nutritional or malabsorptive)
• Ineffective erythropoiesis
• Sickle-cell anemia
• Hemolytic anemia
• α-thalassemia
• Hemoglobin H disease
• Hypoplastic anemia
• Chronic hemolysis or blood loss
• Certain malignancies
(polycythemia vera, myelofibrosis)
• Recombinant human
erythropoietic therapy
Decreased Levels:
• Hypoplastic anemia
• Anemia of chronic inflammation
(eg, rheumatoid arthritis)
• Post transplant aplasia
• Hereditary hemochromatosis
Indications for Quantification: Differential diagnosis of hypochromic,
microcytic anemia (iron deficiency vs anemia of chronic inflammation
vs. hemoglobinopathy). Calculating the ratio sTfR/ferritin enhances the
difference between iron deficiency and normal subjects. The ratio is
also used in determining the endpoint of phlebotomy therapy for
patients with hereditary hemochromatosis. The ratio rises dramatically
as phlebotomy treatment begins to induce iron deficiency.
sTfr References:
Hillman RS. Iron Deficiency and other hypoproliferative anemias In: Fauci AS, Braunwald E,
McGraw-Hill Co; 1998:638-645.
Lee GR. Anemia. A diagnostic strategy. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP,
1999:908-940.
142
Mr: ~85 kDa monomer
TRANSFERRIN (Tf)
Function: Tf binds and transports iron (ferric state) from the
gastrointestinal tract or sites of heme breakdown to the bone marrow
or the liver for storage. It also regulates the ferric form of iron, thus
preventing iron intoxication and protecting the loss of iron from
urinary excretion.
Clinical Significance: The cornerstone of iron metabolism,
circulating Tf is normally one-third saturated with iron. In iron
deficiency, elevated Tf levels precede anemia by days to months.
Unsaturated Tf may be important in the control of infections by
iron-requiring organisms. In iron overload, there is complete
saturation of Tf with a corresponding increase of iron stores.
Age (yrs.)
0 to 1
2 to 30
31 to 60
>60
Males
1.40
1.89
1.78
1.63
to
to
to
to
3.19
3.58
3.54
3.31
Females
g/L
g/L
g/L
g/L
1.48
1.80
1.80
2.47
to
to
to
to
3.16
3.91
3.72
3.66
g/L
g/L
g/L
g/L
Increased Levels:
• Pregnancy and estrogen therapy
• Hypothyroidism
Decreased Levels:
(inflammation; tissue necrosis,
trauma, surgery)
• Malignancy
• Liver disease
• Malnutrition (in the absence
of inflammation)
• Iron overload conditions (eg, hereditary
hemochromatosis); hypotransferrinemia;
genetic atransferrinemia (rare)
• Dialysis patients
Indications for Quantification: Differential diagnosis of anemia
in combination with ferritin and percent transferrin saturation and
evaluation and monitoring of patients at risk for development of
iron overload.
Genetic Variants: Many described, with Tf C1 and C2 accounting for
the majority of the population in all races. Tf D occurs in 1% to 2% of
American Blacks. No clinical implications have been reported.
Tf References:
Jeppsson J-O.Transferrin. In. Ritchie RF, ed. Serum Proteins in Clinical Medicine. Scarborough, ME:
Foundation for Blood Research; 1996:9.02.1-9.02.8.
Lee GR, Herbert V. Nutritional Factors in the Production and Function of Erythrocytes.
In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM, eds. Wintraube’s Clinical
Hematology. 10th ed. Maryland:Williams & Wilkins; 1999:247-249.
Mr: 79.7 kDa
EP Zone: β1
143
Section II
• Iron deficiency
• Acute hepatitis
REFERENCES FOR REFERENCE RANGES:
1. Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O, Ledue TB, Craig WY.
Reference distributions for the negative acute-phase serum proteins, albumin,
transferrin, and transthyretin. A practical, simple and clinically relevant approach
in a large cohort. J Clin Lab Anal. 1999;13:373-279.
2. Johnson AM, Guder WG. Albumin. In: Ritchie RF, ed. Serum Proteins in Clinical
3.Whicher J, Bienvenu J. Orosomucoid. In: Ritchie RF, ed. Serum Proteins in Clinical
4. Tietz Clinical Guide to Laboratory Tests. 3rd ed. Philadelphia, PA:W.B. Saunders Co;
1995:58-59.
