liverdisordersffiffiþW

"An exccllent resource for people affected by liver
disease."
past chairpcrson and presidcnt,
-l(HOLIA L ÐLlCHT,
American Livcr Foumlaticn (Crearer New York Chaptcr)
ffiffiþW ffiffiffiffiffi
EVERYTHING YOU NEED TO KNOW ABOUT:
.
.
Hepatitis C and other types of hepatitis
Cirrhosis of the liver
o Liver
.
.
cancers
Autoimmune and inherited liver diseases
Prevention, diagnosis, and treatment of liver
and ailments
diseases
,rTHE DISEASED TIVER
Aminotransferases
(ALI
and AST)
Aminotransferases are enzymes that facilitate certain chem
E
e
reactions within cells. Two major aminotra¡sferases are pre{
in hepatocytes, the primary liver cells. These are alanine ami
transferase (ALT) and âspartate aminotransferase (AST). ('
older names for these enzymes, stjll used by some doctors
clinical laboratories, were SGPT arld SGOT, respectivell'.) 1
in hepatoc¡es while AST is prer
in cells of some other tissues, such as heart and skeletal mus
ALT and AST leak out from dead or damaged cells a¡d into
bloodstream. As a result, their activities (activity is a uni
measurement used by biochemists that is roughly proporti<
to amount) in the blood can be measured. In healthy indivi
als, the activities (amounts) of ALT and AST in the blood
into normal ranges that vary slighdy from one laboratory to
other. When hepatocyte death is increased, as in hepatitis, I
and AST leak out of dying cells at grearer rates and their acl
ties in the blood are increased. Elevations in blood AIT
AST
saggest incre øse d. h ep øto cyte d.e øth.
is present almost exclusively
and,\ST
,are measu¡ed on routine blood
as
of
and nurses refer to them
also come to be
as
lng
t
liver disease. Some doc
" AI-T and AST
t
tests." This is un
blood AIT and AST activities do not relatr
tlre liver's./ønction. The activities of these enzymes in the bl
correlate roughly to the degree of ongoing liver cell deatl
damage , but not liver function.
In most cases of hepatoc¡e death, blood AIT and AST
tivities are both elevated to approximately equal Ìevels. One
table exception is alcoholic hepatitis, where for reasons that
unclear, the blood AST activity is frequently more highly
vated than the AIT activity. Blood AST acriviry, but not .A
24
activity, can also be elevated in non-liver diseases such as heart
attack and skeletal muscle damage as fhis enz]¡rne is present in
heart and muscle cells as well as in hepatocytes. Sometimes,
only the blood ALT activiry will be elevated in liver disease
while AST activity remains normal.
Blood aminotransferase activities are elevated in many difFerent liver diseases. In chronic hepatitis from any cause (e'g.t
viruses, drugs, alcohol), they are usually less than ten times norand ,{ST are also elevated in cases of acute liver cell
necrosis (death) caused by shock, drugs, toxins, viral hepatitis,
shock, for
or other insults. In cases of massive
the
toxlc
to
of
an
overdose
after
example, or
normal
aminotransferase activities can be
mal.
AIT
immediately after the injury and then rapidly return to near
normal in a few days.
The degree of elevation of blood AST and AIT activities
roughly approimates the amount of liver cell death from inflarnmation or other causes. Some individuals with hepatitis can
have significant inflammation on biopsy and only mild elevations of blood aminotransferase activities' however. In rare
ceses, some individuals will exhibit very high blood aminotransferase activities and only mild inflammation on liver biopsy' This
is one reason why liver biopsy is usually essential to the evalua-
I
tion of patients with cb¡onic hepatitis.
The most important things to remember about blood AST
and ALT activities are:
1.
Blood AST a¡d ALT activities are elevated in many different
liver cell death from inflammation or
other causes occurs. Elevations in blood ALT and AST activities are not specific for any particular diagnosis and firrther
liver
i,r
'l
jri
ir¡
iìi
i-d
II
THE DISEASED TIVER
THE TIVER DISORDERS SOURCEBOOK
diseases where
evaluation is necessarY.
2. AST and ALT activities are not "liver ft¡nction tests" despite
common jargon used by doctors and patients' ALT and AST
25
activities can be very high in someone with acute liver cell
death and reasonably good liver function who will completely recover. On the other hand, t}rey can be normal in
someone with end-stage cirrhosis and virtually no remaining
liver function.
3. Elevations of blood aminotransferase activities strongly suggest the presence of liver disease and should be evaluated by
a doctor.
4. In individuals with known chronic liver disease such as viral
hepatitis, blood AIT and AST should be periodically followed as approximate ma¡kers of the amount of liver inflamcell death.
should be tested in people at risk for
disease. Examples include those taking certarn drugs
of inthat can affect the liver and people with a past
ALT and AST
jection drug use.
Alkaline Phosphatase and
Gamrna- glutamyltranspeptidase
(
GGTP )
Two other enzyme activities measured routinely in the blood
are important to diagnosing liver disease. These are the alkaline
phosphatase and GGTP activities. Alkaline phosphatase is fou¡d
ducts
in many different cells including those
phosphatase also
and very tiny bile ducts in the liver.
present in cells of the
lntestlne,
elevated in disorders
Blood alkaline phosphatase acuvrty can
involving any of these tissues. GGTR on the other hand, is present almost exclusively in the parts of the hepatocytes that secrete bile plus the bile duct cells.
Elevations in blood alkaline phosphatase and GGTP activi-
ties, especially in the setting of normal or only modestly elevated .{LT and ,tST activities, suggest bile duct disease or
7
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ir
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26
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ffiffir,¡
?i.ìtà.ir,
knows a patient's entire history can determine if and how an
isolated elevation in blood GGTP activity needs to be evaluated
tions are usually more modest and ALT and AST activities
hepatoc¡es.
become elevated to a more significant degree when hepatocyte
death predominates.
In contrast, liver diseases that pämarily affect the bile ducrc
are characterized by more marked elevations in blood alkaline
phosphatase and GGTP activities and only modesdy elevated or
Bilirubin
Abnormally high blood alkaline phosphatase may also be
seen in a patient with bone disease. In addition, blood alkaline
phosphatàse activity may be elevated in pregnanry as it is pro-
|
¡1
Gtfr
27
abnormal bile flow. These can be diseases of either the large bile
ducts outside the liver, for example, obstruction by a gallstone
Many drugs
or cancer) or of the tiny bile ducts
resultant elof bile flow,
also cause
actlvltles.
evaü.ons rn
In liver diseases not directly affecting the bile ducts, such as
hepatitis or cirrhosis, blood alkaline phosphatase and GGTP activities may also be elevated. In these diseases, however, eleva-
normal blood ALT and AST activities.
ffii
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THE DISEASED TIVER
THE LIVER DISORDERS SOURCEBOOK
duced by the placenta. In these instances, blood GGTP activity
should be normal. If blood alkaline phosphatase activity is elevated together with serum GGTP activity, bile duct or liver disease is the likely cause.
Elevations in only blood GGTP activity can be problematic
to evaluate. SGTP activiw is an extremelv sensitive and variable
liver
test and may be elevated to
be elei¡ated in some normal individuals and
can
people with very subde and clinically insignificant liver abnorinduced bv manv,druFs. including alcomalities.
99IP-iE-aIso
hol, and lts activity in the blood may be increased in heavy
drinkers. Isolated elevations in blood GGTP acrivity suggest
liver diseases, heavy alcohol use, or
duct
can also be elevated in the absence
use.
drug
liver disease. Only an experienced physician who
of
firrther.
