Patient's Value Reference Range Alanine aminotransferase (ALT): 80 U/L 8-20 U/L Alkaline phosphatase: 60 U/L 20-70 U/L Aspartate aminotransferase (AST): 50 U/L 8-20 U/L Albumin: 2.0 g/dL 3.5-5.5 g/dL Bilirubin, serum, total: 5 mg/dL 0.1-1.0 mg/dL Bilirubin, serum, direct: 4.2 mg/dL 0.0-0.3 mg/dL Prothrombin time (PT): 28 s 11-15 s Partial thromboplastin time (PTT): 50 s 28-40 s
· What is the most likely diagnosis?
· What are the possible etiologies of this disorder?
· What other tests would be appropriate?
· What are the possible complications?
ANSWERS TO CASE 3: Hepatitis Summary: A 57-year-old man with a prior history of blood transfusion presents with jaundice and ascites, along with mildly elevated transaminases as well as evidence of impaired hepatic synthetic function (hypoalbuminemia and coagulopathy).
· Most likely diagnosis: Chronic hepatitis/cirrhosis.
· Possible etiologies of this disorder: Most commonly caused by chronic toxin exposure (alcohol) or chronic viral infection; sometimes chronic hepatitis may be caused by inherited metabolic disorders such as hemochromatosis.
· Other appropriate tests: Hepatitis virus serologies and possibly a liver biopsy.
· Possible complications: Hepatic failure, gastrointestinal bleeding, hepatocellular carcinoma.
CLINICAL CORRELATION
Introduction
This patient had a blood transfusion in the early 1980s, before the discovery of and the institution of screening for hepatitis C virus. He had a long asymptomatic period and now has signs of advanced liver disease. His firm nodular liver probably represents cirrhosis, with scarring of the liver parenchyma along with regenerative nodules. His transaminases (ALT and AST) are only mildly elevated but these tests may be within normal limits, particularly early in the course of disease. The fact that he has impaired hepatic synthesis of albumin and coagulation factors indicates that he has very advanced disease, especially in light of the enormous reserve and regenerative capacity of the liver. The accumulation of ascitic fluid in the peritoneum usually represents portal hypertension, an increase in pressure in the portal venous system that typically results from increased intrahepatic resistance to portal blood flow because of perisinusoidal deposition of collagen.
Approach to Liver Pathology
Definitions
Cirrhosis: Although often used as a clinical description, cirrhosis is really a pathologic diagnosis that is characterized by disruption of normal liver architecture by interconnecting fibrous scars and the creation of parenchymal nodules by regenerative activity and the network of scars. This pathologic process can be thought of as the final common pathway of many causes of chronic hepatic injury. The inciting factor causes hepatocyte necrosis and deposition of collagen. At some point the fibrosis becomes irreversible, and cirrhosis then develops. Cirrhosis can be classified according to morphologic features (micronodular, most often caused by alcohol, or macronodular, most often resulting from viral hepatitis) or according to the etiology: alcoholic, cardiac, biliary, or drug-induced. However, a single cause of hepatic injury can produce a variety of pathologic patterns, and any given morphology can result from a variety of causes.
Acute hepatitis: The influx of acute inflammatory cells, which may follow or precede hepatocyte necrosis. The morphologic changes in both acute and chronic hepatitis are common to the hepatitis viruses and can be mimicked by drug reactions.
Chronic hepatitis: Can be due to numerous causes, all of which result in hepatic inflammation and necrosis for at least 6 months, but without the nodular regeneration and architectural distortion of cirrhosis.
Hepatic steatosis: Also known as "fatty liver," this entity commonly is due to alcohol ingestion but also can be due to many other causes of altered lipid metabolism (diabetes, obesity, glucocorticoid use, total parenteral nutrition, some drug reactions), resulting in the accumulation of fat first in cytoplasmic microvesicles in the hepatocyte. Later, the vacuoles coalesce into macrovesicles, compressing and displacing the nucleus so that the hepatocyte resembles a lipocyte. Grossly, the liver becomes enlarged with a yellow, greasy appearance. Steatosis is usually reversible with discontinuation of the underlying cause, but it may lead to the development of fibrosis around the central veins and sinusoids and ultimately to cirrhosis.
Approach to Liver Disease
Normal Anatomy and Function
The liver receives two-thirds of its blood supply from the portal vein and one-third from the hepatic artery, and its venous drainage via the hepatic vein flows into the inferior vena cava. Its microarchitecture is arranged around this vascular supply and the biliary ducts, which join to form the hepatic duct, which leads to the common bile duct and into the duodenum. The liver is organized into 1- to 2-mm hexagonal lobules, with cords or plates of hepatocytes radiating out from the central vein, the terminal venules of the hepatic vein. At each corner of the hexagon are the portal tracts, composed of the terminal branches of the portal vein and the hepatic artery, as well as the bile duct. Arterial and portal venous blood flows through sinusoids, between the cords of hepatocytes, giving them a rich vascular supply (25 percent of cardiac output) before draining into the central vein. Bile is secreted into bile canaliculi between adjacent hepatocytes and flows into the canals of Herring and then to the lobular bile ducts.