5. Jeppsson JO. α1-Antitrypsin. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
6. Guder WG, Johnson AM: α1-Microglobulin. In: Ritchie RF, ed. Serum Proteins
in Clinical Medicine. Scarborough, ME: Foundation for Blood Research;
1996:9.03.1-9.03.4.
Section II
7.Weber MH,Verwiebe R. α1-Microglobulin (protein hc): features of a promising
indicator of proximal tubular dysfunction. Eur J Clin Chem Clin Biochem.
1992;30:683-691.
8. Davis AE. α2-Macroglobulin. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
1995:64-65.
10. Craig WY, Stein E. Apolipoprotein AI. In: Ritchie RF, ed. Serum Proteins in Clinical
Medicine. Scarborough, ME: Foundation for Blood Research; 1996:12.01.112.01.11.
11. Craig WY. Apolipoprotein B. In: Ritchie RF, ed. Serum Proteins in Clinical
Medicine. Scarborough, ME: Foundation for Blood Research; 1996;12.02.112.02.10.
12. Ivandic M, Hofmann W, Guder WC. An Information system about urine
protein differentiation.Website: [email protected].
13. Dati F, Schumann G,Thomas L, et al. Consensus of a group of professional
societies and diagnostic companies on guidelines for interim reference ranges
for 14 proteins in serum based on the standardization against the
IFCC/BCR/cap reference material (CRM 470). Eur J Clin Chem Clin Biochem.
34: 517-520, 1996.
14. Johnson AM. Ceruloplasmin. In: Ritchie RF, ed. Serum Proteins in Clinical
Medicine. Scarborough, ME: Foundation for Blood Research; 1996:13.01.113.01.8.
15.Whicher J. Complement component C3. In: Ritchie RF, ed. Serum Proteins in
1996:10.01.1-10.01.7.
16. Johnson AM. Complement component C4. In: Ritchie RF, ed. Serum Proteins in
1996:10.02.1-10.02.11.
144
17. Tietz Clinical Guide to Laboratory Tests. 3rd ed. Philadelphia, PA:W.B. Saunders
Co; 1995:156-157.
18. Randers E, Krue S, Erlandsen E, Danielsen H, Hansen L. Reference intervals
for serum cystatin C in children. Clin Chem. 1999;9:1856-1858.
19. Norlund L, Fex G, Lanke J,Vonschenck H, Nilsson J-E, Leksell H, Grubb A.
Reference intervals for the glomerular filtration rate and cell-proliferative
markers. serum cystatin C and serum Beta-2-microglobulin/cystatin C-Ratio.
Scand J Clin Lab Invest. 1997;57:463-470.
Co; 1995:234-235.
Co; 1995:240-241.
Co; 1995:240-243.
23. Jeppsson JO. Haptoglobin. In. Ritchie RF, ed. Serum Proteins in Clinical Medicine
Vol. 1. Foundation for Blood Research, pp. 7.04.1-7.04.6, 1996.
Co; 1995:318-319.
26. Bienvenu J,Whicher J, Aguzzi F. Immunoglobulins. In: Ritchie RF, ed. Serum
Proteins in Clinical Medicine. Scarborough, ME: Foundation for Blood Research;
1996:11.01.1-11.01.15.
Co; 1995:356-357.
Co; 1995:358-359.
29. Dati F, Lammers M,Adam A, Sondag D, Steinen L. Reference values for 18 plasma
proteins on the Behring Nephelometer System. Lab Med. 1989;13:87-90.
Co; 1995:400-401.
31. Ledue TB,Weiner DL, Sipe JD, Poulin SE, Collins MF, Rifai NR. Analytical
evaluation of a particle-enhanced immunonephelometric assays for C-reactive
protein, serum amyloid A, and mannose-binding protein in human serum.
Ann Clin Biochem. 1998;35:745-753.
Co; 1995:442-443.
Co; 1995:490-491.
34. Bienvenu J, Jeppsson JO, Ingenbleek Y.Transthyretin (prealbumin) & retinol
binding protein. In: Ritchie RF, ed. Serum Proteins in Clinical Medicine.
145
Section II
25. Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia, O, Ledue TB, Craig WY.
