Non-Neoplastic Disorders of the Liver

Laboratory Values

Most patients show markedly elevated serum AST and ALT levels (often >15-fold normal levels). Bilirubin and ALP may also be elevated. Viral serologies may be negative during the early course of disease. Polymerase chain reaction (PCR)–based testing is frequently used as a confirmatory test.

Pathologic Features

Gross Findings

The liver may be swollen and congested with a yellow or green discoloration or shrunken with a “loose” capsule in extensive parenchymal injury or collapse. In cases of submassive or massive hepatic necrosis ( Fig. 17.2 ), the liver may be friable and hemorrhagic with obvious areas of necrosis upon sectioning.

Microscopic Findings

Acute viral hepatitis represents the prototype acute hepatitis pattern of injury, exhibiting the diffuse lobular-predominant inflammation and hepatocyte injury with lobular disarray (see Figs. 17.3A and B ) . Acidophil bodies are prominent, and in severe cases, portions of lobules or entire contiguous lobules may undergo necrosis (see Fig. 17.3C). As part of parenchymal regeneration, there may be pronounced regenerative bile ductular reaction. Cholestasis may be present, including in some cases of hepatitis E (Fig. 17.3D). Portal inflammation may be present but is usually less prominent than the lobular inflammation and injury. Biopsies taken after the initial illness may show only residual Kupffer cell hyperplasia. There is no fibrosis unless the patient has preexisting chronic liver disease.

Acute Viral (Hepatotropic) Hepatitis—Pathologic Features

Gross Findings

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  Hepatomegaly

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  Congestion; possibly yellow or green discoloration if cholestasis

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  In fulminant hepatitis, the liver is friable with hemorrhagic and necrosis areas and the capsule is flaccid

Microscopic Findings

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  Lobular disarray caused by hepatocyte injury or necrosis, regeneration, and Kupffer cell hyperplasia

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  Predominantly panlobular mononuclear inflammatory infiltrate

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  Cholestasis may be present

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  Bridging necrosis to submassive or massive necrosis only in severe cases

Differential Diagnosis

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  Drug-induced liver injury

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  Nonhepatotropic viral hepatitis

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  Acute exacerbation of autoimmune hepatitis

Differential Diagnosis

The differential diagnoses include nonhepatotropic viral infections, chronic viral hepatitis, DILI, and AIH. Distinguishing these entities often requires clinical information (e.g., history of travel, new drug or toxins) along with viral serologies and serum autoantibody titers.

Nonhepatotropic viral infections may follow a variable clinical course depending on the specific underlying infection. Classic histologic clues to these diagnoses are discussed in the following section. In chronic viral hepatitis, the inflammatory cell infiltrates are centered within the portal tracts and fibrosis is common. Prominent lobular inflammation and hepatocyte injury can be seen in AIH; however, AIH is usually associated with brisk interface activity, plasma cells, elevated serum autoantibodies, and polyclonal hypergammaglobulinemia. Exclusion of drug- or toxin-induced injury may be difficult clinically and histologically. Wilson’s disease can mimic any clinical or histologic pattern of injury, including acute hepatitis, and a low threshold for performing serum ceruloplasmin and tissue copper quantitation is warranted. The differential diagnosis for submassive or massive necrosis includes infections (e.g., herpes simplex virus [HSV]), vascular injury, and DILI.

Pathologic Features

Gross Findings

Mild hepatomegaly and variable congestion are common in all nonhepatotropic viral infections. An HSV-infected liver may show a hyperemic and mottled cut surface with foci of geographic necrosis ( Fig. 17.4 ).

Microscopic Findings

In general, nonhepatotropic viral hepatitis exhibits histologic features similar to those described in hepatotropic virus infections, including lobular-predominant inflammation and hepatocyte injury.

The most characteristic histologic feature of EBV hepatitis is “sinusoidal lymphocytosis” characterized by a diffuse sinusoidal infiltrate typically composed of small lymphocytes arranged in a single-file “string-of-beads” pattern ( Fig. 17.5A ). Acidophil bodies are rare. Small lobular Kupffer cell aggregates may be present. The portal tracts demonstrate mild lymphocytic infiltrates but significant interface hepatitis. Immunosuppressed patients may show more pronounced necroinflammatory activity and even bile duct injury. Extensive necrosis is only seen in those with fulminant EBV hepatitis ( Fig. 17.5B ).

Cytomegalovirus hepatitis histologically mimics EBV infection in immunocompetent hosts. The typical intranuclear or intracytoplasmic viral inclusions that are often present in immunocompromised patients may not be seen. As with other causes of acute hepatitis, lobular inflammation and injury predominate. Acidophil bodies and spotty necrosis are common. Neutrophilic microabscesses may be seen but are neither sensitive nor specific for CMV hepatitis. Diagnostic viral inclusions can be detected on hematoxylin and eosin (H&E) stain or IHC in infected endothelial cells, hepatocytes, or biliary epithelial cells ( Fig. 17.6 ).

Herpes simplex virus hepatitis has distinct histologic features, which, when present, should promptly suggest this diagnosis. The hepatic parenchyma typically shows irregular foci of nonzonal or “geographic” necrosis ( Fig. 17.7A ) with relatively mild lobular and portal chronic inflammation. Diagnostic viral inclusions (Cowdry type A) with multinucleation, margination, and molding are usually present within viable hepatocytes adjacent to foci of necrosis ( Figs. 17.7B and C ). IHC may be needed to confirm the diagnosis.