The liver serves many functions, including maintenance of carbohydrate, lipid, and amino acid metabolism; synthesis of nearly all serum proteins; and detoxification and excretion of noxious substances in the bile. One such substance is bilirubin, a waste product that is the metabolite of the breakdown of heme from senescent red blood cells. In its initial form, unconjugated or "indirect" bilirubin, it is insoluble in aqueous solution, circulates highly bound to albumin, and is toxic to tissues. It undergoes conjugation with glucuronic acid in the hepatocyte to form conjugated or direct bilirubin, which is water-soluble and nontoxic, and then is excreted into the bile canaliculus. When liver disease causes jaundice, affected individuals usually have reflux of conjugated bilirubin into the blood, which causes the visible icterus when deposited in tissues, as well as the dark urine resulting from urinary excretion of elevated levels of water-soluble conjugated bilirubin.
Approach to Viral Hepatitis
Because of its rich vascular supply, the liver may be involved in any systemic blood-borne infection, but the most common and clinically significant infections are those with one of
five hepatotropic viruses: hepatitis A, B, C, D, and E. Each virus can produce virtually indistinguishable clinical syndromes. Affected individuals often present with a prodrome of nonspecific constitutional symptoms, including fever, nausea, fatigue, arthralgias, myalgias, headache, and sometimes pharyngitis and coryza. This is followed by the onset of visible
jaundice caused by hyperbilirubinemia, tenderness and enlargement of the liver, and
dark urine caused by bilirubinuria. The clinical course, outcomes, and possible complications vary with the type of virus causing the hepatitis. A comparison of features of these five viruses is shown in
Table 3-1.
| Table 3-1. CLINICAL AND VIROLOGIC CHARACTERISTICS OF THE HEPATITIS VIRUSES |
| VIRUS TYPE | TRANSMISSION | INCUBATION | SEROLOGIC MARKERS | CARRIER STATE | CHRONIC HEPATITIS |
Hepatitis A | RNA | Enteral (fecal-oral) | 15-45 days (mean 30 days) | Anti-hepatitis A IgM | No | No |
Hepatitis B | DNA | Parenteral | 30-180 days (mean 60-90 days) | HBsAg, anti-HBsAb or anti-HBcAb IgM (acute) | Yes | Yes |
Hepatitis C | RNA | Parenteral | 15-160 days (mean 50 days) | Anti-hepatitis C virus HCV RNA | Yes | Yes |
Hepatitis D | Defective DNA | Parenteral | Same as hepatitis B | Anti-hepatitis D virus IgM | Yes | Yes |
Hepatitis E | RNA | Enteral (fecal-oral) | 14-60 days (mean 40 days) | Anti-hepatitis E virus | No |
Hepatitis A and hepatitis E are very contagious and are transmitted by the fecal-oral route, usually by contaminated food or water in areas where sanitation is poor, and in day-care situations by children. Hepatitis A is found worldwide and is the most common cause of acute viral hepatitis in the United States. Hepatitis E is much less common and is found in Asia, Africa, and Central America. Both hepatitis A and hepatitis E infections usually lead to self-limited illnesses and generally resolve within weeks. Almost all patients with hepatitis A recover completely and have no long-term complications. Most patients with hepatitis E also have uncomplicated courses, but some patients, particularly pregnant women, have been reported to develop severe hepatic necrosis and fatal liver failure.
Hepatitis B is the second most common type of viral hepatitis in the United States, and it is usually sexually transmitted. It also may be acquired parenterally, for example, through intravenous drug use, and during birth, from chronically infected mothers. The outcome then depends on the age at which the infection was acquired. Up to 90 percent of infected newborns develop chronic hepatitis B infection, which places an affected infant at significant risk of hepatocellular carcinoma later in adulthood. Among individuals infected later in life, approximately 95 percent recover completely without sequelae. Between 5 and 10 percent of patients will develop chronic hepatitis and may progress to cirrhosis. Also, a chronic carrier state may be seen in which the virus continues to replicate but does not cause hepatic damage in the host.
Hepatitis C is transmitted parenterally by blood transfusions or intravenous drug use and rarely by sexual contact. It uncommonly is diagnosed as a cause of acute hepatitis, often producing subclinical infection, but frequently is diagnosed later as a cause of chronic hepatitis. The natural history of infection is not completely understood, but 50 to 85 percent of patients with hepatitis C will develop chronic infection.