Reference Distributions for Immunoglobulins A, G, and M. A practical, simple,
and clinically relevant approach in a large cohort. J Clin Lab Anal. 1998;12:
363-370.
1995:542-543.
1995:544-545.
37.Tucker E, Nakamura R. Rheumatoid factors. In: Ritchie RF, ed. Serum Proteins in
1996:11.06.02.1-11.06.02.4.
38.Whicher J. Serum amyloid A. In: Ritchie RF, ed. Serum Proteins in Clinical
Medicine. Scarborough, ME: Foundation for Blood Research; 1996:702.1-7.02.6.
39. Package Insert for soluble transferrin receptor latex assay. Dade Behring
Incorporated. April 1999.
40.Allen J, Backstrom KR, Cooper JA, et al. Measurement of soluble transferrin
receptor in serum of healthy adults. Clin Chem. 1998;44:35-39.
Section II
41. Jeppsson JO, Aguzzi F.Transferrin. In: Ritchie RF, ed. Serum Proteins in Clinical
Medicine. Scarborough, ME: Foundation for Blood Research; 1996:9.02.1-9.02.8,
146
Index
Acromegaly 124, 136
Acute phase response 1, 3, 21, 23, 27,
30-32, 38, 47, 48, 54, 66, 67, 69, 7880, 83, 86, 93-97, 107-110, 117-120,
123-126, 134, 135, 138, 139, 143
Albumin 107
ASCVD 28, 29, 30
Biliary cirrhosis 69
Biliary obstruction 69
Cancer, GI 46, 47
Cancer, lung 80
Diabetes 38, 39
Drug effects 12, 13, 14
Gastroenteropathy protein-losing 46, 47
Hepatic cirrhosis 68
Hepatic disease 68, 70, 71
Hepatic failure, fulminant 69, 70
Hepatitis, viral 67, 68
Inflammation 1, 3, 4, 7
Inflammatory bowel disease 48, 49
MCTD 95
Multiple myeloma 54
Multiple sclerosis 75
Nephrotic syndrome 82, 83
Nutritional status 20-24
Renal failure 83, 84, 85
Rheumatoid arthritis 97, 98
SLE 99, 100
Stroke 31, 32
Thyroid disease 40, 41
Alcohol 12, 66, 68-70, 110, 114, 123,
128, 138
Allergy 79, 130
α1-Acid glycoprotein 108
Ankylosing spondylitis 93
ASCVD 28, 29, 30
Cancer, GI 47, 49
Diabetes 38
Hepatic disease 68, 69
Inflammation 1, 4, 7
Myocardial infarction 30
Renal failure, chronic 83, 84
α1-Antichymotrypsin 110
Cancer, GI 46, 47, 48
Hepatitis, viral 67
Inflammation 1
Polymyalgia rheumatica 96
Rheumatoid arthritis 97
α1-Antitrypsin 110
ASCVD 27, 28
Cancer, GI 46, 47
Deficiency 65, 87
Glomerulonephritis 87
Hepatic cirrhosis 68, 69
Hepatic failure, fulminant 69
Inflammation 1, 4
Nutritional effects 20
Polymyositis 90
Pulmonary disease 78, 79
Thyroid disease 41
α1-Microglobulin 111
Glomerular filtration rate 85
α1-Macroglobulin 112
Diabetes 40
Drug effects 12, 14
Gastroenteropathy protein-losing
Hepatic disease 68
Nephrotic syndrome 82, 83, 87, 100
Nutritional assessment 20
Amyloidosis 46, 52, 55, 56, 85, 116,
122, 138, 139, 144
Androgens 12, 108, 114, 126, 134, 137,
138
Anemia 7, 22, 48, 54, 58-60, 70, 84,
115, 117, 123, 126, 142, 143
Angioneurotic edema hereditary 119,
120
Ankylosing spondylitis 93, 128, 141
Antibiotics 13, 22
Antiepileptic drugs 12
Antihypertensive drugs 12
Antinuclear antibodies 2, 39, 41, 67,
94-101
Antithrombin III 113
ASCVD 28, 29
Diabetes 39
Drug effects 12
Hemostasis (renal disease) 83
