CPC: A 74-year-old white female with elevated LFT`s and fatigue

Clinical Pathology Case
Gastroenterology
October 7, 2005
Ari Banerjee, M.D.
Chief Complaint
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74 yo wf presents to liver clinic with
elevated Liver FunctionTests (LFT) and
fatigue
Has nonspecific loss of energy, diffuse
arthritis and overall feels poorly - however
she states that this is “nothing new.”
Her most pressing issue is constipation
necessitating milk of magnesia several
times a week.
History of Present Illness
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No recent jaundice, pruritus, new arthritis, increased
abdominal girth, lower extremity swelling, confusion,
melena, hematochezia, abdominal pain.
Acute hepatitis spell in 1970’s prior to cholecystectomy.
Heavy alcohol use in the 60’s and 70’s, but quit in 1973.
No known history of liver disease or family history of liver
disease.
No family history of autoimmune disorder other than
possibly her mother having blood clot at age 47
Denies foreign travel.
PM History
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PMH: Hypercholesterolemia, DJD, H/O blood
clots, DM II, Obesity, Glaucoma, CAD, HTN
PSH: Thrombectomy right leg 11/2003,
Appendectomy 1946, Cholecystectomy 1970’s,
R ovarian cyst resection, PTCA 1996, CABG
1996, R femoropopliteal 1997, R CEA 1997
Allergies: PCN, Sulfa, Motrin, Codeine
Medications
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Meds: Dipyridamole, Trental, Captopril,
Norvasc, Zocor, Coumadin, Synthroid, HCTZ,
Insulin, Tylenol, Ex-Lax, MOM, Benadryl
Only new medications or medication adjustment
has been an increase in dose of Zocor as well
as an increase in dose of Synthroid and addition
of HCTZ within the last year
Denies herbal medications of OTC meds other
than those listed below.
Social/Family History
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SH: 1 ppd continues, no recent ETOH
use. Widowed and lives with daughter.
FH: Mother died at age 47 after blood clot
associated with cholecystectomy. Father
had heart disease and colon cancer; died
at age 85. Two siblings, both died in their
70’s. 5 children; 1 recovering from throat
cancer who is a smoker.
Physical Examination
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PE: 132/62, 86, 5’5”, 197 lbs, 98.3
Gen: A&O, NAD, wheelchair bound, requires much
assistance to transfer to exam table, no confusion, no
visible or palpable rashes
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CV: RRR no M/R/G
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Pulmonary: CTA B no W/R/R
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Abdomen: Obese, S/NT/ND, no hepatospenomegaly, no
free fluid, no rebound/guarding/masses
Imaging
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BE 9/2003: normal
CT 8/2001: multiple cysts less than 1 cm
in liver, fatty liver
U/S 6/2004: heterogeneous liver with
several cysts, gallbladder absent
Laboratory
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12/2003 - AST 17, ALT 23.
7/2004 - AST 251, ALT 335, Alk phos 172, TBili
1, protein 6.9, albumin 3.2, INR 2.5, WBC 6.8,
H/H 17/50, Platelets 217, Cholesterol 136, TG
130, HDL 43, LDL 67, Na 143, K 3.9, Cl 99, CO
30, BUN 11, Creat 0.7, TSH 0.6,
ANA negative, ASMA 1:80, anti liver kidney
microsome antibody negative, AMA negative.
Elevated LFTs:
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ALT - cytosolic enzyme in liver
AST - 20% cytosolic and 80% mitochondrial
in liver and in heart, skeletal muscle, kidney,
brain, pancreas, lungs, leukocytes, and
erythrocytes
The absolute level of transaminase
increase in serum does not correlate with
extent of hepatocellular injury and is
neither specific for the cause of liver
disease nor predictive of outcome.
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Very high enzyme increases (>15-fold)
typically seen in acute viral hepatitis, toxin/
drug-induced liver damage, ischemic
hepatitis, hepatic artery ligation, and
fulminant Wilson’s disease.
Moderate increases (5-15-fold) can be
seen in acute or chronic viral hepatitis,
autoimmune hepatitis, alcoholic hepatitis,
hemochromatosis, and Wilson’s disease.