Hepatitis D is a defective RNA virus that requires the presence of the hepatitis B virus to replicate. It can be acquired as a coinfection simultaneously with acute hepatitis B or as a later superinfection in a person with a chronic hepatitis B infection. Patients with chronic hepatitis B virus who then become infected with hepatitis D may suffer clinical deterioration; in 10 to 20 percent of these cases, the infected individuals develop severe fatal hepatic failure.
Hepatitis Serologies
Clinical presentation does not reliably establish the viral etiology, and so serologic studies are used to establish a diagnosis. Anti-hepatitis A immunoglobulin M (IgM) establishes an acute hepatitis A infection. If anti-hepatitis C antibody is present, acute hepatitis C is diagnosed, but the test may be negative for several months. The hepatitis C polymerase chain reaction (PCR) assay, which becomes positive earlier in the disease course, often aids in the diagnosis. Acute hepatitis B infection is diagnosed by the presence of hepatitis B surface antigen (HBsAg) in the clinical context of elevated serum transaminase levels and jaundice. HBsAg later disappears when the antibody (anti-HBs) is produced .
There is often an interval of a few weeks between the disappearance of HBsAg and the appearance of anti-HBsAb, which is referred to as the window period. During this interval, the presence of anti-hepatitis B core antigen IgM (anti-HBe IgM) will indicate an acute hepatitis B infection. Hepatitis B precore antigen (HBeAg) represents a high level of viral replication. It is almost always present during acute infection, but its persistence after 6 weeks of illness is a sign of chronic infection and high infectivity. Persistence of HBsAg or HBeAg is a marker for chronic hepatitis or a chronic carrier state; elevated or normal serum transaminase levels distinguish these two entities.
Pathologic Changes in Hepatitis
As was mentioned before, the pathologic findings in acute hepatitis can be caused by various insults, such as viral infection and toxic injury, and are not pathognomic for any particular cause. There may be hepatocyte swelling called ballooning degeneration, as well as liver cell necrosis, including fragmentation and condensation of hepatocytes, forming intensely eosinophilic Councilman bodies, which are characteristic of viral hepatitis. Formation of ropelike eosinophilic structures within hepatocytes, called Mallory bodies, is typical of alcoholic hepatitis. Another finding in acute hepatitis is an inflammatory infiltrate in the portal tracts.
Chronic hepatitis C is characterized by the formation of lymphoid aggregates in the portal tracts as well as fatty changes in hepatocytes. Ground glass cells often are seen in chronic hepatitis B. If inflammation is limited to the portal tracts, the disease is milder and the prognosis is better. When it spills over into the periportal parenchyma, destroying the limiting plate (piecemeal necrosis) or extending across lobules, such as the portal area to the central vein, which is termed bridging necrosis, the disease is more progressive and the prognosis is poorer.
Complications of Chronic Hepatitis
Many patients with chronic hepatitis have stable disease, but a significant fraction develop ongoing fibrosis and ultimately cirrhosis, as was described previously. As a result of the loss of functioning hepatic mass, patients have impaired synthesis of albumin and consequent edema, as well as diminished production of coagulation factors, leading to a coagulopathy. The fibrosis causes increased intrahepatic resistance to portal venous blood flow and thus increased pressure in this venous system. Portal hypertension in turn leads to the development of ascites, or the accumulation of intraperitoneal fluid, and the formation of collateral venous circulation, such as esophageal varices, which often produce life-threatening hemorrhages. Finally, patients with chronic hepatitis and cirrhosis of almost any cause, especially hepatitis B or hepatitis C, are at increased risk for developing hepatocellular carcinoma.
Approach to Toxic Liver Disease
Alcoholic Liver Disease
Alcohol-related liver disease occurs in three overlapping forms: hepatic steatosis (fatty liver), alcoholic hepatitis, and cirrhosis. The pathologic features of these conditions were described above. The major points to note here are that fat begins to accumulate within hepatocytes after even a moderate intake of alcohol and, with continued exposure, continues to accumulate until the liver may be 3 to 4 times its normal mass. Up to the point where fibrosis appears, the fatty change is reversible with abstention from alcohol. Alcoholic hepatitis is characterized by acute hepatocyte necrosis, particularly after bouts of heavy drinking, and is usually reversible. It typically includes some sinusoidal and perivenular fibrosis and, if superimposed on fatty liver, often progresses to cirrhosis.