Hepatic disease, chronic 67
Hepatic failure, fulminant 69-71
Sepsis 4-7
Thrombosis 82, 83
Apolipoprotein A1 114
Inflammation 6
ASCVD 28, 29
Myocardial infarction 30, 31
Stroke 32
Diabetes 38, 39, 40
147
Index
Thyroid disease 41
Apolipoprotein B 115
ASCVD 28, 29
Diabetes 38, 39
Hepatic cirrhosis 68, 69
Inflammation 6
Multiple myeloma 55
Myocardial infarction 30, 31
Nephrotic syndrome 82, 83, 87
Renal failure, chronic 83, 84, 85
Stroke 32
SLE 99, 100
Thyroid disease 41
Asthma 78, 79, 109, 131
Behçet’s syndrome 111
Biliary cirrhosis 69, 117, 132, 134,
140
β2-Microglobulin 116
Amyloidosis 56, 83
Cancer, GI 47
HIV 3
Hyperthyroidism 44
Infection 3, 7
Monoclonal gammopathy 53
Multiple myeloma 54, 55
Renal failure, chronic 84
Sjögren’s syndrome 98, 99
Waldenström’s macroglobulinemia
55, 56
c1-Esterase inhibitor 118
Hepatitis, viral 67
Cardiovascular disease 6, 27-29, 83,
84, 114, 115, 14, 134, 135
Ceruloplasmin 117
ASCVD 27
Biliary cirrhosis 68, 69
Diabetes 38, 39
Gastroenteropathy protein-losing 46
Hemochromatosis 66
Hemodialysis 85
Hepatic disease 68
Hepatitis, viral 67
Inflammation 1
Wilson’s disease 66
Chronic obstructive pulmonary
disease 78, 79, 110
Coagulation, disseminated
148
intravascular 5, 112, 113, 124, 125,
135
Complement component C3 118
Acute phase response 2
Asthma 79
Deficiency 5, 87
Diabetes 38
Hemodialysis 85
Hepatitis, viral 69
Infection 5
JRA 93, 94
MCTD 94, 95
Multiple myeloma 54
Nephrotic syndrome 82
Nutritional status 20
Osteoarthritis 95
Polymyositis 96
Sepsis 6
SLE 100
Complement component C4 119
COPD 78
Deficiency 5, 87
Diabetes 38
Hepatitis, viral 67
JRA 93, 94
MCTD 93, 95
Multiple myeloma 54
Nutritional assessment 20
Osteoarthritis 95
Polymyositis 96
Sepsis 6
SLE 100
Contraceptives, oral 12, 113, 125,
137
Index
Corticosteroids 13, 22, 49, 83, 87,
108, 116, 121, 126, 136, 137
C-reactive protein 121
Amyloidosis 56
Anemia 59, 60
ASCVD 6, 27, 28, 29, 30
Cancer, GI 46, 47
Cancer, lung 80
COPD 78, 79
Diabetes 38, 39, 40
Drug effects 13, 14
Glomerulonephritis 85, 86, 87
Hepatic cirrhosis 6-8
Infection 3, 4
Inflammatory bowel disease 48
JRA 93, 94
MCTD 93, 94
Monoclonal gammopathy 53
Multiple myeloma 54
Nutritional status 20, 22, 23
Osteoarthritis 95, 96
Polymyositis 96
Sepsis 6
SLE 99
Stroke 31, 32
55, 56
CREST syndrome 101
Crohn’s disease 46, 48, 49
Cryoglobulins 2, 53, 56, 57, 67, 68,
86, 87, 100, 118, 119, 139
Cystatin C 123
Dermatomyositis 96, 140
Diabetes 38-40, 66, 112, 114, 115,
118, 124
Drug effects 12-14, 113-116, 124,
131, 134
Embolism, pulmonary 125
Erythropoiesis 58, 59, 84, 126, 142
Estrogen 14, 22, 58, 70, 108, 110, 112,
113, 115, 117, 125, 126, 138, 143
Exercise 59, 60, 115, 117, 126, 136
Extractable nuclear antigens 99-101
Ferritin 123
Anemia 58, 59, 60
ASCVD 29
Cancer, GI 46, 48
Cancer, lung 80
Diabetes 38, 39, 40
Drug effects 14
Hemochromatosis 66
Hepatitis, viral 67
Hyperthyroidism 44
Infection 3
Inflammation 1, 7
JRA 94