As is the case witfi aminotransferase activities, elevations in
blood alkaline phosphatase or GGTP activities are not diagnostic for any specific disease. Their elevations suggest disorders of
the bile ducts or bile flow. They may also be elevated to a lesser
degree than ALT and AST in liver diseases that primarily affect
An elevated concentration of bilirubin in the blood is known as
hyperbilirubinewiø. Hyperbilirubinemia occurs as a result of
four problems: l) increased production; 2) decreased uptake by
the liver; 3) decreased conjugation; or 4) decreased secretion
from the liver. The normal bilirubin concentration in the blood
is approximately less tlan I mg per deciliter. When the blood
bílirubin exceeds about 2 mg per deciliter, jaundice becomes
aPPafent.
In disorders causing increased production of bilirubin,
the indirect bilirubin concentration in the blood will be elevated. Increased bilirubin production results from conditions
that cause increased destruction ofred blood cells and not from
liver diseases. In such conditions, the di¡ect bilhübin concentra-
tion in the blood will be normal
as
long
as
liver function is not
compromised.
Indirect bilirubin concentration in the blood is also primarily increased in conditions tåat cause decreased bilirubin uptake by the liver or decreased conjugation within the liver.
Decreased bilirubin uptake by hepatocytes can be caused by
some drugs, fasting, and infections. Serious problems with
THE DISEASED LIVER
2E THE TIVER DISORDERS SOURCEBOOK
I
bilirubin conjugation almost always present in childhood' These
that
cond.itions include hereditary diseases in which the enzyrne
conjugates bilirubin is lacking or abnormal, and jaundice of premafi.ue babies in which conjugation of bilirubin is impaired'
Most acquired liver diseases in adults cause impairment in
bilirubin secrerion from liver cells that results in elevations pri-
marily in the direct bilirubin concentration in the blood' In
most ch¡onic acquired liver diseases, the blood bilirubin concentration is usually normal until a significant amount of liver
damage has occu¡red and cirrhosis is present' The rise in blood
bitirubin concentration is roughly proportional to the amou¡t
of liver dysfuIction. In acute liver diseases, the serum bilirubin
concentration usually rises in proportion to the severiry of liver
damage.
Disorders that cause obstruction of the small and large bile
ducts also cause elevations in the direct bili¡ubin concentration
in the blood. Some drugs also impede bile flow in the liver and
cause elevations
in direct bilirubin concentration' In these dis-
orders, the blood alkaline phosphatase and GGTP activities a¡e
usually elevated concurrentlY.
When the concentration of direct büirubin in the blood becomes high, some of it is filtered by the kidneys' This excreted
bili¡ubin tu¡ns the urine yellow or brown in color. Bilirubin can
also be detected bY urinalYsis.
Albumin
Albumin is the most abr:ndant protein in the bloodstream. It is
synthesized in the liver and secreted into the blood' If liver
function is abnormal, the blood albumin concentration may fall'
This usually occurs in patients with cirrhosis who have moder-
ateoradvancedliverdysfi:nction.Thealbuminconcentrationin
dJ.
29
the blood can also be low in conditions other than liver diseases
including serious malnutrition, kidney diseases, and rare forms
of intestinal dysfunction. Low albumin concentration in the
blood is sometimes referred to as hypoølbarninemiø.
Prothrombin Time (PT)
When liver function is compromised, the synthesis of several
blood clotting factors may be decreased. The prothrombin
time, often called the "PT," is a blood clotting test thet measu¡es the function of several blood clotting factors. The prothrombin time is prolonged when blood concentrations of
some of the clotting factors made by the liver are low In
chronic liver diseases, the protlrombin time is usually not significantly prolonged until cirrhosis has developed and the
amount of liver damage is significant. In acute liver diseases, the
prothrombin time can be prolonged due to severe liver damage
and then return to normal as the patient recovers. The protì¡ombin time can also be prolonged in other conditions besides liver diseases, such as vitamþ K deficiency (which can arise
from malabsorption in some bile duct diseases) and inherited or
acquired blood clotting disorders. Drugs, for example wa¡farin
(Coumadin@), which is used therapeutically as an anticoagulant,
can also prolong prothrombin time.
Complete Blood Count (CBC) and
Platelet Count
The complete blood cou¡t (CBC) is an important laboratory
test in patients with liver diseases. Although not specific for liver
problems, abnormalities may be seen on the complete blood
I
30
THE LIVER DISORDERS SOURCEBOOK
counr in patients with liver diseases. Individuals with chronic
liver disease, especially cirrhosis, can be anemic and have low
serum hemoglobin concentrations and hematocrits, which are
roughly proportional to the number of red blood cells' Patients
with cirrhosis can also have decreased white blood cells counts
(white blood cells are the cells that fight infection)' On the
other hand, the white blood cell count cari be increased in indi-
vidualswitlracuteinflammatoryliverdiseasessuchasvi¡aloralcoholic hepatitis.
An important part of the complete blood count in individuPlâtelets are the smalla1s with liver disease is the platelet count'
in blood clotting' In
involved
are
est of the blood cells and
the
individuals with cirrhosis or very severe' acute liver disease,
is
liver
the
spleen can become enlarged as blood flow through
impeded. Platelets may become traPped in the enlarged spleen
and, as a result, the platelet count can fall' A low platelet count
(thromboc¡openia) in a patient with ch¡onic liver disease sugsPegests the presènce ofcirrhosis' Low platelet counts are not
cific for liver d-iqeases, however, and can be observed in many
THE DISEASED LIVER
3I
Am¡rronia
Blood ammonia concentrations can increase when the liver fails.
Ammonia is absorbed from the intestine where it is generated
by the breakdown of proteins by bacteria that live in the colon.
Ammonia is not effectively removed from ttre blood by the failing liver or the liver with advanced cirrhosis. As a result, tìe
concentration of ammonia in the blood increases.
Elevations in blood ammonia concenrration very roughly
correlate to the degree of hepatic encephalopat_hy. Ilowever,
hepatic encephalopathy shouJd be followed by physical signs
and symptoms and not by serial determinations of the blood
ammonia. Onetime determination of blood ammonia concentration will suggest that the liver may not be properþ functioning if it is elevated. Blood ammonia concentrations can be
elevated in conditions other than liver failure, including rare
metabolic disorders.
different conditions.
Laboratory Tests of Specific Liver Diseases
Serum Protein ElectroPhoresis
Several blood tests are performed for the diagnosis of specific
liver diseases. Specific tests for viral components in serum and
antibodies against viruses are used to diagnose viral hepatitis.
for certain "autoantibodies" are useful in the diagnosis of
autoimmune liver d-iseases. Measurements of various metabolic
Tests
products or minerals are helpful in the diagnosis of i¡herited
liver diseases. Some of the various laboratory tests for specific
viral, autoimmune, and congenital liver diseases are outlined in
Table 2.2. These tests are discussed in greater detail
quent chapters on the specific liver diseases.
the liver's firnction.
in
subse-
82
THE LIVER DISORDERS SOURCEBOOK
DISEASES OF THE LIVER
Abstinence from alcohol is often easier said than done.
develop cirrhosis from chronic
Substance abuse and dependence are diseases, and a component
Some
to stop using the substance deIndividuals with alcohol dependence may suffer withdrawal upon stopping drinking and this
can prove fatal. Hospital admission for detoxification may
therefore be required for alcohol-dependent individuals. In
many cases) detoxification should ideally be followed up by inpatient rehabilitation for at least one month. Additional outpatient psychotherapy is often necessary and participation in
Alcohoiics Anonl'rnous should probably be continued for life.
atic failu¡e.
of these
diseases is an inability
spite knowing
it is harmful.
