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Acute Hepatitis and Fulminant Hepatic Failure

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FULMINANT HEPATIC FAILURE

ACUTE HEPATOTROPIC VIRAL INFECTIONS

OTHER INFECTIOUS HEPATITIDES

FIBROSING CHOLESTATIC HEPATITIS

DRUG-INDUCED HEPATIC NECROSIS

PREGNANCY-RELATED ACUTE HEPATITIS

 

Fulminant Hepatic Failure

DEFINITION

Potentially reversible severe liver dysfunction developing in 8 weeks or less from the initial symptom with no prior history of liver disease

CLINICAL FEATURES

image Encephalopathy, coagulopathy.

image Emergency transplantation may be indicated.

image Etiologies include acetaminophen toxicity (46%), idiosyncratic reaction to other drugs (11%), hepatitis B (7%) (Figure 1-1A), hepatitis A (3%), autoimmune hepatitis (5%) (Figure 1-1B), ischemia (4%), Wilson’s disease (2%), others (7%), or unknown etiology (14%).

image Serologic studies generally required to identify etiology.

PATHOLOGIC FINDINGS

image Massive hepatic necrosis: confluent necrosis throughout the liver; liver size and weight reduced by one-half to two-thirds.

image Sub-massive necrosis: course more protracted, liver forms regenerative nodules (Figures 1-1C, D).

image Recognition and diagnosis of autoimmune hepatitis (central venulitis, plasma cell infiltrate, interface hepatitis) crucial due to available treatment by immunosuppressive therapy.

image Zonal distribution of necrosis helpful in identifying etiology: zone 3 necrosis favoring acetaminophen toxicity; zone 2 necrosis traditionally reported in yellow fever; zone 1 necrosis suggestive of hepatitis A.

DIFFERENTIAL DIAGNOSIS

image Prior history of viral hepatitis

image Exacerbation of known autoimmune hepatitis

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FIGURE 1-1     (A) Fulminant hepatic failure due to HBV: normal parenchyma replaced by collapsed fibrous stroma with proliferating bile ductules. The histologic appearance is not specific. Reticulin stain highlights collapse (insert). (B) Fulminant hepatic failure due to autoimmune hepatitis. There is extensive necrosis with marked plasma cell infiltrate (insert). (C) Sub-massive necrosis of unknown etiology. Regenerative nodules are evident in the center of the specimen. The brown areas in the right and left represent parenchyma collapse. (D) Extensive, near-total hepatocyte necrosis, leaving behind sinusoidal stroma, and intact unremarkable portal tract (left upper corner).

 

Acute Hepatotropic Viral Infections

DEFINITION

Elevation of ALT and/or AST caused by one of the hepatotropic viruses (A to G) in a patient without a previous history of liver disease

CLINICAL FEATURES

image Severity varies from a mild asymptomatic infection to fatal fulminant hepatic failure.

image Serology confirms diagnosis; liver biopsy usually not necessary except to rule out secondary contributing factors or atypical clinical presentation.

image Hepatitis A or E rarely progresses to chronic hepatitis.

image Hepatitis C is usually asymptomatic in acute phase.

image Hepatitis Delta requires coinfection with HBV.

image Hepatitis E is endemic in Indian subcontinent; however, recently non-travel-associated hepatitis E has been reported in industrialized countries.

HISTOLOGIC FINDINGS

image Acute hepatitis is characterized by lobular disarray due to hepatocellular damage, swelling, and concurrent regeneration (Figures 1-2A, B). Frequent microscopic changes include ballooning degeneration, scattered acidophil bodies, hepatocytes dropout, lobular and sinusoidal inflammatory cell infiltrate, and Kupffer cell hyperplasia (Figure 1-2C).

image Zonal and bridging necrosis indicates a greater risk for developing fibrosis.

image Acute hepatitis in resolving phase can be subtle, and increased PASD positive histiocytes may be the only finding (Figure 1-2D).