Stroke 31, 32
SLE 100
Fibrinogen 124
ASCVD 27, 28, 29, 30
Cancer, lung 80
COPD 78, 79
Diabetes 38, 39, 40
Hemostasis 87, 88
Hepatitis, viral 68
Inflammation 1
Nephrotic syndrome 82, 83, 87
Sepsis 6, 7
Stroke 31, 32
Fibronectin 125
ASCVD 27, 28
Diabetes 40
Nutritional status 22, 23
Sepsis 6
Gastroenteropathy, protein-losing
45, 46, 100, 129
Giant cell arteritis 96
Glomerular filtration rate 82-84,
111, 116, 139
Glomerulonephritis 58-60, 119
Gout 118, 134
Haptoglobin 126
149
Index
Asthma 79
Diabetes 35
Gastroenteropathy, protein-losing 45
Hemolysis 50, 66, 67, 100
Hepatic disease 70
Hepatitis, viral 67
Inflammation 1, 2
Nutritional effects 20
Polymyositis 96
SLE 100
Hemochromatosis 43, 93, 117, 123,
142, 145
Hemodialysis 23, 83, 85, 125, 143
Hemoglobin 58, 59, 85
Hemolysis 30, 66, 67, 100, 126, 127,
142
Hemopexin 127
Hemostasis (renal disease) 87, 88
Henoch-Schölein purpura 87, 119,
129
Hepatic cirrhosis 66, 68, 69, 112,
123, 126, 128
Hepatic disease 21, 59, 68-71, 107,
108, 110, 112-114, 117-119, 123125, 128, 130, 131, 137-139, 143
Hepatic failure, fulminant 69-71, 124
Hepatitis, viral 23, 67, 68, 117, 123
HIV/AIDS 3, 7, 45, 53, 116, 122, 135
Hyperthyroidism 20, 22, 41, 124, 137
Hypothyroidism 41, 115, 137
Immune complexes 2, 75, 82, 85, 94,
97-100, 118, 119, 124
Immunoglobulin A 128
Amyloidosis 56, 57
ASCVD 28
Cancer, GI 46, 47
COPD 78
Deficiency 5, 93
Diabetes 39, 40
Drug effects 13
Heavy chain disease 57
Hepatic disease, chronic 68, 71
Hepatitis, viral 67
Hyperthyroidism 41
150
Infection 2, 5
JRA 94
MCTD 94
Monoclonal gammopathy 52, 53
Nephropathy
Neuropathy, paraproteinemic 76, 77
Polymyositis 96
SLE 99, 100
Stroke 32
Systemic sclerosis 100
55, 56
Immunoglobulin D 129
Amyloidosis 56
Immunoglobulin E 130
Amyloidosis 56
Asthma 79
Drug effects 13
Hyperthyroidism 41
Monoclonal gammopathy 52. 53
Waldenström’s macroglobulinemia 55
Immunoglobulin G 131
Amyloidosis 56, 57
Asthma 79
ASCVD 28
Cancer, GI 46, 47
Deficiency 5, 93
Diabetes 39, 40
Drug effects 13
Hepatitis, viral 67
Hyperthyroidism 41
Infection 2, 5
JRA 94
MCTD 94
Index
Nutritional status 21
Polymyositis 96
SLE 99, 100
55, 56
Immunoglobulin M 132
Amyloidosis 56, 57
Asthma 79
ASCVD 28
Cancer, GI 46. 47
Diabetes 35, 40
Drug effects 13
Hepatitis, viral 67
Hyperthyroidism 41
Infection 2, 5
JRA 94
MCTD 94
Polymyositis 96
SLE 99, 100
55, 56
Immunoglobulin heavy chains 57
Immunoglobulin light chains 133
Amyloidosis 56
Multiple myeloma 55
Infection 2-7, 20, 45, 53, 55, 59, 79,
86, 93, 94, 99, 118, 119, 121, 126,
129, 130, 131, 132, 133, 135, 141,
142
Inflammation 1-7, 22, 23, 27, 30, 38,
48, 58, 59, 68, 83, 93-101, 107-109,
115, 117-119, 129, 144
Juvenile rheumatoid arthritis 93, 94,
141
Lipoprotein (a) 134
ASCVD 28, 29, 30
Diabetes 40
Hepatic disease 68
Inflammation 7
Stroke 32
Lymphangiectasis 45
Lymphoproliferative disorders 3, 47,
52-57, 116, 117, 120, 124, 129, 130,
132, 133, 135, 138, 140
Malignancy 3, 20, 24, 46, 47, 48, 67,
