Section 2 -

Acute Hepatitis: Diagnostic Problems and Differential Diagnosis Grace E. Kim Associate Professor of Pathology University of California San Francisco

The differential diagnosis of acute hepatitis includes, acute viral hepatitis (hepatotropic hepatitis viruses), autoimmune hepatitis, Wilson's disease, drug reaction, and idiopathic. Acute hepatitis has clinically been defined as hepatitis lasting less than three months (duration has been arbitrarily defined by some as six months). Aminotransferases are usually >500 U/L and typically the levels are higher than those of chronic hepatitis. Histologically, hepatocytic damage by inflammation and necrosis is evident and the fibrosis of chronic hepatitis is lacking. Determining the presence and absence of fibrosis can be assessed using a trichrome stain. Large portal tracts, which have larger caliber artery and ducts, and subcapsular portal tracts should not be erroneously interpreted as having fibrosis. Also, portal tracts solely expanded by inflammation may have the appearance of portal tract fibrosis. Distinguishing hepatocyte dropout, collapse and necrosis attributed to severe necroinflammatory activity from established fibrosis can be difficult. Utilizing reticulin and orcein stains in addition to the trichrome stain can be useful. Necrosis Fibrosis Trichrome Two-tone blue Thin fibers All dark blue Thicker bundles Reticulin Dropout/Collapse Loss of cell plate architecure Orcein Negative for elastic fibers Positive for elastic fibers Acute Viral Hepatitis Hepatitis B and C can cause both an acute and chronic hepatitis, but Hepatitis A only develops an acute hepatitis and usually the disease is not severe enough to warrant liver biopsy. However, it can rarely cause fulminant acute hepatitis, be associated with a cholestatic form of acute hepatitis with a prolonged cholestatic phase and enzymatic picture that may mimic obstruction, or resolve slowly. These latter types of clinical presentations are the ones most likely to result in a liver biopsy. Prominent portal and periportal inflammation with numerous plasma cells can occur [1, 2]. The lack of fibrosis can help to differentiate this lesion from various forms of chronic hepatitis with interface hepatitis. Cholestasis, usually most prominent in the centrilobular zone, and bile ductular reactive changes with pericholangiolitis may also be present in the cholestatic forms. In fact, hepatitis A can frequently cause a so-called "cholestatic" hepatitis, a clinical variant of hepatitis that has a prolonged cholestatic picture without significant ALT and AST elevations, and so mimics obstruction. The pathology in these instances shows a parenchymal cholestasis and can show bile ductular proliferation in the periportal zones, but in addition, to help differentiate the lesion from obstruction, there is typically evidence of spotty necrosis (apoptosis) and some mild degree of mononuclear or Kupffer cell reaction in the lobules. Autoimmune Hepatitis Autoimmune hepatitis (AIH}, (no longer called "lupoid hepatitis" or used with the term "chronic" [3, 4] ), has been subclassified into three forms characterized by differences in clinical presentations or the serum antibodies identified [5]. Most patients respond favorably to immunosuppressive therapy (prednisone), with a resultant decrease in the activity of the disease, so their distinction from viral hepatitis or chronic hepatitis due to other causes is important. Classical Type 1 AIH presents as hepatitis that primarily affects females in the age ranges of 2-15 and 35-70 years. These patients have positive antinuclear antibody (ANA) titers and some association (in about 10-20%] with other autoimmune disorders [6]. Many of these patients will show evidence of fibrosis in the liver when they initially present with symptoms [7]. Type 2 AIH seems to present more in children (girls more than boys, age less than 15 years) and is frequently associated with other autoimmune disorders (about 20%) as well [8]. The anti-liver-kidney microsomal (LKM-1) antibody is present in these patients, who often present with the clinical picture of an acute or fulminant hepatitis. In these cases, it is often difficult to determine whether a preexisting chronic hepatitis was present before the acute phase, so the lesions may be truly more acute in nature [8]. The type 2 variant in adult patients has also been associated with coinfection with hepatitis C virus [9, 10]. In this group, some patients have been reported to respond favorably to interferon therapy [11] while others have been reported to show flares of hepatitis during interferon therapy, and then, subsequently, respond to steroid therapy [10]. It is generally thought that infection with hepatitis C may, in fact, trigger an autoimmune reaction to the LKM-1 target antigen in patients who have a genetic predisposition as evidenced by a high incidence of certain HLA antigens [12]. The most recently