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AST/ALT ratio:
AST>ALT:
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>2 – alcoholic liver disease (pyridoxal 5’
phosphate – cofactor for AST and ALT),
decrease ALT activity to greater extent than AST
activity, and alcohol injury leads to increased
release of mitochondrial AST
>3 – rhabdomyolysis
ALT/AST ratio
ALT>AST:
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Chronic viral hepatitis or non-alcoholic
fatty liver disease
Once fibrosis or cirrhosis of liver sets in,
AST increases due to increase
mitochondrial damage
Elevated Alkaline Phosphatase
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Can be from liver, bone, or derive from placenta
in pregnant women
Increased levels after biliary injury or obstruction
result from de novo synthesis of the protein, not
release of stored enzyme
Therefore, increased levels may not be detected
immediately after biliary injury and may be
preceded by transaminase level increases
GGT may be helpful
Differential Diagnoses
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Acute viral hepatitis
Chronic viral hepatitis
Autoimmune hepatitis
Toxin / drug-induced
liver damage
Primary biliary cirrhosis
Hemochromatosis
Wilson’s disease
Alpha-1 antitrypsin
deficiency
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Alcoholic hepatitis
Ischemic hepatitis
Steatosis/steatohepatitis
Myopathy
Hypo/hyperthyroidism
Strenuous activity
Celiac sprue
Celiac Sprue
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No evidence of malabsorption
Most common presentation is irondeficiency anemia
Serum antigliadin and antiendomysial
antibodies
Strenuous activity
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74 years old with diffuse arthritis and
fatigue / loss of energy
Mild increase of transaminases
Thyroid disease
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Liver is a major site of extrathyroidal deamination of
T4 to T3 or reverse T3
Liver dysfunction can disrupt metabolism of thyroid
hormones and modify the synthesis of binding
globulins
In chronic liver disease, TBG levels are decreased
and total T4 levels are decreased but free T4 and
TSH are normal
Hyperthyroidism can cause mild elevated
transaminases
Primary biliary cirrhosis and autoimmune hepatitis
are associated with Hashimoto’s thyroiditis
Myopathy
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No evidence of myopathy
Mild increase in transaminases
Steatosis / steatohepatitis
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Fatty liver on CT in 2001
Non-specific symptoms including fatigue
ALT > AST
Normal transaminases in 2003
Could be playing a role in her elevated
LFTs but likely not primary disorder
Steatohepatitis
Ischemic hepatitis
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No evidence of ischemic insult
Transaminases not high enough
Alcoholic hepatitis
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No recent alcohol use
ALT > AST
Alpha-1 antitrypsin deficiency
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Very rare cause of chronically elevated
LFTs in adults
Usually mild elevation in transaminases
Diminished serum levels of alpha-1
antitrypsin or lack of peak in alpha-globulin
bands on Serum Protein Electrophoresis
Wilson’s Disease
Hepatolenticular Degeneration
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Usually found in patients under 40 years of
age
Serum ceruloplasmin or 24-hour urine
collection for copper excretion (>100
micrograms copper per day)
Wilson Disease
Hepatolenticular Degeneration
Wilson Disease
Hepatolenticular Degeneration
Hemochromatosis
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Increased intestinal iron absorption
Transferrin saturation > 45%
Hemachromatosis
Primary Biliary Cirrhosis
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Hepatic manifestations include fatigue, pruritus,
xanthoma, portal hypertension, jaundice, and
malabsorption
Nonhepatic manifestations include osteoporosis,
celiac disease, thyroid disease, scleroderma /
CREST syndrome, Sjogren’s, malignant
disease
Antimitochondrial antibody negative
Drug- induced hepatic
injury
NEJM, 2000
Autoimmune Hepatitis
Autoimmune Hepatitis
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Chronic hepatitis of unknown etiology
characterized by immunologic and
autoimmunologic features, generally
including the presence of circulating
autoantibodies and a high serum globulin
concentration
Type I Autoimmune Hepatitis
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Found in all age groups
ANA (antinuclear antibody) present alone
(13%) or with SMA (54%) in 67% of
patients with the disease.