Despite this course of action, tÏe relapse rate is quite high.
Supportive medical care may be necessary for the patient
with alcoholic liver
disease
. Complications of cirrhosis
are
in chapter 3. Acute alcohol hepatitis may
require hospitalization and treatment. Some studies suggest
that steroids may be beneficial in severe cases, and other comtreated as described
plications caused by alcohol such as gastritis may also respond
to treatment. Although medical treatment is often essential to
support patients with alcohol-related illnesses, no nedicøtion or
þroceiløre is ø søbstitøte for øbstinence in the treø'tr?tønt of ølcoholic liver diseøse.
Drugs ond Toxins
Many drugs can cause liver disease. The signs and symptoms associated with liver damage induced by drugs or toxins can vary
tremendously. Many patients will have no obvious problems
and liver damage can only be ascertained by blood testing.
Some patients will have no symptoms for years and eventually
diseases
83
use or toxrn exposure.
will present as
It
is extremely important that doctors and patients realize
can cause liver damage. Â comprehensive history regarding medications-both prescription and
over-the-counter-is an essential part of evaluating a patient
with liver disease. In older adults, prescription medicarions a¡e a
major cause of liver abnormalities picked up on rourine blood
t¡at many different drugs
tests suggesting liver diseases (elevated blood aminotransferase,
alkaline phosphatase, and GGTP activities). One intelligent ap-
proach when faced
problems is to realize
blood test abnormality. This can somerimes be established by
the known adverse event profile of a drug þlus excluding other
disorders. Another way ro determine if a drug is causing a liver
problem is for the doctor (not the patient without rhe docror's
knowledge) to discontinue it. If the abnormality resolves itself,
the drug is likely the cuiprit. Restarting the drug and witnessing
return of the abnormality strongly suggests this.
After a drug is established to be-the cause of liver disease, rhe
decision to stop or continue use of the drug requires the judgment of an experienced physician. For example, mild cholestasis
i¡dicated by slightly elevated blood alkaline phosphatase and
GGTP activities may be less significant t}ran the repercussions of
stoppilg a medication to prevent seiz"'"s or psychosis. On the
other hand, continued use of a particular agent to lower blood
pressure that is causing hepatitis may nor be reasonable if
equally effective alternative drugs are available. Therefore, the
doctor's experience and judgment a¡e critical in deciding if the
risk of continuing a drug affecting the liver ounveighs the potential danger. It is not possible to provide specific guidelines
for these decisions.
Y
rI
E4 THE tf VER DISORDERS SOURCEBOOK
Overdoses ofcertain drugs or exposure to certâin toxins can
also cause acute liver disease and
failure .
Some individuals may also
(idiosyncratic
tions
tlat
can cause severe liver
ofa
generally safe drug, an example being the anesthetic halothane.
In these cases, the goal is to identify the cause of the liver disease, immediately stop the drug or toxin if exposure is ongoing,
and support the patient until liver function recovers.
It is difficult to provide an exhaustive list of drugs and com-
pounds that affect the liver because there are thousands that affect it in many different ways. In this section, I will discuss only
liver toxicities associated with commonly used drugs and classical hepatotoxins (see Table 4.ì.).
Acetaminophen
Acetaminophen is the active ingredient in many over-rhecounter pain relievers including Tylenolo. At recommended
doses and durations of treatment, acetaminophen is an extremely safe compound used by millions of people worldwide.
Despite a few unconfirmed case reports in the literatu¡e, there
are no controlled stì.rdies showing t}rat acet¿minophen is toxic
to the liver when taken as recommended on package labels. An
overdose of acetaminophen, however, is another matter.
Overdose of acetaminophen, which is also known as paracetamol in some parts of the world, was fust recognized as a
method for committing suicide in Great Britain and later in the
U.S. Overdoses of acetaminophen, usually more than 15 g at a
time in adults (each "extra-strength' tablet or capsule contains
half a gram), carr cause fulminant hepatic fajlure. Some individuals have been reported to have taken overdoses of acetamino-
-85-
I
8E THE TIVER
DISORDERS SOURCEBOOK
drug or increasing dosage. They should also be checked period_
ically while on r_he medicarions. If blood,\LT or AST activities
persistendy increase to more tha¡ th¡ee times normal, the med_
ications should probably be discontinued. Any liver inflamma_
tion induced by statins is reversible upon stopping the drugs
E9
son, Iiver biopsy to determine fibrosis is sometimes performed
after a cumulative dose of I to l.S g of methotrexare.
Anticonvulsants
Two commonly used anticonvulsants (drugs to prevent seizures)
can cause liver disease
ilantin) ceuses various
I{alothane
Halothane has been widely used over the years as a general
anesthetic. In about I in I0,000 cases, halothane causes hepatitis. The onset of hepatitis usually begins a few days to within
tiree weeks after receiving anesthesia. Halothane can induce a
mild hepatitis that is detectable only by finding elevated blood
aminotransferase actiyities, or fatal ñ¡Iminant hepatic failure.
Almost all patienrs with halothane-induced hepatitis have had
prior exposure to tÏe drug, and repeated exposure greatly increases the chance of developing hepatitis. Therefore, halothane
should be avoided in individuals for whom repeated surgeries
are anticipated or who have been exposed previously to the
drug. The anesthetics methoxfflurane and enflurane may also
cause hepatitis similar
DISEASES OF THE LIVER
to that
caused by halothane.
Methotrexate
Methotrexate is commonly used to treat severe psoriasis and
other rheumatic diseases. Chronic therapy with methotrexate
can cause fibrosis (scarring) and cirrhosis of the liver. These
changes are dose-related and most studies show that cirrhosis is
rare with total cumulative doses of less than I.5 g. Methotrexate can cause liver damage without causing abnormalities in
the aminotransferase activities or other blood tests. For this rea-
t'?es of liver damage. fts continued
use,
liver abnormalities
occur, depends upon the risk of recurrent seizures and availabil_
ity of alternative effective drugs compared to continued treat_
ment. Rare cases of acute phenytoin liver injury have been
reported tiat can.cause fifminant hepatic failure. Valproic acid
(Depekoteo) and its derivatives can also cause liver ¿iräll¿
elevations i" blSod
activities are nor uncom:
".nittggaaq&!æC
mon and should be followed by reþated blood testing. Valproic
acid can also
Valproic
acid liver
dam
)
s and ac-
cumulation of microscopic fat globules in liver cells.
Psychiatric Medications
c,6tF
Various drugs used in the treatment of psychiatric disorders
can affect the liver. Phenothiazines such as chlorpromazine
(Thorazineo) that are used to,,treat schizophrenia and other
forms of psychosis commonly cáuse cholestasis or impaired bile
flowwithin the liver. This
blood alkaline
can lead to jaundice
in the
and GGTP activities are often the
flons can cause hepatitis, and are usually inferred from elevations
in blood AIT and AST activities. Continued use of drugs for
these conditions depends upon the risk of their discontinuation
lt
I9(l
THE TIVER DISORDERS SOURCEBOOK
patient with chronic hepatitis C. They ultimately discovered
that the genetic material of this vi¡us was different tha¡ that of
the hepatitis C vi¡us. It was the sarne as that of the GB-C discovered by workers at Abbotr Laboratories.
