Biopsy Interpretation of the Liver, 2nd ed

27. Differential Diagnosis: Common Liver Biopsy Problems

A definitive diagnosis is not always established after liver biopsy review, even with the most complete clinical information and comprehensive laboratory testing. Biopsy findings are not always diagnostic. Often the sample size is inadequate (see Chapters 5 and 7). This chapter is a condensed review of some commonly encountered problems, emphasizing features useful in differentiating morphologically similar disorders.

ACUTE VIRAL HEPATITIS VERSUS ACUTE DRUG-INDUCED HEPATITIS (TABLE 27.1)

Portal tract inflammation can be variable. In general, however, inflammation is more prominent in acute viral hepatitis (AVH). In viral hepatitis, a predominantly mononuclear inflammatory infiltrate composed of lymphocytes, histiocytes, and occasional plasma cells predominates. In acute hepatitis A (HAV), for reasons not fully understood, plasma cells may outnumber other inflammatory cells, resembling autoimmune hepatitis, although clinical data usually resolve this question. Eosinophils can be present in viral hepatitis but, in contrast to many drug-induced hepatitis cases, are generally few. Not every drug-induced hepatitis will have increased numbers of eosinophils.

Interface hepatitis (piecemeal necrosis) is usually not prominent in acute viral or acute drug-induced hepatitis, except for acute hepatitis A where it can be significant. Lobular inflammation and necrosis can be variable in both acute and drug-induced hepatitis. Both show lobular inflammation, focal liver cell necrosis with acidophilic body formation, at least some degree of ballooning degeneration, and Kupffer cell prominence, and it is often impossible to distinguish between the two. Some drugs cause massive or submassive necrosis; acetaminophen toxicity is the best example. Bile duct injury is usually mild in drug-induced hepatitis. Rarely, drug-induced bile duct injury leads to true ductopenia, as with chlorpromazine-induced bile duct injury. Mild ductal epithelial changes, including pleomorphism of nuclei and vacuolization of cytoplasm, is often seen with AVH, particularly in HAV and HCV virus infection, but also, rarely, in hepatitis B (HBV). Cholestasis, canalicular or intracellular or both, is more often seen with drug-induced hepatitis. HAV can be morphologically indistinguishable from drug hepatitis when present in the cholestatic form. Granulomas are uncommon in viral hepatitis but are seen with some drugs such as phenylbutazone and allopurinol. Granulomas rarely form in chronic viral hepatitis. Some drugs (e.g., diclofenac) can give the picture of autoimmune hepatitis, with prominent interface and lobular hepatitis.

Fibrosis is not associated with either acute viral or acute drug-induced hepatitis. When acute hepatitis, either viral or drug induced, is superimposed on already existing chronic liver disease, interpretation of histopathology can be exceedingly difficult.

Detailed clinical information is required, including time of onset of symptoms and duration, serologic studies, and history of exposure to new and traditional medications and herbal products, including teas. The clinical picture of an acute hepatitis can be seen in alcoholics at any time in their disease course, including when they are already cirrhotic, and acute inflammatory changes can be seen in the background of chronic injury.

ACUTE VIRAL HEPATITIS VERSUS ACUTE ALCOHOLIC HEPATITIS (TABLE 27.2)

Portal inflammation in acute alcoholic hepatitis is usually relatively mild. The inflammatory infiltrate is predominantly mononuclear, but polymorphonuclear leukocytes (PMNs) are also seen. True interface hepatitis is usually not present, although some spillover of inflammatory cells into the liver parenchyma may be present.

Lobular inflammatory activity in alcoholic hepatitis is characterized by ballooned and distended hepatocytes, often containing Mallory hyalin and surrounded by PMNs. These hallmarks of alcoholic hepatitis can be seen in nonalcoholic steatohepatitis (NASH), associated with obesity, diabetes mellitus, and jejunoileal bypass. In contrast to AVH, acidophilic bodies are unusual. Mallory hyalin is not seen in AVH. Steatosis, predominantly macrovesicular, typically zone 3, is a hallmark of alcoholic hepatitis, although it can be variable. Steatosis is uncommon in AVH. Pure microvascular steatosis rarely occurs. Cholestasis occurs in both acute HAV and alcoholic hepatitis.

Fibrosis, perivenular (central hyaline sclerosis) and pericellular (“chicken-wire”), is typical of alcoholic hepatitis. AVH, by definition, does not show changes of chronicity. Clinical data including symptoms, biochemistry, and serologic markers are invaluable. A careful social history, inquiring about exposure to alcohol and other drugs and toxins is mandatory.

ACUTE VIRAL HEPATITIS VERSUS CHRONIC HEPATITIS (TABLE 27.3)

Portal inflammation is generally mild in the early stages of AVH. In chronic hepatitis (CH), portal inflammation predominates. The inflammatory infiltrate in CH is predominantly mononuclear, including lymphocytes, histiocytes, and occasional plasma cells. In autoimmune CH, plasma cells may be particularly prominent. Lymphoid aggregates, often with true germinal center formation, are typical of chronic HCV but are not specific and can also be seen in autoimmune hepatitis (AIH) as well as in CH resulting from HBV. Interface hepatitis is the hallmark of CH and is usually variable. Focal interface hepatitis and spillover of inflammatory cells is sometimes seen in AVH.

