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.
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