The hepatitis G/GB-C virus appears to i¡fect humans and it
is present in the blood supply. Ir seems ro be rransmitted by
blood and blood products. IIowever, most investigators now
think that the hepatitis G/GB-C virus does nlt calse meaningfirl liver disease. The general feeling is that the hepatitis G/GBC virus is an "innocent bystander" that ca¡ infect humans but
not cause disease.
Due to their similar modes of transmission, rhe hepatitis
G/GB-C virus is often found in patients who are already infected with hepatitis C virus. These individuals do not appear ro
do any worse than those infected wirh only hepatitis C. At the
present time, there is probably no reason to test patients for infection with the hepatitis G/GB-C virus. This recommendarion
may change should it ever be clearly established that it can
cause liver disease. Testing for hepatitis G/GB-C virus in blood
by ?CR is available commercially er some clinical laboratories.
DISEASES OF THE LIVER I!
Some viruses that are generally harmless in healthy indir"idt
als may cause liver disease in patients with compromised irr
mune systems. These viruses may infect patients with AIDS c
cancer. They may also infect patients who have received orga
transplants and a¡e taking medications that suppress their in
mune systems. The most important of these viruses is c1
tomegalovirus or CMV. Cytomegalovirus can cause hepatitis i
recipients of organ transplants, including transplanted liver
CMV can also cause hepatitis and serious bile duct abnormal
ties in patients with AIDS.
Some doctors
will test patients with chronic hepatitis for ar
tibodies against CMV a¡d EBV. These viruses are endemic i
the human population and the detection of IgG antibodie
means virtually nothing. Furthermore, these two viruses do nc
câuse any significant chronic liver disease in people with norm¿
immune systems. If someone tells you that you have chroni
hepatitis caused by EBV or CMV, you should be suspicious.
Fotty Liver
Other Viruses that Cause Ilepatitis
Hepatitis A, B, C, D, and E viruses are the major hepatotropic
vi¡uses that cause liver disease in humans (there is no hepatitis
F). Some other viruses ca¡ also cause acute liver disease in otherwise healthy individuals. In most cases, these viruses cause
systemic diseases that concurrently affect the liver. These vi¡uses
included dengue virus, yellow fever virus, and Epstein-Barr
virus (EBV), which causes mononucleosis. Individuals with
mononucleosis can suffer from a mild form of acute hepatitis
that always resolves. Available data suggest that pox virus and
measles virus may cause chronic hepatitis in child¡en.
Definition and Symptoms
Føtty l.ber arrd steøtosis are terms used to describe a pathologica
observation and not a disease per se. In response to various in
sults, fat accumulaies in the hepatocytes in either large droplet
(macrovesicular) or tinv litde droplets (microvesicular). Thi
on liver biopry So#óf the insults tha
cause fat accumulation in hepatocytes are listed in Table 4.I1.
Although, stricdy speaking, it is a pathological diagnosis, thr
term fø.fly lber is frequently used to refer to a clinical entity
Generally. it is used to describe what would be diaenosed bv :
ãÌãa@úseen
DISEASES OF THE LIVER I93
192 THE LIVER DISORDERS SOURCEBOOK
alcohol use. The initial appropriate blood resrs are for hepatitis
B surface antigen and antibodies against the hepatitis C virus to
exclude ch¡onic viral hepatitis. Ifinvestigation reveals no history
of excessive alcohol consumption a¡d no evidence of hepatitis B
or hepatitis C virus infection, fatty liver is often suspected.
O@
and autoimmune hepatitis shoutd
also be excluded as possibilities where appropriate. The d.iagnosis is more strongly suspected in individuals who are obese or
have diabetes mellitus.
Many doctors will perform an ulüasound examination on
patients with elevated blood ALT and AST activities even
though there are few, if an¡ conditions that cause asl,mptomatic
elevations in these lab tests that can be diagnosed by this procedure. Sometimes an ultrasound scan is reported to be ,.consistent with fatty infiltration of rhe liver.,' Fat has a different
ultrasound density than normal liver tissue and the presence of
fat in the liver can be søggested. úy ultrasound examination.
IIowever, tåe detection of fat density on ultrasound examination cannot clearly establish tJ're presence of fat in hepatocytes.
Furthermore, ultrasound cannot distinguish betvveen steatosis
and steø.tlhepøtitis, a t1,pe of inflarirmation associared rvith fat in
hepatocytes. Furthermore, in patients with steatosis or sreato-
pathologist as macrovesicular steatosis and not attributable to
alcohol. Patients usually do nothave symptoms or physical signs
of liver disease. Abnormalities usually detected by routine blood
tests, or tests performed to evaluate other conditions, are usually the first indications of fatty liver. Patients with fatty liver are
usually, bu.t not always, obese and/or diabetic.
hepatitis, the ultrasound examination will frequently be normal.
IJltrasound, and for that matter CAT scan, are not reliable tests
for the diagnosis of farty liver. The diagnosis of fatty liver can be
made only by liver biopsy.
Tlpicall¡ "farry liver"
is suspected when:
1. The patient has elevated ,LLT and/or AST activities on
blood tests.
2. The patient does not drink significanr amounts of alcohol
Diøgnosis
lVhen a patient is found to have elevated ALT and AST activities in blood tests. the first ouestions asked usuallv concern
3.
and does not take medications t}rar can affect the liver.
The patient is usually (not aìways) obese and/or suffers from
diabetes mellitus.
19ó THE I.IVER DISORDERS SOURCEBOOK
. Weight loss
if
obese or even
if slightly overweight
. Better control ofblood sugar ifdiabetic
. Low-fat diet
. Aerobic exercise
. Strictly limit or avoid alcohol
Patients who are obese, or even only slightly overweight,
should lose weight. In the experience of many liver specialists,
and in small observation studies, weight loss has been shown to
improve fatty liver based upon return of blood ALT and AST
activities to normal. Weight loss is best achieved by a combination of diet and exercise; either one alone will not be as efÊcient.
Even in patients who are not overweight, or once a patient
reaches ideal body weight, a low-fat diet and exercise should be
continued. People who have, or have had, fatty liver are likely
predisposed to develop it. Therefore, such individuals should
pay careful attention to maintaining a low fat intake and to
"burning off"
fats by aerobic exercise.
Alcohol is the major cause of fatty infiltration of tÏe liver, and
NASH appears identical to alcoholic hepatitis on liver biopsy.
Common sense therefore dictates tìat patients with steatosis or
steatohepatitis should limit alcohol intake, although there is no
strict lower limit. Besides its direct effects on the liver, alcohol
also contains needless calories tåat are best avoided. Patients
with steatohepatitis should probably completely refrain from alcohol consumption. Although there ere no studies to suPport
it, ttre fact that steatohepatitis and alcoholic hepatitis look so
similar strongly suggests that alcohol will worsen the condition.
Steatosis añd steatohepatitis can be present in patients with
diabetes mellitus, and diabetics whose blood sugars are less well
controlled may be more likeþ to develop them. Tight control
of blood sugars should therefore be attempted in diabetics with
fatty liver.
