INTRODUCTION
A 55-year-old woman presents to the emergency department with profuse bright red bleeding with emesis diagnosed as bleeding esophageal varices. She also is icteric and is suspected of having cirrhosis. She has been followed for several years for Sjogren syndrome and Raynaud syndrome. Investigation into the cause of her cirrhosis reveals negative hepatitis antibodies but elevated antimitochondrial antibodies.
· What is the most likely
underlying etiology for her liver disease?
· What is the most likely
mechanism?
Summary: A 55-year-old woman has cirrhosis and
elevated antimitochondrial antibodies.
· Most likely diagnosis:
Primary biliary cirrhosis.
· Most likely mechanism:
The etiology of primary biliary cirrhosis is not known; however, evidence points
toward an autoimmune basis to the disease.
CLINICAL
CORRELATION
Introduction
This 55-year-old woman presents with bleeding
esophageal varices and cirrhosis. The first priorities in her management include
ABC: airway, breathing, and circulation. She should receive oxygen by a nasal
cannula, and two large-bore intravenous lines should be established. Her blood
pressure and heart rate should be monitored to assess for volume loss and
replacement with blood as needed. Because of her liver disease, she may have a
coagulopathy caused by depletion of vitamin K-dependent factors (factors II,
VII, IX, and X). Transfusion with coagulation factors and initiation of vitamin
K may be indicated. Endoscopic examination to determine the etiology of the
upper gastrointestinal bleeding is paramount. Bleeding esophageal varices may be
treated with sclerotherapy injected into the bleeding vessels. Also, a tamponade
may be attempted with special esophageal devices.
After the acute situation has been addressed, attention
should be directed to the etiology of her liver disease. A careful history and
physical examination and selected laboratories usually yield the diagnosis.
Toxic effects such as with alcohol use and infections such as with hepatitis
viruses are the most common causes of cirrhosis. This patient's hepatitis
serology studies are negative, but she does have a history of Sjogren syndrome,
Raynaud syndrome, and antimicrosomal antibodies. These findings are consistent
with primary biliary cirrhosis. Careful history may reveal pruritis years before
frank cirrhosis.
Approach to
Chronic Liver Disease
Definitions
Primary biliary cirrhosis (PBC): A chronic
progressive cholestatic liver disease associated with intrahepatic biliary tree
destruction and finally cirrhosis.
Chronic liver disease: Liver disease that lasts
for 6 months or more and includes chronic hepatitis and cirrhosis.
Cirrhosis: Progressive and irreversible
condition of the liver in which hepatocyte damage and destruction occur.
Regenerating hepatocytes form nodules.
Discussion
Primary Biliary
Cirrhosis
The etiology of primary biliary cirrhosis is not known;
however, evidence points toward an autoimmune basis of the disease. Other
autoimmune diseases are associated with this condition and include Sjogren
syndrome, scleroderma, rheumatoid arthritis, and thyroiditis. Abberant human
lymphocyte antigen (HLA) class II molecules are expressed in the biliary
epithelium of patients with PBC; this might be responsible for the triggering of
an inflammatory response. Defective immunoregulation allows cytotoxic T cells to
damage bile ducts. A liver biopsy usually shows a portal tract infiltrate
composed of mainly lymphocytes and plasma cells (see Figure 8-1). In
approximately half the patients, granulomas may be seen. Destruction
of medium-sized bile ducts with bile ductular proliferation will be evident.
With time, hepatocyte necrosis and fibrosis are apparent. After years to
decades, the clinical features of cirrhosis will be present. There is an
increased synthesis of IgM because of failure to switch from
immunoglobulin M (IgM) to IgG antibody synthesis. Most patients have
antimitochondrial antibodies in their serum, with the antigen M2 being
specific to PBC. The role of this antibody in the pathogenesis of PBC is not
clear.
Features of cholestatic liver disease dominate
the initial clinical picture. This includes pruritus, which may precede
jaundice by years. High serum alkaline phosphatase with normal or nearly
normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) is
characteristic in the early part of the disease. Secondary
hypercholesteremia with features such as xanthelasma may be seen. After a
variable amount of time (usually years), the features of cirrhosis, such as
icterus, bleeding, and ascites, may become apparent. Table
8-1 shows the laboratory findings that are consistent with a diagnosis of
PBC.
Table 8-1. LABORATORY FINDINGS CONSISTENT WITH PRIMARY BILIARY CIRRHOSIS
1. High serum alkaline phosophatase
2. High serum cholesterol
3. High serum IgM
4. High antimitochondrial antibodies; M2 antibody is specific
5. Liver biopsy; portal infiltrate with lymphocytes and plasma cells; granulomas; bile duct damage with ductular proliferation; eventual cirrhosis
Management
Treatment addresses the symptoms and disease course of
the patient. Because the disease is thought to be autoimmune, corticosteroids
have been tried. These agents improve the biochemical and histologic picture of
the disease but lead to significant osteoporosis. Patients with primary biliary
cirrhosis are prone to osteoporosis caused by cholestasis and subsequent
impaired malabsorption of vitamin D. Complications associated with cirrhosis
require management. Liver transplantation remains the specific treatment
and has a 5-year survival of at least 80 percent.
