Final Diagnosis: Cirrhosis due to autoantibody negative
autoimmune hepatitis (AIH).
The endoscopy [use back buttone to
return] showed grade 2 esphageal varices (with no stigmata of recent hemorrhage)
and portal hypertensive gastropathy.
The MRI of the abdomen [use back button
to return] revealed a very enlarged spleen [use back
button to return], a small-contracted and lobulated liver
consistent with cirrhosis [use back button to return], no focal hepatic masses,
and patent portal vein [use back button to return],
splenic vein, and hepatic veins [use back button to
return].
The liver pathology showed lymphocytes
and numerous plasma cells (highly suggestive of autoimmune hepatitis)
within portal tracts, at the borders of the portal tracts and lobule (interface
hepatitis) and within the liver lobule. This is chronic hepatitis with grade
3 inflammation. Bile duct proliferation was proportionate to the degree of fibrosis.
Masson-Trichrome stain confirms the presence of cirrhosis. No steatosis (HCV,
alcohol), no ground-glass cytoplasmic change (HBV), no Mallory hyaline, no granuloma
(sarcoid, mycobacterial, fungal), no viral inclusions, no dysplasia or malignancy
is seen. In conclusion, cirrhosis (grade 4 fibrosis), grade 3 inflammation/hepatitis,
consistent with autoimmune hepatitis.
Autoimmune hepatitis (AIH) is a chronic liver disease
in which injury is mediated through an abnormal immune response directed
against hepatocyte antigens. It is primarily a disease of women aged 20
to 40 years. Most patients have identifiable autoantibodies: anti-nuclear
antibody and anti-smooth muscle antibody in Type 1; anti-liver/kidney microsome
antibody in Type 2; and anti-soluble liver antigen in Type 3. Approximately
13% of patients lack the immunoserological markers required for classification
and are regarded as cryptogenic chronic hepatitis or autoantibody negative
AIH. Our patient clearly had chronic liver disease and cirrhosis. All forms
of chronic liver disease had to be considered. The biopsy was crucial in
arriving at the final diagnosis. His case of AIH is very unusual in that
he is a male and is antibody negative. The patient was started on oral
steroids, with rapid improvement in liver chemistries (see followup laboratory).
1. What is the differential diagnosis of chronic hepatitis?
Acute versus Chronic Liver Disease - Most acute
liver disease (viral, drug, alcohol, toxin, ischemic) resolves in a few
weeks to several months. Chronic liver disease is suspected by history,
physical examination, or laboratory values that suggest that liver disease
has been present for over six months. Our case is a good example. By history
the patient had had multiple episodes of jaundice for many years. On physical
examination there was splenomegaly that suggested portal hypertension from
chronic liver disease and also testicular atrophy. The liver blood test
abnormalities (AST, ALT, Alkaline Phosphatase, Bilirubin, Albumin, PT)
could be from either acute or chronic liver disease, but, given the history
and physical examination, they also suggest severe chronic liver disease
and perhaps cirrhosis. If the patient had had other physical stigmata of
cirrhosis (clubbing, palmar erythema, spider angiomata, enlarged parotid
glands, gynecomastia, ascites, prominent venous collaterals on the abdomen,
and edema) then both chronicity and severity would have been obvious.
Chronic Hepatitis versus Chronic Cholestasis -
The chronic cholestatic liver diseases affect mainly the portal
tracts and bile ducts. Primary biliary cirrhosis, sclerosing cholangitis,
extrahepatic bile duct disease and a variety of uncommon "ductopenic"
liver diseases are the main examples. The hallmark of these diseases is
that the alkaline phosphatase is elevated 5-10 times normal but the ALT
and AST are normal or less than 5 times normal. We say these liver diseases
are cholestatic. In contrast, the chronic liver diseases in which
the alkaline phosphatase is only mildly elevated but the ALT and AST are
elevated 5-15 times the normal are called hepatitic. Our patient
is a good example of chronic hepatitis. The liver
chemistries showed AST and ALT elevated about 6-9 times normal but
the alkaline phosphatase was only mildly elevated. Therefore, he had chronic
hepatits. The initial laboratory evaluation was directed toward the causes
of chronic hepatitis. So the patient was screened for viral (HBV
serologies, HCV serologies and PCR), autoimmune (ANA, ASMA, Anti-LKM,
IgG level), and the important genetic metabolic diseases that can present
in adulthood as chronic hepatitis: hemochromatosis (iron studies),
alpha-1-antitrypsin deficiency (a-1-AT levels), and Wilson's
disease (ceruloplasmin). Biopsy was needed in this case because the
laboratory evaluation did not give a definitive diagnosis and because there
are certain causes of chronic hepatitis that can only be diagnosed by biopsy:
steatohepatitis, sarcoidosis, and other causes of granulomatous
hepatitis. Sometimes the chronic cholestatic liver diseases present
as chronic hepatitis. Please note that elevations of bilirubin can occur
in both chronic hepatitis and chronic cholestatic liver diseases. The bilirubin
is a marker of disease severity and not useful in the differential diagnosis
of cholestatic versus hepatitic liver diseases.
2. How do you diagnose cirrhosis and assess its severity?
Any of the above forms of chronic liver disease (either
cholestatic or hepatitic) can lead to cirrhosis. Cirrhosis is suspected
in any patient with chronic liver disease who has physical stigmata of
cirrhosis or portal hypertension (clubbing, palmar erythema, spider angiomata,
enlarged parotid glands, gynecomastia, splenomegaly, ascites, prominent
venous collaterals on the abdomen, testicular atrophy, female hair distribution
on a male, and edema). It can also be suspected by laboratory tests that
may indicate decreased liver function (low albumen, prolonged PT, and high
conjugated bilirubin). It can also be suspected by imaging studies (ultrasound,
CT, MRI) that show a small, irregular liver, with or without dilated porto-systemic
collaterals. It should be emphasized that cirrhosis can be present even
in patients with a normal physical examination, normal lab studies, and
normal imaging studies. In general, the more florrid the abnormalities,
the more severe the cirrhosis. Definitive diagnosis is by liver biopsy.