DISEASES OF THE TIVER I9I
Overall, the prognosis for most patients with fatty liver is
quite good-from a stricdy 'liver point of view." IIowever,
$çatohepatitis can lead to ci¡rhosis. And although no snrdies
have proven this, steatosis
turn rnto steatohepatitis if the
patient accumulates excess
Therefore, patlents
steatosis
should make the necessary lifestyle changes to prevent this from
ønd
otreøted.' by møin-
øn overøll heøbhy ltftttyh.Eating well, exercising, main-
taining ideal body weight, and limiting alcohol intake will
improve not only fatty liver but also, perhaps even more signiûcantly, owrøllhealth. I often tell an obese patient with fatty liver
thatsdf although ttre fat in the liver will probably nor lead to
significant liver disease, oyou showld thinþ øboøt whøt excessipe
føt in yoør bod.y will do to yoør lteørt.'Patients with fatty liver re sulting from obesity and poorþ controlled diabetes are ar increased risk
for serious
diseases such as
heart attack, stroke, and
possibly carcer. Obese patients with fatty liver who lead unhealthy lifestyles should consider fatry liver a wørning sþn for
development of other serious diseases. They should heed t-his
warning and start living healthier lives.
Auloimmune Liver Diseoses
.tutoimmune diseases are those in which tissue injury is caused
by the person's own immune system attacking the body. Some
autoimmune diseases, such as systemic lupus erythematosus, ere
"systemic" in that many dìfferent organs are attacked. Others
are relatively organ-specific, including the liver diseases we will
discuss in this section.
0
I94
DISEASES OF THE LIVER I95
THE LIVER DISORDERS SOURCEBOOK
4. Hepatitis B and hepatitis C vi¡us infections are reliably
ex-
cluded by history and laboratory testing.
5. Metabolic and autoimmune .liver diseases are unlikely based
upon history and, if necessary, the results of laboratory testing.
ó. An ultrasound examination is done and mây or may not be
consistent with fatty in-filuation of the liver.
At this point, what will most doctors do) And what should
be donel As in many other a¡eas of medicine, there are no absolute right or wrong answers.
One important consideration is whether elevations in the
blood ALT and/or AST activities have persisted for more than
six months. In patients presenting for the fi¡st time with only
modest elevations in the aminotransferase activities, when other
causes of liver disease have already been reliably excluded, it is
k
reasonable to perform repeat blood testing over the next six
monflrs. If physical examination atd/or laboratory tests such as
bilirubin, albumin, *dggþgþL" time suggest abnormal
liver function, however, liver biopsy should probably be performed sooner.
if the patient has had elevations in blood ALT and
activities for six months or longerf If tìe diagnosis of fatry
What
AST
liver is strongly suspected on clinical grounds, for example, if
the patient is obese and/or suflers from diabetes) many doctors
will defer liver biopsy and say that the patient has "fatty liver."
I
have already mentioned, the diagnosis can be suspected
b:ut not diagnosed without a liver biopsy. For these reasons'
most liver specialists would probably perform liver biopsies in
patients suspected of having fatty liver to definitely establish tÏe
But
as
diagnosis.
Why is liver biopsy critical in the evaluation of patients with
suspected fatry liverì First, it ís the only way to establish the diagnosis. Second, it is necessary to exclude other possible condi-
tions that were deemed to be unlikely based on history, physical
examination, and laboratory testing. Even in patients in whom
fatty liver is strongly suspected, a¡other diagnosis will sometimes be discovered by liver biopsy. Third, liver biopsy is the only
d this is
wø1 to
a critical distinction. Steatohepatitis, which is often called nonølcoholic steøtobepøtitis or N,4SII if it is not caused by alcohol
consumption, carries a worse prognosis than steatosis. Patients
with steatosis probably do not have progressive liver disease.
Ilowever, 'l{,4.Sfl cøn prlgress to cirrhosis ønd cøn be d.iøgnosed.
only by liver biopsy. A doctor cø.nnlt state that you have NASH
without doing a biopsy.
To summarize some of the major points about fatty liver and
its diagnosis:
l.
The most common causes of fatty liver (excluding excessive
alcohol consumption) are obesity and diabetes mellitus. It
can occur in individuals without these conditions, however.
2. Eatty Iiver can be suspected but not diagnosed without performing a liver biopsy.
3. Fany liver can be definitively diagnosed only by liver biopsy.
4. The distinction benveen steatosis and steatohepatitis can be
made on-ly by liver biopsy.
Treøtm,ent
How is fatty liver treatedl To the best of my'knowledge,
there are no prospective randomized studies that have established this. Based on clinical experience and common sense,
however, it is likely t}rat several reasonable interventions will
"cure" or improve steatosis and steatohepatitis.
The basic approach to treatrnent is to remove the r:lderlying
cause of fatty infiltration of the liver and lessen exposure to
things that can worsen it such as:
)
c
Vv (A
214 THE IIVER DISORDERS
OURCEBOO
ø.nd. follow -øp
Current medical
Treø,tn ent
on PSC.
not have a significant iinpact
(Actiga[ or lJrso improves laboratory test
that it does not prolong
results but
survival until liver transplantation is necessary. Treatment in patients with PSC is directed at complications. Itching can be
treated with bile acid-binding resins such as cholestyramine and,
possibly, the opioid antagonist naltrexone. Deficiencies in fatsoluble vitamins, such as vitamin K *d vitamin D, are treated
by supplementation.
Episodes of bacterial cholangitis can be life threatening, and
immediate antibiotic therapy in the hospital is necessary. There
may be some role for dilatation of dominant bile duct strictures
by ERCP in some cases of PSC, but there have been no controlled trials proving t}tat this is effective. If søch ø. þrlced.nre is
recornrnend.ed., ø physic,iøn with considerøble experience in treøting pøtients with PSC should. be consølted. Inappropriate or im-
properþ performed procedures to dilate the bile ducts can be
dangerous and lead to additional damage, worsening the patient's prognosis. As there is an increased incidence of cholangiocarcinoma in patients with PSC, this should always be
suspected, especially in patients with long-standing disease
whose condition worsens. Therefore, ERCP or CAT scan to
look for bile duct cancer may be necessary in a patient whose
'
condition deteriorates.
Liver transplantation is higtr-ly effective in the treatment of
patients with advanced liver disease caused by PSC. Indications
for liver transplantation are complications of cirrhosis. In some
cases, patients with PSC and recurrent, life-threatening episodes of bacterial cholangitis werrant consideration for liver
transplantation.
DISEASES OF THE
Ti
lnheriled Liver Diseoses
frorn ølterøtions in ø single gez¿. These disreferred to as .,inherited" or ,.genetic." They
are also said to demonstrate Mend.eliøn inÍteritønce. The term
Mendeliøn derives from the monk Gregor Mendel, who was the
frst person to describe single gene inheritance based on his
work breeding pea plants (an excellent database of human genetic disease is Dr. Victor McKusick's ,.Online Mendelian
Some d.iseøses resølt
eases are generally
Inheritance in Man," which can be found on tlre \4/orld Wide
Web at URI- hnp / /www3.ncbi. nlm. ni h. gov/ Omim/
).
In genetic disorders, the normal gene is referred to as wild.tyþe and the gene that causes the disease as mutønL In øøtosowøl d.owiniz.nt disorders, affected individuals need possess
only one mutant copy of the responsible gene to cause disease.
In øutoso¡nøl recessive d-isorders, a¡ individual with the disease
must have two copies of tÏe mutant gene . Individuals with two
copies of a mutant gene are said to be hornozygotes.Individuals
:
with
are
or ttca¡riers." Some genetic dis-
on by mutant genes on
X chromosome. In
mammals, females have two X chromosomes and males only
one. Therefore, in X-linh¿l recessive disorders, men need have
only one copy of a mutant gene to have a disease while women
eases are passed
need to have two.