DIFFERENTIAL DIAGNOSIS

image Drug-related liver injury

image Autoimmune hepatitis

image Acute alcoholic hepatitis

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FIGURE 1-2     (A) Acute hepatitis with lobular disarray due to increased regenerative activity and swelling of hepatocytes. (B) Trichrome stain shows no significant fibrosis. Edematous areas with light staining are indicative of collapsed framework. (C) Acute hepatitis A. Lobular disarray with loss of normal trabecular pattern. Portal lymphoplasmacytic infiltrate with interface activity. Multinucleated giant cells are present in the lobules as well (insert). (D) Resolving acute hepatitis A. PASD highlights increased PAS positive macrophages (phagocytosed cellular debris).

 

Other Infectious Hepatitides

DEFINITION

Acute hepatitis due to nonhepatotropic viruses such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and yellow fever virus (YFV)

CLINICAL FEATURES

image EBV is a member of herpesvirus family and causes hepatitis and lymphoproliferative disorders. Infectious mononucleosis typically occurs in adolescents or young adults and presents with fevers, fatigue, malaise, sore throat, jaundice, and lymphadenopathy.

image Most CMV infections are clinically silent. Clinically significant infections are seen in setting of immunosuppression (organ transplantation, acquired immunodeficiency, and congenital infection).

image HSV hepatitis is seen in neonates, pregnant women, and immunocompromised patients. Immune competent individuals may rarely develop fulminant infection.

image Yellow fever still occurs in people travelling to tropical regions without proper vaccination or rarely as a small outbreak due to vaccine adverse effect.

PATHOLOGIC FEATURES

image Herpes hepatitis: nonzonal coagulative necrosis, eosinophilic intranuclear inclusions surrounded by halo (Cowdry Type A), multinucleated cells with molding (Figure 1-3A).

image Cytomegaloviral hepatitis: cytoplasmic and nuclear enlargement with intranuclear and intracytoplasmic inclusions, neutrophilic microabscesses formation; microgranuloma may be seen (Figure 1-3B).

image EBV hepatitis: diffuse sinusoidal infiltration by lymphocytes in string of beads pattern (Figure 1-3C).

image Yellow fever viral hepatitis: focal or confluent hepatic coagulative necrosis.

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FIGURE 1-3     (A) HSV hepatitis. Inclusions characterized by smudged nuclei are seen in the setting of extensive hepatic necrosis; some inclusions are multinucleated. Immunohistochemical staining (insert) for both HSV1 and HSV2 should be performed. (B) CMV hepatitis. A hepatocyte with an enlarged nucleus; intranuclear and intracytoplasmic inclusions are present in the hepatocyte (left), and in an endothelial cell of the portal vein (right). Inclusions can be seen in biliary epithelium or Kupffer cells as well. (C) EBV hepatitis. Diffuse sinusoidal lymphocytic infiltration in string of beads pattern, with occasional acidophil bodies.

 

Fibrosing Cholestatic Hepatitis

DEFINITION

A rare form of aggressive hepatitis occurring in immunocompromised or immune suppressed patients that is associated with poor outcome. Though originally reported in liver transplant recipients with recurrent hepatitis B, this entity has now been recognized to occur in chronic hepatitis B or C patients who are under immunosuppression or have HIV co-infection.

CLINICAL FEATURES

image Most patients diagnosed within the first year post-liver transplant.

image High serum transaminase elevation, increased bilirubin, and jaundice.

image High viral load.

PATHOLOGIC FEATURES

image Extensive portal fibrosis with delicate septa extending into sinusoids (perisinusoidal fibrosis) (Figure 1-4A).

image Marked canalicular and hepatocellular cholestasis with ballooning (Figure 1-4B).

image Minimal to mild inflammatory cellular infiltration.

DIFFERENTIAL DIAGNOSIS

image Biliary obstruction

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FIGURE 1-4     (A) Extensive portal fibrosis with delicate septa extending into sinusoids. (B) Fibrosing cholestatic recurrent hepatitis C. Bile ductular proliferation and hepatocyte ballooning, with minimal inflammatory infiltrates.