In cirrhosis, as with our patient, the biopsy shows fibrosis bridging from
portal tract to portal tract or central vein. In addition, regenerative
nodules are seen. This is called Stage 4 fibrosis.
The severity of cirrhosis is most frequently assessed
by the Child Turcotte Classor
quantified by calculating the Child's-Pugh score.
The score can be used to place the patient in catagory A (mild), B (moderate),
or C (severe). Although the modified Child classification is not a perfect
assessment of disease severity, the score is probably the most useful way
to communicate the severity of liver disease to other health care workers,
to assess survival, to assess prognosis in surgery, and in making decisions
about usefulness or harmfulness of certain therapies. Our patient had cirrhosis
by physical examination (splenomegaly, testicular atrophy), laboratory
values (albumen, bilirubin, PT), and imaging (MRI). See if you agree that
his Child's-Pugh score was 6 and he had Child's A cirrhosis by both scoring
systems.
3. Would you have performed a liver biopsy on this
patient?
Liver biopsy is the most specific test to assess the nature
and the severity of liver diseases (7). Indications
(7) for liver biopsy are shown in the visual. There are three ways to perform
needle liver biopsy: percutaneous, transjugular, or laparoscopic. Percutaneous
liver biopsy needles are classified as suction needles (Menghini, Klatzkin
and Jamshidi), manual cutting needles (Vim-Silverman, Tru-cut), and spring-loaded
needles. Suction needles are manually pushed in and out of the liver with a
quick motion while applying suction. Manual cutting needles require longer time
in liver for the cutting movement to be applied. This may increase the risk
of bleeding. If cirrhosis is suspected, cutting needles are more reliable to
procure a sample as cirrhotic tissue may fragment with suction needles. Spring-loaded
cutting needles provide the advantage of cutting needles with the speed of a
suction needle. Hepatologists usually recommend liver ultrasound prior to a
percutaneous liver biopsy, either performing the exam themselves or having a
radiologist mark the proper spot before the biopsy. However, cost effectiveness
of routine liver ultrasound is debated. Percutaneous liver biopsy can be contraindicated(7)
and is associated with complications
(10). If the biopsy is indicated but the percutaneous route is risky, then another
method is selected. Our patient's biopsy was indicated (diagnosis of chronic
hepatitis) but was relatively contraindicated by the percutaneous technique
(coagulopathy). Transjugular (TJ) liver biopsy is done by percutaneous
puncture of the right internal jugular vein and the introduction of a catheter
into the right hepatic vein with fluoroscopic guidance. This method is used
when there is increased risk of bleeding from coagulopathy. Needle biopsy of
the liver is performed via the catheter. Indications for TJ liver biopsy are
shown in (Visual6)
(7). This procedure usually takes 30-60 minutes. The disadvantage is that specimens
are small and fragmented. It is also highly operator dependent. TJ biopsy can
be done with either an aspiration or modified Tru-cut system (9).
Complications of TJ biopsy may range from 1.3% to 20%
and include abdominal pain, neck hematoma, transient Horner syndrome, dysphonia,
cardiac arrhytmia, perforation of liver capsule, fistula formation between
hepatic artery to portal vein (and/or biliary tree) and pneumothorax. Mortality
is reported to be between 0.1% and 0.5%. Laparoscopic liver biopsy
indications are shown in (Visual7) (7). Poniachick et al. (12) studied 169 patients
who had laparoscopic evidence of cirrhosis. 115 of them (68%) had prior
percutaneous liver biopsy showing cirrhosis. Thus sensitivity of percutaneous
liver biopsy to detect cirrhosis was 68%. Another 2 of 265 patients (1%)
had percutaneous liver biopsy showed features of cirrhosis but a normal
laparoscopic exam (specificity 99%). Currently, the majority of laparoscopies
in U.S. are being performed by surgeons.
To avoid sampling error, even in diffuse liver diseases,
a specimen length of 1.5 cm is needed or fragments which contain 6-8 portal
triads. Specimens obtained with thin-bore or spring-loaded needles measure
between 1.4-1.8 mm in diameter. With a Menghini or Tru-cut needle, they
measure up to 2 mm in diameter. TJ biopsies are small so multiple
specimens should be obtained.
4. Screening procedures in patients with cirrhosis.
Patients with cirrhosis should be screened for hepatocellular
carcinoma with yearly hepatic ultrasound and serum alpha-fetoprotein measurement.
Also patients with cirrhosis should be screened for esophageal varices (13).
This is especially true for Child B and C where the risk of varices is high.
But it is also important for Child A patients with clinical evidence of portal
hypertension (splenomegaly, thrombocytopenia and large portal vein or collaterals
on abdominal imaging). Arguedas et al. (4) studied 125 patients with cirrhosis
referred for transplantation. In their cohort study, they concluded that screening
for esophageal varices was not routinely performed in clinical practice. This
delayed timely implementation of primary prophylaxis. Primary prophylaxis in
their study consisted of oral propranolol. A meta-analysis by Imperiale (12)
concluded that compared with beta-blockers, prophylactic esophageal variceal
ligation reduces the risk for first variceal bleed but has no effect on mortality.