SMA (antismooth muscle antibody)
present alone (33%) or with ANA (54%) in
87% of patients with the disease.
Type II Autoimmune Hepatitis
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Found in girls and young women
Defined by the presence of antibodies to
liver/kidney microsomes (ALKM-1) and/or
to a liver cytosol antigen (ALC-1)
Clinical manifestations
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Asymptomatic
Fulminant hepatic failure
Hepatomegaly, splenomegaly, stigmata of
chronic liver disease, and/or deep jaundice
Fatigability, lethargy, malaise, anorexia, nausea,
abdominal pain, and itching
Although not specific to autoimmune hepatitis,
arthralgia involving the small joints is a
characteristic clinical feature
Extrahepatic manifestations
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Hemolytic anemia
Idiopathic thrombocytopenic purpura
Type 1 diabetes mellitus
Thyroiditis
Ulcerative colitis
Autoimmune Hepatits
Autoimmune Hepatitis
Acute and Chronic Viral
Hepatitis
Hepatitis A
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Acute, self-limited illness
Fatigue, malaise, nausea, vomiting, anorexia,
fever, and right upper quadrant pain
Dark urine, acholic stool, jaundice, and pruritus
Jaundice and hepatomegaly, which occur in 70
and 80 percent of symptomatic patients
Hepatitis A
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Laboratory findings in symptomatic patients are
notable for marked elevations of serum
aminotransferases (usually >1000 IU/dL), serum
total and direct bilirubin, and alkaline
phosphatase
Extrahepatic manifestations have been
associated with acute HAV infection including
vasculitis, arthritis, optic neuritis, transverse
myelitis, thrombocytopenia, aplastic anemia, and
red cell aplasia
Hepatitis A
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May serve as a trigger for autoimmune
hepatitis in genetically susceptible
individuals
Acute Hepatitis B
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A serum sickness-like syndrome may develop
during the prodromal period, followed by
constitutional symptoms, anorexia, nausea,
jaundice and right upper quadrant discomfort
The symptoms and jaundice generally disappear
after one to three months, but some patients
have prolonged fatigue even after normalization
of serum aminotransferase concentrations.
Acute Hepatitis B
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Laboratory testing during the acute phase
reveals elevations in the concentration of
ALT and AST levels up to 1000 to 2000
IU/L during the acute phase
ALT > AST
5% adults develop chronic carrier states –
asymptomatic, chronic persistent hepatitis,
and chronic hepatitis B
Chronic Hepatitis B
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30-50% have history of acute hepatitis
Asymptomatic
Fatigue
Stigmata of liver disease
Most patients have mild to moderate
elevation in serum AST and ALT
Extrahepatic manifestations
Extrahepatic manifestations
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Polyarteritis nodosa – hepatitis B surface
antigen found in 20-30%
Systemic symptoms including fatigue,
weakness, fever, arthralgias and signs of
multisystem involvement including
hypertension, renal insufficiency,
neurologic dysfunction, abdominal pain
Extrahepatic manifestations
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Membranous nephropathy and, less often,
membranoproliferative glomerulonephritis
Complications
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Chronic hepatitis to cirrhosis — 12 to 20%
Compensated cirrhosis to hepatic
decompensation — 20 to 23%
Compensated cirrhosis to HCC — 6 to
15%
Acute Hepatitis C
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Asymptomatic
Jaundice in < 25%
Malaise, nausea, and right upper quadrant
pain
Typically lasts for 2 to 12 weeks
60-80% develop chronic hepatitis
Chronic Hepatitis C
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Asymptomatic
Fatigue, nausea, anorexia, myalgia,
arthralgia, weakness, and weight loss
Wide variation in transaminases
Smooth muscle antibodies can be seen
Hepatitis C antibody
Complications
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Cirrhosis – 50% of chronic hepatitis C
Hepatic decompensation – 4% per year
Hepatocellular carcinoma – Hepatitis C
accounts for 1/3 of cases
Most patients die of End Stage Liver
Disease
Further Diagnostic Studies
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Iron studies
Viral hepatitis serologies
Serum Protein Electrophorsis
Liver biopsy
Chronic Viral Hepatitis
Dr. D. Sears
GI Senior Staff Response
Significant Findings
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Elderly female
Elevated LFTs with fatique
Statin and Synthroid increases
Addition of Hydrochlorothiazide
Underlying fatty liver disease
Unrevealing Autoimmune workup
Normal thyroid function
Request additional laboratory
testing