The most important inherited liver diseases are aurosomal
recessive. Theiefore, a brief discussion on their pattern of inheritance is warranted. If a heterozygote, or ,rcarrüerr" breeds with
an individual with two wild-type genes> none of the ofßpring
will have the disease but 50 percent of the ofßpring will be carriers of the mutant gene. If two carriers breed, 50 percent of
,K
216 THE LIVER DISORDERS SOURCEBOOK
DISEASES OF THE
the ofßpring will be carriers, rvirh 25 percenr having the disease
and 25 percent having two copies of the wild-type gene. If an
f,.
individual with the disease breeds with a carrier, 50 percent of
the ofßpring will be carriers and 50 percefrt will have the disease. If two individuals with the disease breed, I00 percent of
the offspring will have the disease. If someone with the disease
breeds with a normel individual, all the offspring will be carriers. These situations a¡e oudined schematically in Figure 4.ó.
A detailed discussion of all inherited diseases that affect the
liver is beyond the scope of this book. This chapter will address
the "big three" : hereditary hemoch¡omatosis, alpha- I -antitrypsin
d.fi.i.n.¡ and Wilson disease. A discussion of Gilbert syndrome, a very common i¡herited condition that causes elevated
unconjugated bilirubin concenrrations in the blood and sometimes jaundice, is also included. For additional details on rlese
conditions, and for information on the more esoteric genetic
liver diseases not discussed in this book, I refer all readers to
"Online Mendelian Inheritance in Man" (http:/ /www3.ncbi.
nlm.nih. gov/O mm/ ) on the Internet.
Nornol
(onier
efCI ry er-@ w
il-t-t-t tú-t-t fr-t-t-t t-t-ú-t
[onier and
Affeced ond Normol
(orrie¡ ond
[orrier ond
Key: I
*
l*
l*
Àffeded
Affeced ond Affeaed
Normol chromosome
Chromosome with mufont gene
Fother's chromosomes
Mother's chromosomes
tigure 4.ó. Schemolic diogrøn showing polterns of inherílønce în on oulosonol rccessíve
genelic diseose.
LI
I{emochromatosis
Heredita¡y hemoch¡omatosis, or primary hemocb¡o'inatosis, is
the most common inherited disease in persons of European descent. It occurs in 3 to 5 people in I,000. About I in I0 individuals a¡e carriers who possess one copy of tÌre mutant gene.
People with hereditary hemochromatosis have increased absorption of iron resulting in excess deposition in the liyer. heart,
joints, and otlrer organs. This abnormal accumulation of iron
can cause cirrhosis, heart disease, arthritis, diabetes mellitus, pituitary gland abnormalities, and a bronze coloring of the skin.
The problem with hemoch¡omatosis is that in most cases,
tÏe disease is not diagnosed until complications develop. Most
individuals will have high body iron for many years without
symptoms. Men usually present with symptoms earlier in life
than women because youngerwomen constantly lose iron during menstruation. Many patients have ci¡rhosis of r¡nclea¡ cause
until a liver biopsy indicates increased iron content. Sometimes,
patients will present with complications from iron deposition in
other organs such as arthritis, diabetes, or heart disease. These
may occur along with, or independendy from, liver disease .
The diagnosis of hereditary hemochromatosis is suspected.
from the results of blood tests suggesting elevated body iron
concentrations. There are tìree simple blood tests related to
iron metabolism: iron, transferrin saturation) and ferritin.
Elevations in these, especially elevations in both transferrin saturation and ferritin toget¡er, suggest, but are not specific for, hemoch¡omatosis. A diagnosis of hereditary hemochromatosis is
usually made by liver biopsy and determination of liver iron
content. The doctor should send a sample of liver tissue obtained from the biopsy for measurement of iron content. In
hereditary hemochromatosis, the liver iron content is significandy elevated.
a
0
2IE THE
DISEASES OF THE LIVER
TIVER DISORDERS SOURCEBOOK
For many years, it was known that the gene resPonsible for
hereditary hemoch¡omatosis was on chromosome 6. In 199ó,
investigators at the biotechnology comPany Mercator Genetics
identified a candidate gene for hemochromatosis on this chromosome. They initially called this gene HL,A-H, but the name
IIFE is now recommended for this gene- It appears that about
ü
B
fl
H
H
q
is;rather late and organ damage, such as cirrhosis, has already
occurred.
rSecondary hemochromatosis is a condition thar mimics
hereditary hemochromatosis. Secondary hemochromatosis results from iron deposition in the body, including the liver, sec-
ondary to nongenetic causes. A common cause is repeated
90 percent of individuals with hereditary hemoch¡omatosis have
tlre same mutation in the IIFE gene, which can be detected in
blood transfusions over many years, as may be necessary in individuals with blood diseases such as tlalassemias. Some individu-
the laboratory.
The genetic test for mutations in the HFE gene now plays
als
an important role
with alcoholic liver
disease
so dev CI op secondary
hemoch¡omatosis for unclear reasons
in diagnosis of carriers and patients with
It
is especially important in
screening the children, brothers, and sisters of patients with the
disease as ttrey are also at risk. Some doctors may argue that
liver biopsy is not essential if heredita¡y hemochromatosis is diagnosed by genetic testing. Others will state that biopsy is still
necessary to establish
ence or absence of cirrhosis. Because the genetic test is relatively new, no studies have yet been completed assessing the
need for liver biopsies in patients in whom hereditary he-
hereditary hemochromatosis.
*
219
mochromatosis is diagnosed using the genetic test.
There is an effective treatment for heredita¡y hemochromatosis if the disease is diagnosed early' As the damage to organs in hemoch¡omatosis results from excessive iron deposition,
lowering the body's total iron load will prevent it- The treatment, t¡erefore, is "blood letting" or, in medical terminology,
phlebotomy. Repeated ptrlebotomy is performed to reduce the
red blood cell count to a level slightly below normal' It is maintained there by periodic repeat phlebotomies. If hereditary hemochromatosis is diagnosed earl¡ phlebotomy is extremely
effective in preventing ensuing complications. IJnfornrnatel¡
hereditary hemochromatosis is frequently not diagnosed until
it
Alpha- I -Antitrypsin D efi ciency
Inherited deficiency of the protein alpha-l-antitrypsin, which is
in t}re liver and secreted into the blood, can cause
h:ng and liver disease. The major function of alpha-l-antitrypsin
in the body is to inhibit tÏe fi:nction of an en4.ryne known as
elastase. Elastase breaks down a structural component of the
lungs known as elastin. If its activity is not partially inhibited by
alpha-I-antitrypsin in the body, excessive lung damage and emslmthesized
physema may occur.
Certain mutations in the gene for alpha-l-antitrypsin lead to
production of an abnormal form that is not properly secreted
from liver cells. The mutant form of alpha-l-antitrypsin that
causes this abnormality is known as the Z murarion. In individuals who have inherited two abnormalZ genes, about 85 percent
of synthesized alpha- I -antitrypsin accumulares in hepatoc¡es
and forms aggregates. Retained aggregates of the Z form of
alpha-l-antitrypsin in the liver can cause hepatitis and evenrually cirrhosis.
)
12.