76, 80, 93, 107, 110, 116, 117, 118120, 125, 126, 128-131, 134, 137,
139, 141-143
Mannose-binding protein 135
Infection 5, 6
Menke’s disease 117
Microalbuminuria 40
Mixed connective tissue disease 94,
95, 124, 140
M-components
Amyloidosis 56
Cancer, GI 46, 47
Cancer, lung 80
Infection 2, 5
Neuropathy, paraproteinemic 77
SLE 99
Monoclonal gammopathy 7, 46, 52,
53, 76, 79, 100, 130
Multiple myeloma 5, 54, 55, 56, 76,
111, 116, 124, 128, 131, 134
Myelin basic protein 49
Myocardial infarction 30, 119, 121,
136, 141
Myoglobin 136
Hemodialysis 85
Nephropathy, diabetic 40
Nephropathy, IgA 87, 111, 119
Nephrotic syndrome
Neuropathy 76
Nonsteroidal anti-inflammatory
agents 13, 47, 48, 97, 121
151
Index
Nutritional status 7, 20-24, 59, 70,
100, 107, 108, 110, 117, 119, 139,
140, 143
Osteoarthritis 95, 124
Plasminogen 137
Diabetes 38
Drug effects 12
Hemostasis 87, 88
Inflammation 1, 7
Sepsis 6
Polymyositis 94, 96
Prealbumin 138
Diabetes 39, 40
Hepatic disease, chronic 68, 69, 70, 71
Infection 4, 5
Inflammation 1, 7
Nutritional status 7, 20, 21, 22, 23, 24
Polymyositis 96
Pregnancy 14, 58, 107, 108, 110-112,
117, 119, 121, 123, 124-126, 132,
134, 137, 138
Protein C 87, 88
Protein S 87, 88
Pulmonary disease 78, 79, 101
Pulmonary embolism 124
Raynaud’s phenomenon 101
Renal failure 21, 40, 46, 59, 82-88, 99,
108, 111, 114, 116, 118, 122, 123,
133, 136, 139, 142, 143
Respiratory distress syndrome 65,
110, 113, 118, 137
Retinol-binding protein 139
Inflammation 1, 7
Nutritional status 7, 20-24, 70
Diabetes 39
Rheumatoid arthritis 7, 97, 98, 108,
112, 116, 117, 121, 124, 126, 128,
130, 136, 140, 141
Rheumatoid factor 140
Hepatitis, viral 67
Infection 7
JRA 93, 94
MCTD 94, 95
Rheumatoid arthritis
152
Systemic sclerosis 100, 101
Sarcoidosis 130, 140
Scleroderma
Sepsis 3, 4-7, 20, 124
Serum Amyloid A 144
ASCVD 27
Diabetes 38
Infection 4
Inflammation 1, 7
Osteoarthritis 95
Sicca syndrome 98, 99
Sjögren’s syndrome 98, 99, 116, 119,
140
Soluble transferrin receptor 142
Anemia 58, 59, 60
Still’s disease 94, 98, 123
Stroke 31, 32, 125, 134
Systemic lupus erythematosus 46,
82, 86, 87, 94, 95, 99, 100, 118, 119,
124, 130, 131, 140
Systemic sclerosis 99, 100, 130, 140,
141
Tangier disease 114, 115
Thrombosis 27, 29, 30, 69, 78, 84, 87,
88, 113, 118, 123, 124, 137
Tobacco use 13, 114
Transferrin 141
Anemia 58-60
Cancer, GI 46, 47
Drug effects 12, 14
Gastroenteropathy, protein-losing 45,
46
Hemochromatosis 66
Infection 3, 4
Inflammation 1, 7
Nutritional status 7, 20-24
Renal failure, chronic 83-85
Ulcerative colitis 48, 49, 109, 121,
126
Urticaria 109
Vasculitis 96, 97, 98, 119, 140
Waldenström’s macroglobulinemia 5,
55, 56, 76, 132, 133, 140
Wilson’s disease 65, 66, 117
FBR
www.fbr.org
Foundation for Blood Research
PO Box 190
Scarborough, Maine 04070-0190
(207) 883-4131 or (800) 639-8605

Plasma Proteins Clinical Utility

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