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Hepatitis B and C
Hep C negative
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Work up for Hepatitis B
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Hep Be Ag +
Hep Be Ab Hep B DNA >200,000,000 copies/ml
Hep B core Ab IgM +
Repeat LFT’s
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Alk phos 156, AST 236, ALT 298, TBili 1.2, Alb 3.4
Treatment
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Advised of contact precautions and need to get
household contacts vaccinated
Initiated Lamivudine 100mg po every day
6 weeks later:
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3 months later:
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Alk phos 129, AST 136, ALT 196
HBV DNA 226,000 copies/ml
Alk phos 114, AST 28, ALT 32
HBV DNA Undetectable
Placed on Crestor
1 year later:
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AST 19, ALT 22
Discussion
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Chronic Hepatitis B
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Blood Transfusion with CABG and other
vascular procedures
Common in Asian immigrant population
May become evident with routine LFT check
while on statins
Screen every 6 months indefinitely for
hepatocellular carcinoma (Alpha-Fetoprotein
and Ultrasound)
Discussion
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Treatment for Hep B if:
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Elevated LFT’s
Hep B surface Ag positive
Hep B DNA > 105
Liver biopsy necroinflammation
Treatment options:
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Lamivudine 100 mg po QD
Adefovir po
Interferon 1 year SQ
Entecavir po
Treatment
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Lamivudine
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Decrease symptoms, decrease inflammation
and cirrhosis progression, decrease HCC
incidence
Buying time, awaiting resistance
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50% will have mutated resistant strain by year 3 of
therapy
Then will need to switch to:
Adefovir
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There’s always a price to
pay…
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Pegasys x 1 month $1527.75
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Lamivudine x 1 month $181.58
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X 3 year = $6,536.88
Adefovir x 1 month $555.23
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X 1 year = $18,333
X 3 year = $19,988.28
Entecavir/Baraclude x 1 month $740.00+
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X 3 year = $27,000
Autoimmune Hepatitis
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Higher Autoimmune pattern with this high
of LFT’s
Must be considered- as treatable
Must be considered- as may progress to
cirrhosis
Liver Biopsy if high suspicion
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Plasma cells
Necroinflammation
Statin-induced liver disease?
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Most patients will have transaminitis if statin
given at high enough doses
Studies do not relieve chronic liver disease due
to statin use
Crestor 90% excreted in feces and other
metabolized by CYP2C9- most others by
CYP3A4
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Crestor has been studied in cirrhotics
Studies relieve patients with NASH placed on
statin will normalize LFT’s after 12 months
compared with placebo
Take home points…
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Simple fatty liver should not:
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Result in rapid increases of LFT’s
Result in LFT’s in the 300’s as a general rule
Be aware of chronic Hepatitis B
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Most patients are asymptomatic
Can cause cancer prior to cirrhosis
Treatments are available to slow/contain the
disease
The end
The end
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Proceed to post test
Complete post test
Return to Dr. Sandra Oliver
TAMUII 407i
Post test question 1
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True or False
The absolute level of increased
serum transaminase correlates
significantly with the extent of
hepatocellular injury, is specific for
the cause of liver disease and is
predictive of outcome.
Post test question 2
AST>ALT in which of the following?
1.
2.
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Chronic viral hepatitis
Non-alcoholic fatty liver disease
Alcoholic liver disease
Post test question 3
Extrahepatic manifestations associated with
Hepatitis B infection includes which of the
following?
1. Vasculitis, arthritis, optic neuritis, transverse
myelitis, thrombocytopenia, aplastic anemia, and
red cell aplasia
2. Fatigue, weakness, fever, arthralgias and signs
of multisystem involvement including hypertension,
renal insufficiency, neurologic dysfunction,
abdominal pain