described variant, Type 3 AIH also occurs mostly in women but with a later onset (mean age 37) [6]. About 25% of these patients will display the anti-soluble liver antigen (SLA) only. These patients are seronegative for ANA and liver-kidney-microsomal antibody, but 75% will have anti-smooth muscle antibody (SMA) or liver membrane antibody (LMA). In contrast to types 1 and 2, systemic autoimmune manifestations are not typical. Autoimmune Hepatitis - Diagnostic Considerations AIH is often characterized by prominent plasma cell infiltrates not typically seen in HCV or HBV hepatitis, but may display the prominent lymphoid aggregates and duct damage seen with HCV hepatitis. However, patients with AIH seem to have more diffuse and severe interface hepatitis, an increased incidence of bridging and confluent necrosis, and more rapid progression to cirrhosis than patients with HCV. In addition, infiltration of mononuclear inflammatory cells tends to be diffuse with AIH and focal with chronic HCV [13]. Multinucleate hepatocytic giant cells have also been reported to occur in autoimmune hepatitis [8, 14, 15]. The histology doesn't differentiate the clinical types. Wilson's Disease Wilson's disease is an autosomal recessive disorder that results from the accumulation of copper in various tissues due to the lack of synthesis of a membrane-associated copper transport protein. The patients essentially never present before the age of 5, and generally present as teens or young adults [16]. The disease may present with either hepatic disease (more frequently seen in children, young adults) or neurological symptoms (older patients), and the hepatic disease may also present in a variety of forms, including in acute and chronic patterns. The acute presentations mimic acute or fulminant viral hepatitis [17] with the latter severe form associated with severe hemolysis as a distinguishing feature. Kayser-Fleischer rings tend to be found in the later stages. The diagnosis depends on the finding of low serum ceruloplasmin (although 5-10% of patients may have normal ceruloplasmin, especially those with a fulminant course with hepatic necrosis [16] ), and increased hepatic copper content (greater than 250 µg/g dry weight). The early diagnosis of Wilson's disease is important, as chelation therapy with penicillamine will prevent the complications of copper overload. Wilson's Disease - Diagnostic Considerations Wilson's disease can present as fulminant hepatitis, chronic hepatitis, and fibrosis/cirrhosis. The hepatic disease may take several different forms. The earliest changes that may be seen in asymptomatic patients include fatty change, glycogenated nuclei in the periportal zone, and rare hepatocyte spotty necrosis [18]. This lesion may eventually progress to fibrosis and cirrhosis, but the patients may also present with hepatitis syndromes, including acute, fulminant, and chronic types. If the presentation is that of portal hypertension and cirrhosis is present, the latter often tends to be a macronodular type [18], but micronodular forms may also be seen, especially in the younger patients with superimposed fulminant failure [17]. The amount of inflammatory infiltrate may vary. The chronic hepatitic form usually has the features of active chronic hepatitis with interface hepatitis, and variable degrees of lobular inflammation and necrosis; bridging necrosis may be present. The chronic hepatitic changes may be associated with bridging fibrosis or cirrhosis. The histopathology of the various forms of Wilson's disease may be indistinguishable from other causes of hepatitis or cirrhosis by light microscopy, but features such as fatty change, glycogenated hepatocytic nuclei, Mallory bodies in periportal hepatocytes, and moderate to marked copper deposits may help to make the diagnosis of Wilson's disease. The copper deposits may be patchy, and typically should be seen in the hepatocytes. In cirrhotic livers, many nodules may have no copper in them while in others the copper may be found in abundance [18]. In addition, in the presence of extensive hepatocyte necrosis, the copper may also be found in Kupffer cells and portal macrophages [17]. Both rhodanine and rubeanic acid stains will identify copper in Wilson's disease and the orcein stain will identify copper-associated protein. The intensity of copper staining by histologic means may not correlate with the dry weight copper results, especially if the sample is taken from a small needle biopsy [16]. Copper deposits in cytoplasm would need to be identified to make a diagnosis of Wilson's disease; but copper can be patchy in this disease, so sampling can be a problem. Therefore, the variable histology, negative copper staining, and normal ceruloplasmin levels in 5% of patient can be problematic in diagnosing Wilson's disease. Drug Reaction Drug reactions must often be considered in the differential diagnosis of hepatitis of various types [19]. The hepatitis-like