Hepatitis
226
Llvnr rrssur
Metabolic Causes of Hepatitis
227
Treatment
CHANGES
as
The chelating compounds D-Penicillamine and trientine hydrochloride are used to bind and remove excess copper. Treatment used life-long
is effective although at the onset improvement is slow, usually taking six
months for noticeable effects. Failure to improve after two years of therapy suggests that irreparable tissue damage may have occurred. Elemental
zinc is also used to reduce the absorption of dietary copper in patients who
show a poor respense to chelating agents.
Individuals with genetic test results indicating homozygous lVilson's
disease respond well to treatment even in the absence of overt symptoms.
Wilson's disease can cause coPPer deposits to accumulate in the
Studies indicate that early treatment prevents copper accumulations and disease progression. Untreated, Wilson disease is progressive and fatal. Fatality is also high in cases of fulminant hepatitis caused by Wilson's disease.
Death is caused by liver failure and related bleeding abnormalities.
Wilson's disease causes a condition of liver cell destruction known
of glycogen, and fatty changes'
KIDNEY, BRJ,IN, AND OTHER ORGAN CHANGES
Pregnancy
Women with untreated Wilsons disease may have fertility problems
and a higher rate of miscarriage. In women who become pregnant, both
the mother and infant are considered at high risk. Women who are treated
successfully and have nearly normal body copper levels regain fertility and
are reported to have uneventful pregnancies and normal babies.
insuffi ciency (hypoparathyroidism).
Iron Overload States and Hemochromatosis
Diøgnosis
Iron metabolism
lron is derived from dietary sources and supplements. Iron is central
to aerobic metabolism and is found in various enzymes and orygen-binding components of protein. Depending on the body's stores, about 1-1.5 mg
of iron is absorbed daily from the 10-20 mg of iron usually provided by
diet. The iron is added to a nutrient pool and distributed as needed.
a
(two alleles with the
even in the absence
sons disease show
Some
coPPer transPorter gene
nt) and should be treated
howing an elevated liver
copper level is used to confirm Wilson s disease'
Itr,r¡cwc resrs
Imaging tests are generally not required for diagnosis' Brain scans may
show an"eniarg.rn.ni of the ventricles, and MRI may show localized
anatomical changes.
li
of the absorbed iron is stor
cells. Degraded
as
some
ody's
ferritin molecules are converted into
rr fm
a compound known
hemosiderin, which can be identified as blue granules in cells stained
with special dyes.
Normall¡ the body contains about 4 grams of iron. About 3 grans of
this iron are present in the protein components of blood (hemoglobin) and
muscle (myoglobin) and in respiratory enzymes. About 0.3 grams of iron
stored in the liver and another 0.2 grams are stored in other tissues
including the pancreas and adrenal glands.
WW
evWv5Tþ4'+y
12.
Hepatitis
228
Iron overload
Hemochromøtosis
body to retaln excesHemochromatosis is a condition that causes the
iron uptake and
regulate
that
controls
normal
The
sive amounts of iron.
Hemochrooverload.
iron
release are disruPted in this condition, causing
hereditarY
called
condition
matosis is PrimarilY caused bY a genetic
to
secondarY
occur
also
(HH).
may
It
hemochromatosis
red blood cell
sideroblastic and sickle-cell anemias, and beta
as a side effect of excesthallassemias. Hemochromatosis may also occur
transfusions
blood
multiple
from
or
sive iron therapy
Hen¡ott¡rv
HEMocHRoMATosIS
(HH)
heart, skin and intestinal lining'
Disease course
in HH and iron orerload
butwhen they
Chil,dren rarelydevelop symptoms of hemochromatosis'
increased skin pigmentado they show a more acutå dittåte course with
pigmentation is. due
Bronze
tion, endocrine changes and cardiac disease'
superficial epideratrophied
an
and
layer
basal
io il.r."r.¿ melanin in the
Metøholic Cøuses of Hepøtitis
229
mis, resulting in skin that is shiny, thin and dry with a gray-bronze cast.
The liver may be enlarged and firm with fast progression to cirrhosis.
Typicall¡ hereditary hemochromatosis is diagnosed in adults who
present with symptoms of hepatitis, diabetes, heart disease or decreased
pituitary function. About 70 percent of adults present with cirrhosis; 55
percent present with adult onset diabetes; 20 percent present with cardiac
failure; 45 percent present with joint inflammation and pain; 80 percent
present with skin pigmentation; and 50 percent present with sexual dysfunction. As liver damage increases, ferritin levels rise, and an increased
ferritin level is one of the first signs of hemochromatosis. In other conditions of iron overload, iron levels, transferrin, ferritin, and total iron binding capacity (TIBC) rests aid with diagnosis.
Genetics
There are five major subtypes of hereditary hemochromatosis and a
of different subgroups. Most HH is caused by Type I HH.
Hemochromatosis Type 1, which is considered classic HH, is an autosomal
recessive disorder caused by a defect in the HFE gene on chromosome 6,
which regulates iron absorption. There are at least 40 different alleles on
this gene but most mutations occur on C282Y-and-ÉI6,ilÀ¡¿hich is the most
common mutation. In Caucasians, about 0.5 percent of the population has
a homozygote distribution (affected), and 8-10 percent of the population
are heterozogyte carriers. In the United States about I million people are
affected by HH. Carriers dq,not develop hemochromatosis but show disturbances of iron metabolism that lead to hemolytic anemia. The disease
is most prevalent among individuals of Celtic descent, such as the Irish,
Scottish, and Welsh.
so known as juvenile hemochromatosis. It is an autosomal recessive disorder that occurs in two distinct forms. Mutations on
the HJV (hemojuvelin protein) gene are seen in HH Type 2^A, and mutations on t
seen in HH type.2B. These
genes are
nile HH may occur in the
teens but usually occurs in the second and third decades oflife. Iron accumulates more rapidly than in adult-onset forms of HH. Congestive heart
failure or arrhythmias caused by accumulations of iron in heart tissue may
cause fatal heart failure before age 30.
HH Type 3 is caused by a mutation on the transferrin receptor gene
(TFR2) on chromosome 7, andÉHType 4 is caused by a mutation on the
$!j$lg.re regulating ferroportin on chromosome 2.Type 4 HH is the
only form that has an autosomal dominant pattern. Patients with HH Type
4 usually develop excessive iron stores in the Kupffer cells of the liver
number
X
12.
Hepatitis
230
Metabolíc Cøuses of Hepatitís
although their blood levels of iron may be low' Some Type 4 HH patients
have high transferrin saturation
hlebotomy is performed
moglobin and iron levels
with excessive iron stores in hepatocytes.
fall into the normal range. Periodic monitoring of ferritin helps in determining when future phlebotomies are needed. The hormone
Diagnosis
may
Hemochromatosis is suspected in patients with signs of liver disease
or diabetes with high levels of serum iron, Percentage transferrin saturation and ferritin. Patients with HH usually have elevated ALT and AST
Inborn errors of metabolism (IEM) are rare disorders caused by genetic
defects that result in the abnormal s)¡nthesis or metabolism of proteins, carbohydrates or fats. Although each IEM is a rare disorder, collectively IEMs are
ed transferrin sa
ug/l in women or greater than
for hereditary hemochrospecitc
300 ug/l in men) is more than 90 percent
matosrs.