Acetaminophen Toxicity
A relatively common and treatable form of hepatotoxic exposure that otherwise may lead to hepatic failure and death is acetaminophen poisoning. A minor metabolite of acetaminophen is produced by cytochrome P-450 2E1 in the form of a hepatotoxin, which normally is detoxified by binding to glutathione. Hepatotoxicity is most likely to develop in patients with single very large ingestions (such as suicide attempts) or patients with enhanced activity of this cytochrome, as well as those with depleted levels of glutathione, such as chronic alcoholics. Blood levels of acetaminophen correlate with the severity of hepatic injury. Patients with toxic levels of acetaminophen may be treated with doses of N-acetylcysteine, which replaces glutathione stores, allowing detoxification of the metabolite.
Approach to Metabolic Disorders
Hemochromatosis
Hereditary hemochromatosis, a disorder caused by the inheritance of a mutant HFE gene, is a common disorder of iron storage that most often is found in persons of northern European descent. The disease classically was referred to as bronze diabetes because of the deposition of iron causing skin pigmentation, diabetes, as well as micronodular cirrhosis, with increased levels of ferritin and hemosiderin within hepatocytes. It now can be diagnosed before the occurrence of end-organ damage resulting from iron deposition by screening for transferrin saturation >45 percent and confirmed by HFE genotyping.
a1-Antitrypsin Deficiency
a1-Antitrypsin (A1AT) deficiency is an inherited disorder in which there is an abnormally low level of this serum protease inhibitor. In some patients, the abnormal A1AT is synthesized in the liver but cannot be secreted, and so it accumulates in cytoplasmic globules. The spectrum of liver diseases ranges from neonatal hepatitis, to childhood cirrhosis, to adult cirrhosis. Diagnosis is achieved by finding low levels of serum A1AT activity and by A1AT phenotyping.
Wilson Disease
Wilson disease is an inherited disorder of copper metabolism in which there is accumulation of copper in multiple tissues, including liver, brain, and eye. Clinical manifestations may include acute or chronic hepatitis, fatty liver, and cirrhosis, along with extrapyramidal movement disorders or psychiatric disturbances. Diagnosis is made by finding Kayser-Fleischer rings in the cornea, which are pathognomonic, or by low levels of serum ceruloplasmin (a serum copper-transport protein), as well as increased levels of hepatic or urinary copper.
COMPREHENSION QUESTIONS
[3.1] Which of the following statements best describes infection with hepatitis B virus?
A. Acute infection can be diagnosed by the presence of anti-HBsAb IgM or anti-HBc IgM.
B. It is nearly always a self-limited infection without a chronic or carrier state.
C. It is an RNA virus that usually is acquired from contaminated food and water.
D. It typically is associated with the formation of Mallory bodies on biopsy.
E. When it is acquired in adulthood, more than 85 percent of patients develop chronic hepatitis.
[3.2] A 25-year-old woman develops tender hepatomegaly and hemiballism when walking. Her liver biopsy shows hepatocyte necrosis and inflammatory portal tract infiltrate. Which of the following tests is most likely to yield the diagnosis?
A. Staining of liver specimen with Prussian blue
B. Measurement of serum alpha1-antitrypsin activity
C. Hepatitis C PCR
D. Ophthalmologic slit-lamp examination
E. Serum acetaminophen level
[3.3] A 44-year-old man is found to have jaundice, ascites, and hepatic insufficiency. The prothrombin time is elevated. Which of the following is the liver biopsy most likely to reveal?
A. Ballooning of the hepatocytes
B. Bridging necrosis
C. Fatty infiltration of the liver
D. Hepatocellular carcinoma
ANSWERS
[3.1] A. Acute hepatitis B infection is characterized by the presence or shedding of HbsAg, followed by a rise in anti-Hbc IgM. Adult infection has a much better prognosis (only 5 to 10 percent of patients develop chronic hepatitis) compared with perinatal infection (more than 90 percent develop chronic infection). Councilman bodies can be seen in viral hepatitis; Mallory bodies are characteristic of alcoholic hepatitis.
[3.2] D. The pathologic findings of acute hepatitis are nonspecific. The distinguishing feature in this case is the presence of hemiballism, an extrapyramidal movement disorder, suggesting Wilson disease. Kayser-Fleischer rings are green to brown deposits of copper in the Descemet membrane near the corneal limbus and are diagnostic.
[3.3] B. Bridging necrosis is most typical of end-stage cirrhosis and may be seen with a variety of disorders, such as viral hepatitis and alcoholic hepatitis. The inflammation leads to fibrosis, extending across lobules, for example, from the portal area to the central vein.
REFERENCES
Crawford JM. The liver and biliary tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:878-927.
Dienstag JL, Isselbacher KJ. Acute viral hepatitis. In: Braunwald E., Fauci AS, Kasper DL, et al., eds. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:1822-1837.
Ishak KG, Markin RS. Liver. In Damjanov I, Linder J, eds. Anderson's pathology, 10th ed. New York: Mosby, 1996:1779-1858.
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