Cirrhosis and
Chronic Hepatitis
Chronic liver disease includes chronic hepatitis and
cirrhosis (see Table
8-2). In chronic hepatitis, inflammatory cells consisting of lymphocytes,
macrophages, and plasma cells are present in the portal tract. Interface
hepatitis and bridging necrosis are signs of active liver damage.
Lymphoid aggregates are seen in cases caused by hepatitis C virus.
The hallmark of irreversible liver damage is deposition of fibrous tissue. This
brings about the onset of cirrhosis. Initially, the fibrosis is periportal. With
time, bridging fibrosis between lobules is seen. Regenerating nodules
from surviving hepatocytes complete the picture of cirrhosis. Based on the size
of the nodules, there are two types of cirrhosis: micronodular (nodules less
than 3 mm) and macronodular. Micronodular cirrhosis is seen in
alcoholics, whereas macronodular cirrhosis is seen after
hepatitis.
| Table 8-2. CAUSES OF CHRONIC HEPATITIS | |
Viruses
| |
Hepatitis B and
C
| |
Autoimmune
| |
Hereditary
| |
Alpha1-antitrypsin
deficiency, Wilson disease
| |
Drugs
| |
Methyldopa, isonicotine
hydrazine, ketoconazole
| |
Causes of
cirrhosis
| |
Alcohol
(common)
| |
Viral hepatitis caused by
B or C (common)
| |
Autoimmune
hepatitis
| |
Primary biliary
cirrhosis
| |
Wilson
disease
| |
Hemochromatosis
| |
Alpha1-antitrypsin
deficiency
| |
Drugs:
methotrexate
| |
Complications of
cirrhosis
| |
Portal hypertension and
gastrointestinal hemorrhage
| |
Ascites
| |
Autoimmune
Liver Disease
Autoimmune liver disease is seen most frequently in
females and is associated with other autoimmune diseases. Autoantibodies such as
antinuclear, anti-smooth muscle and anti-liver and kidney microsomal antibodies
(anti-LKM) are frequently present. Serum IgG levels may be
elevated.
Alpha1-Antitrypsin Deficiency
Alpha1-antitrypsin deficiency is inherited
as an autosomal recessive condition. Alpha1-antitrypsin is a
glycoprotein whose main role is to inhibit the proteolytic enzyme neutrophil
elastase. Deficiency results in liver damage and emphysema, especially in
smokers. Serum levels are low, and liver biopsy shows periodic acid-Schiff (PAS)
positive diastase-resistant globules within the hepatocytes.
Wilson
Disease
Wilson disease is inherited as an autosomal
recessive condition. The copper-transporting protein ceruloplasmin is
reduced in amount because of poor synthesis. There is also failure of biliary
excretion of copper. As a result, free copper is deposited in various sites,
including liver basal ganglia and cornea (with resultant Kayser-Fleischer
rings), resulting in damage to those organs. Urinary excretion of free
copper also is increased. Acute hepatitis, chronic hepatitis, cirrhosis, and
extrapyramidal features (caused by basal ganglia damage) are the usual
clinical features.
Hereditary
Hemochromatosis
Hereditary hemochromatosis also is inherited as an
autosomal recessive condition. There is an association with HLA-A3. Excessive
iron absorption results in iron deposition and damage to various organs,
including liver, pancreas, heart, joints, and pituitary gland. At the same time
excess iron deposition is observed in the skin. This results in bronze
discoloration of skin. This, along with diabetes resulting from pancreatic
damage, explains the synonym of hemochromatosis, bronze diabetes. Other features
include cirrhosis, cardiomyopathy, hypogonadism, and arthropathy. As
females lose iron through blood loss from menstruation, the features are milder
or are seen later in them.
Alcoholic Liver
Disease
The spectrum of alcoholic liver disease includes
fatty liver, acute hepatitis, and cirrhosis. Fatty liver (hepatic
steatosis) consists of microvesicular lipid droplets in the liver
cells, displacing the nucleus to the periphery. On gross inspection, the
liver appears yellow and greasy. Refraining from alcohol generally leads to
reversal of these changes. In acute hepatitis, there is infiltration
with polymorphonucleocytes and hepatocyte necrosis. Cytoplasmic inclusions
resulting from intermediate filaments known as Mallory bodies are seen.
Eventually, fibrosis ensues. Finally, cirrhosis develops as an end-stage
result of chronic alcohol use. The liver is small and shrunken.