Hereditary hemochromatosis accounts for five percent of all cases of
150
common disorders that can show up at birth or later in life. The incidence of
IEMs is between I in 4000 and I in 5000 live births, and the prevalence of some
IEMs is increased in certain ethnic groups. The effects or symptoms in IEMs
are related to toxic accumulations
ilybe
metabolized or by deàciencies of
pro-
cirrhosis and is often confused with other forms of cirrhosis. Liver biopsy
has been the traditional method of confrrming diagnosis, with high levels
of liver iron indicators of disease. In recent years, newer' genetic tests for
the HE mutation are more often used to confirm diagnosis. In addition,
when
duced. IEMs are suspected
consistent with metabolic disorders, especially if there is a family history of disease
or early infant death. Blood and urine tests for amino acids and genËtic profiles
can be used to diagnose IEMs. The following IEMs can cause hepatitis.
MRI tests can also be used to measure liver iron levels'
Orunn IRoN
:,1
.,c
ï
i.,l
:1
id
rï
liìi¡
sroRAGE DISEASES
other conditions of iron storage can cause s)¡rnPtoms similar to those
of hemochromatosis. These conditions include genetic mutations causing
low transferrin levels; abnormal forms of ferritin related to bronchial cancer; porphyria cutanea tarda, erythropoietic siderosis, a condition of
in.r.us.å iron deposits in various body cells; and sideroblastic anemia.
Galøctosemiø
Galactosemia is a rare autosomal recessive disorder affecting one in
ofblood glucose and reducing substances in the urine, and the inability to metabolize galactose, a constituent
in milk. Affected infants lack the enzyme needed to metabolize galactose.
Symptoms in galactosemia include vomiting, diarrhea, jaundice, liver damage, failure to thrive, cirrhosis, cataracts, kidney damage, and mental retardation, after ingesting milk. Many states now include galactosemia
screening in their neonatal blood screening profiles.Treatment includes a
diet free of milk and milk products.
62,000 people characterized by low levels
Risk factors
1
several factors contribute to increased iron stores. These include maldeûcienc
hemodial
blood tra
Tyrosinemia
ough the
of neonatal hemochromatosis.
Tyrosinemia is a genetic disorder causing liver disease, low blood sugar,
and kidney damage caused by the inability to metabolize the amino acid
t¡rosine. In severe liver disease, tyrosine crystals are found in urine.
Treatment
Iron can be removed in a Process ofvenesection phlebotomy (removal
ofblood through a needle similar to withdrawing blood from blood donors)
at rates as high as 130 mg/day. Large quantities of blood must be removed
of 500 ml removes about 250 mg of iron and
in the process.
grven to
Inborn Errors of Metabolism (IEM)
ï#i'ï:,iä;
with an increased ferritin (greater than
231
,
Alph a- 1- øntitr y p s in def cien cy
Alpha-l-antitrypsin deficiency is an inherited condition occurring in
apþroximately one in 5,000 live births. It is the most common genetic dis-
t
232
ease
Hepatitis
for which liver transplantation is done. In this condition, which is
caused by a defective gene on chromosome 14, the liver's production of the
amino acid alpha-1-antitrypsin is impaired' Without the normal protective
properties of alpha-l-antitrypsin the lungs and liver are damaged.
The normal range for alpha-l-antitrypisin is 100-190 mg/dl. Alpha-l-
antitrypsin deficiency is diagnosed by demonstrating very low blood
levels of alpha-l-antitrypsin (less than 100 mg/dl) and with an alpha-lantitrypisin genotype profile showingaZZ or SS genotype causing a
homozygous recessive disease. Carriers have aZlrrcn-Z or Slnon-Z genotype. The genotype in unaffected people is non-Zlnon-S. When results are
inconsistent, a phenotype is performed.
Hereditary fructose intolerance (HFI)
Hereditary fructose intolerance (HFI) is an autosomal recessive disorder characterized by nausea, abdominal pain, liver inflammation, low
blood sugar, and elevated urine fructose levels. Infants with this disorder
appear normal at birth, only showing symPtoms when fed formulas high
in fructose or fruit juices. Fructose is a naturally-occurring fruit sugar, and
it also occurs as a synthetic sweetener in foods and drinks- Patients with
HFI also react to table sugar or sucrose, which is cane or beet sugar.
HFI is caused by a deficiency of the enzyme fructose-l-phosphate
aldolase activity. This deficiency results in an accumulation of fructose-lphosphate in the liver, kidney and small intestine. This accumulation, in
turn, inhibits the normal breakdown of glycogen and the normal s)¡nthesis of glucose. The result is an extremely low blood sugar (hypogþemia)
following the ingestion of glucose or other sugars. Prolonged fructose ingestion in infants with this disorder ultimately leads to hepatic or renal failure and death. Treatment consists of a diet free of fructose and sucroseThe incidence of HFI varies among different ethnic groups. Due to the
difficulty in diagnosing HFI, the true incidence of this disorder is unknown
but suspected to be about 1 in 10,000 Persons. Diagnose is made by analyz'
ing aldolase activity in liver biopsy specimens or by a fructose tolerance test
in which fructose is administered intravenously under controlled conditions, and levels of glucose, fructose, and phosphate levels are tested. A
DNA analysis is also available to test for hereditary mutations but a negative result does not rule out HFI because there may be other causes'
Ly so s omal sto rage di sorder s
Lysosomal storage disorders are a grouP of hereditary disorders that
interfere with the normal storage and processing of lipids. Several of these
disorders, for instance cholesterol esterifcation defect secondary to a defect
12.
Metabolic Causes of Hepatitis
233
in cholesterol trafficking (formerìy known as Neimann_pick
type C disease)
can cause neonatal hepatitis.
Neonatal Hepatitis
Neonatal hepatitis is a conditio r of river inflammation
occurring from
childb.irth to the age of rwo months. Symptoms
include jaundice, failure
to thrive, enlarged liver and enlarged ,pl.årr. th.r.
symptoms are similar
to those ofbiliary âtresia, anotheilivei disease
,..n irf"".y
bile duct destruction. However, infants with biliary
i'
biochemical abnormalities and show normal g.o*¡r.
l""r.Jti
atresia have different
About
.bacterial
20 percent ofall cases ofneonatal he"patiti
infections contracted around the time o
cytomegalovirus, rubella, congenital syphilis,
toxop
tion, human immunodeficiency virus, ui."f
fr.p",i,ir, and herpes. Most cases
are not identified and referred to as idiopathic
conditions. flo*.lr.r, *i.ì
family history indicates IEMs and the
neonatal hepatitis is often found to be
cystic fibrosis, shock in congenital hea
atitis, and other infections in which th
of virus isolated or inborn error of
t cell hepatitis (idiopathic hepatitis)
mplications. phenobarbital is some_
Non-Alcoholic Fafty Liver Disease (NAFLD)
Non-alcoholic
fatty liver disease (NAFLD) is a condition of excess
accumulations of fat in the liver caused by conditions
other than alcohol
abuse. NAFLD can occur in obesit¡ in diabetes,
in rapid weight loss, as a
complication of pregnanc¡ in tuberculosis,
in malnutrition, as a consequence of intestinal bypass surgery for
obesit¡ and as
a side effect
tain
ofgg
ls one
most common liver
seen in the United
to 24 percent of the population, including 90 percent of obese people and 50 percent of
people with type II diabetes. people who carry excess weight around their
abdomen or waist have a higher
¡isk than people with lower body fat.
States and may affect rtp
liver disease steatosis
Fatty liver
or steatosis is caused by increased accumulations
of fat in the liver. Fatty liver disease affects people
of all ages, including