Lobular activity is typical of acute hepatitis, including lobular inflammation and acidophilic body formation. The constellation of hepatocyte pleomorphism, with ballooned cells, pyknotic cells, acidophilic bodies, and patchy inflammation imparts a disordered look to the lobules, so-called lobular disarray, sometimes also described as dirty appearing. Reticulin stain helps demonstrate focal liver cell loss (dropout).

Immunohistochemistry and histochemistry can be helpful. In chronic HBV infection, viral antigens, hepatitis B surface antigen (HBsAg), and hepatitis B core antigen (HBcAg) can be demonstrated. HBsAg can also be seen with Victoria blue or orcein stains.

Wilson disease can present as a CH. Some hepatocytes exhibit deeply eosinophilic cytoplasm, whereas others may be distended with Mallory or Mallory-like material. Macrovesicular steatosis and glycogenated nuclei are often seen without any particular zonal distribution. Special stains, rhodanine and rubeanic acid, can confirm the presence of copper but are not always positive, and quantitative copper assay is often needed.

Fibrosis is a feature of CH regardless of cause. Fibrosis varies from mild portal/periportal fibrosis to extensive fibrosis, bridging fibrosis, and then cirrhosis. Minimal fibrosis is best seen with reticulin silver stain.

LARGE BILE DUCT OBSTRUCTION VERSUS CHOLESTATIC HEPATITIS (TABLE 27.4)

Portal edema is characteristic of large duct obstruction (LDO), developing a few days after obstruction. The inflammatory infiltrate is usually mild and predominantly mononuclear cells, with a variable number of PMNs surrounding, but not usually infiltrating, bile ducts (pericholangitis). PMNs increase with persistence of obstruction when ductules proliferate secondarily (marginal bile ductular proliferation). Interlobular bile ducts and bile ductules may be dilated. True ascending cholangitis can develop with PMNs seen in the bile duct lumen. If obstruction persists, portal fibrosis and then portal-portal bridging fibrosis develops. These changes are not seen in AVH or CH, although ductular reaction (proliferation) is common in severe hepatitis.

Portal edema is less prominent in posttransplant LDO, in which the principal manifestations are acute pericholangitis and ductular reaction (proliferation).

Lobular activity is not prominent in LDO except in zone 3 when cholestasis is prominent. Cholestatic changes include hepatocyte ballooning with a foamy cytoplasm (feathery degeneration).

Zone 3 canalicular cholestasis is the first sign of LDO, progressing rapidly during the first week to include other zones when obstruction is not relieved. Numerous bile plugs (bile thrombi) are seen in zone 3. Intracellular cholestasis and hypertrophied Kupffer cells are also seen. In long-standing LDO, bile lakes and bile infarcts form when dilated bile ducts rupture with extravasation of bile into the liver parenchyma. Consequently, hepatocytes undergo degeneration and necrosis and become surrounded by reactive, foamy macrophages.

In contrast, cholestatic hepatitis has only mild intracanalicular and intracellular cholestasis. Bile lakes or bile infarcts are not seen.

Helpful clinical information includes onset (acute versus gradual onset), duration of symptoms, jaundice, epigastric pain, biochemistry (e.g., disproportionately elevated alkaline phosphatase and bilirubin would be more indicative of LDO), serologic markers, and endoscopic and radiologic findings.

CHRONIC HEPATITIS VERSUS PRIMARY BILIARY CIRRHOSIS (TABLE 27.5)

Portal inflammation in primary biliary cirrhosis (PBC) is variable in intensity. The inflammatory cell infiltrate is predominantly mononuclear and consists of lymphocytes, histiocytes, some plasma cells, and some eosinophils. Interface hepatitis is often present, although the inflammatory infiltrate is often intermingled with ductular reaction (proliferation), referred to as ductular interface hepatitis. Granulomas and granulomatous occur with bile duct injury in early (stage 1) PBC. So-called florid bile duct injury is typical of early PBC. Variable degrees of destructive bile duct injury are seen, ultimately leading to bile duct loss. Cholate stasis with ballooning of the periportal and periseptal hepatocytes, often with Mallory material and copper-associated protein, is almost invariable in late PBC (stages 2 to 4).

Mild lobular inflammation and focal liver cell necrosis are not common in PBC in contrast with CH. Granulomas are often in the PBC portal tract but may be scattered throughout the parenchyma.

Differentiating between CH and early PBC can be problematic. In late stage PBC, bile duct loss and biliary-type fibrosis are seen, features not seen in CH. In contrast, AIH and early PBC can be histologically quite similar. Indeed, a true overlap syndrome with clinical and morphologic features of both AIH and PBC exists.