Microscopy reveals fibrous septae that create a micronodular and macronodular
pattern with regeneration. Clincally, the patient may develop portal
hypertension, ascites, jaundice, and peripheral edema.
COMPREHENSION
QUESTIONS
[8.1] A 37-year-old woman presents with fatigue and
pruritus. Laboratory evaluation finds the presence of antimitochondrial
antibodies in her serum, but the tests for viral hepatitis antibodies were
negative. A biopsy of her liver reveals numerous lymphocytes in the portal
tracts, along with occasional granulomas. Which one of the substances listed
below is most likely to have markedly elevated serum levels in this
individual?
A. Acid phosphatase
B. Alanine aminotransferase
C. Alkaline phosphatase
D. Aspartate aminotransferase
E. Conjugated bilirubin
[8.2] A 42-year-old woman presents with signs of
jaundice and hepatic failure. Physical examination finds that she has
uncontrolled choreiform movements of the arms, and a rust-colored ring is seen
at the periphery of both corneas. Laboratory examination finds increased serum
and urine levels of copper with decreased levels of ceruloplasmin. What is the
best diagnosis?
A. Alpha1-antitrypsin
deficiency
B. Budd-Chiari syndrome
C. Primary biliary cirrhosis
D. Whipple disease
E. Wilson disease
[8.3] Which one of the abnormalities listed below is
most likely to be found in an individual with hereditary
hemochromatosis?
A. Black cartilage
B. Blue sclera
C. Bronze skin
D. Red pupils
E. White hair
ANSWERS
[8.1] C. The presence of antimitochondrial
serum antibodies, particularly to the M2 antigen, in an individual with liver
disease is highly suggestive of primary biliary cirrhosis. Individuals with this
autoimmune disorder, which is more common in women, develop clinical signs of
cholestatic liver disease with pruritus. Before the development of jaundice,
however, patients will have high serum levels of alkaline phosphatase with
normal or nearly normal levels of ALT and AST.
[8.2] E. Increased serum levels of copper with
decreased levels of ceruloplasmin in a patient with liver disease are diagnostic
of Wilson disease. This autosomal recessive disorder is characterized by the
deposition of copper in multiple sites, which include the liver, the basal
ganglia, and the cornea of the eye. Destruction of the basal ganglia leads to
extrapyramidal signs such as choreiform movements, whereas deposition of copper
at the periphery of the cornea produces characteristic Kayser-Fleischer
rings.
[8.3] C. Patients with hereditary
hemochromatosis develop clinical signs because of the deposition of excess iron
in many organs. The classic triad of clinical signs includes a bronze skin
color, diabetes mellitus, and cirrhosis. The combination of the bronze skin
color and diabetes mellitus sometimes is referred to as bronze diabetes.
Deposition of iron in the islets of Langerhans in the pancreas leads to the
destruction of the beta cells, and subsequent decreased levels of insulin lead
to diabetes mellitus. The abnormal skin color results from the deposition of
iron in the skin. In addition, deposition of iron in the adrenal cortex leads to
decreased cortisol levels. This in turn will increase levels of
proopiomelanocortin (POMC) and lead to increased melanin-stimulating hormone
(MSH) activity.
PATHOLOGY
PEARLS
· Primary biliary cirrhosis
is thought to be an autoimmune disease seen predominantly in middle-aged
women.
· In PBC patients, serum IgM
is elevated and antimitochondrial antibody (M2 is specific) is found.
· Cirrhosis is a progressive
and irreversible condition of the liver in which there occurs hepatocyte damage
and destruction. Regenerating hepatocytes form nodules.
· Complications of cirrhosis
include portal hypertension, gastrointestinal hemorrhage, ascites, portosystemic
encephalopathy, hepatorenal syndrome, and hepatocellular carcinoma.
·
Alpha1-antitrypsin deficiency is an autosomal recessive condition in
which liver damage and emphysema are the main features.
· Wilson disease is an
autosomal recessive condition characterized by liver and basal ganglia
damage.
· Hereditary hemochromatosis,
or bronze diabetes, also is inherited in an autosomal recessive fashion.
Deposition of iron and organ damage occur in liver, pancreas, heart, joints, and
pituitary gland.
· In alcoholic hepatitis
there occurs infiltration with polymorphonucleocytes and heaptocyte necrosis.
Cytoplasmic inclusions caused by intermediate filaments known as Mallory bodies
are seen.
REFERENCES
Chung RT, Podolsky DK. Cirrhosis and its
complications. In: Kasper DL, Fauci AS, Longo DL, et al. Harrison's principles
of internal medicine, 16th ed. New York: McGraw-Hill,
2004:1860-1862.
Crawford JM. The gastrointestinal tract. In: Kumar V,
Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed.
Philadelphia: Elsevier Saunders, 2004:914-915.
Copyright © 2006 by the
McGraw-Hill Companies, Inc. All rights reserved.