 

Drug-Induced Hepatic Necrosis

DEFINITION

Sudden abnormality of liver biochemical tests (alanine aminotransferase, alkaline phosphatase and/or bilirubin) with underlying liver necrosis related to intake of drug or toxin

CLINICAL FEATURES

image Typically present with new onset of abnormal LFTs, with no causes identifiable by clinical history and serology.

image Patterns of liver enzyme abnormality classified as hepatic type, cholestatic type, or mixed type.

image Hepatotoxic agents sub-classified into 2 groups: (1) intrinsic toxins that are dose dependent and reproducible, such as acetaminophen (Figure 1-5A); (2) idiosyncratic toxins that are not dose dependent and are unpredictable, such as isoniazid (Figures 1-5B, C).

image Obtaining drug history and a literature search for each drug the patient is taking is necessary to confirm the diagnosis in suspected cases.

image Measurement of serum level of drug helpful but may be noncontributory due to metabolism.

image Antinuclear or anti-smooth muscle antibodies may be present.

image Normalization of liver enzymes takes weeks or months after the drug is stopped.

PATHOLOGIC FEATURES

image Many types of histologic patterns have been reported; therefore, a drug etiology should always be in the differential diagnosis when evaluating a liver biopsy.

image Fulminant necrosis, zonal necrosis, prominent eosinophils, granulomas, and cholestatic hepatitis are suggestive of drug-related liver injury.

image Severe steatohepatitis mimicking alcoholic hepatitis: amiodarone, phenytoin (Figure 1-5D).

image Massive centrilobular necrosis: acetaminophen.

DIFFERENTIAL DIAGNOSIS

image Viral hepatitis

image Autoimmune hepatitis

image Ischemic necrosis

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FIGURE 1-5     (A) Acetaminophen toxicity. Zone 3 necrosis without significant inflammation. Necrosis without inflammation is often seen with intrinsic toxins. This may be accompanied by marked steatosis in some cases. (B) Acute fulminant liver failure due to isoniazid required emergency transplantation. (C) Isoniazid-related acute hepatitis. Zone 3 necrosis with lymphoplasmacytic infiltrate is suggestive of drug-related liver injury. A necroinflammatory pattern is often seen with idiosyncratic toxins. (D) Ballooning degeneration and Mallory-Denk bodies due to amiodarone toxicity. Chronic changes such as prominent pericellular and centrilobular fibrosis are common as these occur in patients with heart failure with congestive fibrosis.

 

Pregnancy-Related Acute Hepatitis

DEFINITION

Acute liver diseases associated with pregnancy, including hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, preeclampsia/eclampsia, hemolysis (H), elevated liver tests (EL) and low platelets (LP) and acute fatty liver of pregnancy. HELLP syndrome and acute fatty liver of pregnancy present with acute liver failure.

CLINICAL FEATURES

image About 2–12% of severe eclampsia cases complicated by HELLP syndrome.

image Both HELLP syndrome and acute fatty liver of pregnancy occur in the 3rd trimester.

image Early diagnosis and delivery critical.

HISTOLOGIC FEATURES

image HELLP syndrome: focal necrosis, periportal hemorrhage and fibrin deposits (Figure 1-6A).

image Acute fatty liver of pregnancy: severe microvesicular steatosis, hepatocellular swelling, and zone 3 perivenular canalicular cholestasis (Figure 1-6B).

image Oil red O stain sometimes required to confirm the diagnosis of acute fatty liver of pregnancy (Figure 1-6C).

DIFFERENTIAL DIAGNOSIS

image Liver diseases occurring coincidentally during pregnancy

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FIGURE 1-6     (A) HELLP syndrome: focal hepatocytic necrosis. (B) Acute fatty liver of pregnancy. Hepatocytes with microvesicular steatosis and cholestasis. (C) Oil red O stain highlighting extensive microvesicular steatosis.