reactions with immunologic response are almost always an idiosyncratic form of drug reaction, and histologically, these lesions are often indistinguishable from hepatitis due to other causes. A careful drug history, including the use of over-the-counter medications, herbal remedies, and other "health-food" products should be obtained in patients who lack viral markers for hepatitis. Prominent eosinophilic infiltrates, granulomas, or cholestasis out of proportion with the hepatocellular injury (with or without duct damage) associated with the hepatitis may suggest the possibility of a drug reaction as well. Acetaminophen toxicity should be noted as an exception to the above in that its toxicity is due to overdosage rather than an idiosyncratic effect. The histologic lesion consists of centrizonal necrosis that may also extend to zone 2 and 1 with little or no inflammatory reaction. The absence of inflammation, absence of viral inclusions (as in Herpes hepatitis), and the uniformity of the injury from lobule to lobule are helpful features in distinguishing this lesion from other forms of massive hepatic necrosis due to viral causes or autoimmune hepatitis. Drug Hepatitis vs Toxic "Hepatitis" (Mostly necrosis, minimal inflammation) Acute hepatitis Chronic Hepatitis - rare Cholestatic hepatitis Granulomatous hepatitis Acetaminophen Mushroom poisoning Drug Reaction - Clinical Considerations and Pathology The onset of signs and symptoms of liver failure occur in day 3-5 following the toxic overdose. The hepatocellular necrosis occurs in zone 3 (centrizonal region) and can also involve zone 2. Zone 1 is generally spared, but these surviving hepatocytes can appear swollen or fatty. Cholestasis may be present, but inflammatory infiltrates are sparse or absent. The dead hepatocytes show a uniform pattern of coagulative necrosis from central zone to central zone with endothelial cells remaining intact for the most part. Tylenol (acetaminophen; paracetamol in Europe ) poisoning has become the most common form of drug-induced liver injury due to its popularity for attempted suicide (especially in the United Kingdom ). Minimal toxic levels in adults are between 7.5 grams and 10 grams (therapeutic dose 1-4 grams daily), but severe liver injury is usually not seen unless doses are in the 15-25 grams range. "Active" metabolites produced in oxidative reactions lead to the injury after glutathione is depleted, so therapy with N-acetylcysteine within 12 hours of overdose can significantly decrease the hepatocellular necrosis. Alcohol ingestion, usually chronic excessive alcohol consumption, and other medications (especially isoniazid) that induce the cytochrome P450 lower the toxic threshold for acetaminophen and so enhance toxic effects at much lower doses. The blood level is the most reliable indicator of the risk for injury. Drug Reaction - Differential Diagnosis Other causes of sudden-onset hepatic failure (less than one week) due to centrizonal necrosis include mushroom poisoning and even Herpes simplex virus. The latter, however, should show evidence of intranuclear inclusions in the surviving hepatocytes and often has a more hemorrhagic component. Cocaine overdose can also probably cause this type of lesion, but mid-zonal or periportal necrosis has also been described. The type of acute liver failure is usually clinically differentiated from the hepatotropic viruses (i.e. A, B, C, etc.) by its very rapid onset. These viruses generally present with 3-4 weeks of prodromal illness in contrast to the 3-5 day latent period to symptoms seen after a toxic overdose. Serology can be done, but it should be noted that in fulminant liver failure (or the development of hepatic encephalopathy within 3 weeks of the onset of symptoms) as many as 30% of patients have negative viral serology, and 15% may have no identifiable viral, drug, or other known cause for the failure. These viral hepatitides show an associated inflammatory infiltrate and variability in the pattern and age of the necrotic/degenerative lesion. Significant regeneration is also often present as the longer time course allows this to become more prominent. Drugs Causing Zonal Necrosis acetaminophen tetracycline - dose dependent valproic acid (idiosyncratic and/or dose dependent) street drugs such as cocaine, phencyclidine metals: copper - Zone 3 iron - Zone 1 phosphorus- Zone 1 References Kryger P, Christoffersen P. Liver histopathology of the hepatitis A virus infection: a comparison with hepatitis type B and non-A, non-B. Journal of Clinical Pathology 1983;36:650-654. Teixeira M, Weller I, Murray A, et al. The pathology of hepatitis A in man. Liver 1982; 2:52 -60. Johnson P, McFarlane I. Meeting report: International Autoimmune Hepatitis Group. Hepatol 1993;18:998-1005. Ludwig J, Alvarez, Bianchi F, et al. Terminology of chronic hepatitis. Amer J Gastroenterol 1995;90:181-189. Manns M. 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