Helpful clinical information includes patient's gender (PBC is rare in men) and age, onset of symptoms, pruritus, biochemistry, serologic and autoimmune markers, and antimitochondrial antibody (AMA) titer.

CHRONIC HEPATITIS VERSUS PRIMARY SCLEROSING CHOLANGITIS (TABLE 27.6)

The liver biopsy may be normal in primary sclerosing cholangitis (PSC) (see Chapter 17), and differentiating from chronic hepatitis will not be an issue.

When liver changes are seen, portal inflammation is generally mild to moderate. The inflammatory cell infiltrate is predominantly mononuclear, with lymphocytes, histiocytes, and some plasma cells. Interface hepatitis is not prominent, in contrast to both CH and PBC.

Bile duct injury is always present, but the degree is variable and often very subtle in early PSC. Cholangiography is the standard for diagnosing PSC. Biopsy changes are variable and scattered, and even multiple biopsies may fail to show a typical lesion. Instead of necrosis, bile ducts more often show progressive atrophy, with periductal concentric fibrosis (“onion skinning”). Complete bile duct loss, sometimes leaving a resultant fibrous scar that characteristically has a smudgy appearance with trichrome and is a hallmark of PSC. Bile ductular reaction is more prominent in late PSC than in PBC. In CH, ductular reaction (proliferation) is generally not seen until cirrhosis ensues.

Granuloma is exceedingly rare in PSC. Cholate stasis in periportal and periseptal hepatocytes, with ballooning, Mallory material, and copper-associated protein is similar in late PSC and PBC and is not seen in CH.

Clinical information of value includes include gender, time of onset and duration of symptoms, other associated conditions (e.g., inflammatory bowel disease, especially ulcerative colitis), biochemistry, serologic and autoimmune markers, and antineutrophil cytoplasmic antibody (ANCA) status.

LARGE BILE DUCT OBSTRUCTION VERSUS PRIMARY CHOLANGIOPATHIES (PRIMARY BILIARY CIRRHOSIS AND PRIMARY SCLEROSING CHOLANGITIS) (TABLE 27.7)

Portal edema is typical of LDO and not seen in PBC or PSC. The predominantly mononuclear portal tract inflammatory infiltrate is more prominent in the cholangiopathies. Interface hepatitis is not seen in LDO, in contrast with PBC.

Bile duct injury is the most important histologic feature of both PBC and PSC.

Bile duct loss, characteristic of late PBC and PSC, is not seen in LDO even when long-standing (Tables 28.8 and 28.9). In LDO, a true necroin-flammatory and destructive bile duct injury is not seen. Marginal bile ductular reaction is typical of LDO.

Granulomas and granulomatous bile duct injury are characteristic of PBC and not seen in LDO

Cholestasis may be present in all three conditions. In LDO, cholestasis is centrolobular and intracanalicular. Bile lakes and bile infarcts are virtually pathognomonic. Cholate stasis is common in both PBC and PSC in periportal and paraseptal hepatocytes and is not seen in LDO.

The pattern of fibrosis is the same in LDO and the cholangiopathies. Portal-portal fibrous bridging, with irregular islands of liver parenchyma surrounded by relatively paucicellular fibrous septa, imparts a so-called jigsaw pattern. In the primary cholangiopathies, there is widespread bile duct loss, not seen in secondary biliary cirrhosis caused by LDO.

ALCOHOLIC STEATOHEPATITIS VERSUS NONALCOHOLIC STEATOHEPATITIS (TABLE 27.10)

Steatosis in both alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) is similar. It can be macrovesicular, mixed microvesicular and macrovesicular, or, rarely, purely microvesicular with foamy cells. Zone 3 is typically affected, but steatosis can be diffuse in severe cases.

Mallory material tends to be more abundant and prominent in ASH. In NASH, Mallory material, fat, and glycogenated nuclei, when seen, are prominent mostly in zone 1. Glycogenated nuclei occur in both conditions. Fibrosis, including central hyaline and pericellular (chicken wire) fibrosis, may be identical in both with progression to cirrhosis. Detailed clinical history is crucial.

ALCOHOLIC STEATOHEPATITIS VERSUS DRUG-INDUCED PHOSPHOLIPIDOSIS (TABLE 27.11)

Drug-induced changes caused by amiodarone and perhexiline maleate mimic alcoholic hepatitis. Amiodarone, and sometimes high-dose estrogen therapy, causes drug-induced phospholipidosis, mimicking Niemann-Pick disease. Clinical setting and history are crucial to understanding the biopsy.

Steatosis, predominantly macrovesicular, is generally more prominent in ASH. Mallory material is usually abundant in drug-induced phospholipidosis and can be diffuse in contrast to ASH in which it is usually in zone 1. Portal and pericellular fibrosis may be similar in both conditions. Central hyaline sclerosis is typically not seen in drug-induced steatosis. Electron microscopy in amiodarone-induced phospholipidosis shows characteristic myelin figures. They are not seen in ASH.