Nonhepatotropic Viral Infections—Pathologic Features

Gross Findings

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  Hepatomegaly

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  Herpes simplex virus (HSV): geographic necrosis with hyperemic borders

Microscopic Findings

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  Epstein-Barr virus (EBV): sinusoidal lymphocytic infiltrate (“string of pearls”)

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  Cytomegalovirus (CMV): neutrophilic microabscesses and intranuclear or cytoplasmic inclusions

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  HSV: geographic necrosis and Cowdry A-type inclusions

Ancillary Studies

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  EBV: scattered positive lymphocytes on chromogenic in situ hybridization

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  CMV: positive viral inclusions on immunohistochemistry

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  HSV: positive viral inclusions on immunohistochemistry

Differential Diagnosis

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  Other causes of acute hepatitis, including the hepatotropic viruses (hepatitis A, B, C, D, E)

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  Drug-induced liver injury

• ■

  Other hepatic infections

Ancillary Studies

Serologic testing and PCR-based assay are used clinically to establish the diagnosis and exclude other causes of hepatitis. Immunohistochemical stains (especially for CMV and HSV) and chromogenic in situ hybridization (CISH) for EBV-encoded RNA (EBER) are widely available. EBER-positive lymphocytes are rare in EBV-infected patients; most of the lymphocytes seen in EBV hepatitis do not show positive EBV staining ( Fig. 17.8 ).

Differential Diagnosis

The differential diagnosis includes other causes of acute hepatitis, including hepatotropic and other nonhepatotropic viral infections (adenovirus, human herpesvirus 6 A, parvovirus), other hepatic infections, and DILI. In cases of suspected EBV hepatitis, specimens showing “atypical lymphocytes” should be investigated carefully to exclude the involvement of a lymphoproliferative disorder.

In cases with extensive hepatic necrosis, ischemia and DILI should be considered. The zonal distribution of necrosis (predominantly zone 3), clinical history, and absence of viral inclusions are helpful in distinguishing these entities.

Prognosis and Therapy

In immunocompetent patients, the disease course is self-limited, and symptoms usually resolve in 4 to 6 weeks. In immunocompromised individuals, the disease follows a more severe course and may result in acute liver failure.

In most patients, antiviral therapy is not required. Ganciclovir is administered to CMV-infected patients who are at risk of severe or life-threatening illness. HSV is often treated with acyclovir, but the outcome is generally poor.

Clinical Features

Chronic viral hepatitis has a wide spectrum of clinical manifestations, ranging from asymptomatic infection to decompensated cirrhosis. Symptomatic patients have mild, nonspecific symptoms such as fatigue, anorexia, and weight loss. Patients with cirrhosis may present with esophageal varices, hepatosplenomegaly, spider angiomata, ascites, peripheral edema, muscle wasting, and abdominal collateral blood vessels.

Serum transaminase levels are usually elevated in the 2- to 10-fold range of normal, although patients with mild chronic viral hepatitis may have normal transaminase levels. ALP and bilirubin levels are usually normal to mildly elevated unless hepatic decompensation occurs. Low-titer nonspecific autoantibodies, especially anti–liver/kidney microsomal 1 antibodies (anti-LKM1) and smooth muscle actin (SMA), have been reported in this setting. Fibrosing cholestatic hepatitis (FCH) is a severe, rapidly progressive form of hepatitis B or C that occurs in immunosuppressed or immunocompromised patients.

Pathologic Features

Microscopic Findings

The microscopic findings include the characteristic features of chronic hepatitis pattern of injury: portal inflammation with or without fibrosis and variable degrees of interface hepatitis and lobular necroinflammatory activity. The portal tracts are expanded by inflammatory infiltrates composed of mostly lymphocytes with variable plasma cells and other inflammatory cells. Lymphoid follicles with prominent germinal centers may be seen ( Fig. 17.11A ). Mild bile duct injury with intraepithelial lymphocytes may be seen, but there are no destructive bile duct lesions. Interface activity, also known as “interface hepatitis” or “piecemeal necrosis,” is a frequent feature ( Fig. 17.11B ). It is characterized by extension of the portal inflammation beyond the “limiting plate” into the periportal hepatic lobule and accompanying hepatocyte injury or necrosis.

In most cases, lobular inflammation consists of randomly scattered lobular collections of mononuclear cells associated with hepatocyte injury or acidophil bodies ( Fig. 17.11C ), but confluent and even bridging necrosis can be seen ( Fig. 17.11D ). Ground-glass hepatocytes ( Fig. 17.11E ) are a characteristic feature of HBV infection but are only seen in patients with chronic HBV in the setting of active viral replication.

Fibrosis in chronic viral hepatitis is portal-based and evolves to extend into the periportal region ( Fig. 17.12 ). Bridging fibrosis occurs as portal–portal or portal–central fibrous septa. The end result is cirrhosis.

Fibrosing Cholestatic Hepatitis

The FCH variant of HBV and HCV is an aggressive form of hepatitis that typically occurs in immunosuppressed patients. FCH is characterized by prominent perisinusoidal/pericellular fibrosis occurring in the periportal region, ductular reaction, hepatocellular injury including hepatocyte swelling and ground-glass inclusions (in HBV), and prominent intracellular and canalicular cholestasis ( Fig. 17.13 ). The biopsy usually lacks significant inflammatory infiltrates.

Ancillary Studies

For chronic HBV and HBC infection, the diagnosis is based on serologic testing and confirmatory RNA or DNA by PCR to exclude false-positive serologies (as can occur in the setting of AIH). Cytoplasmic and nuclear accumulation of hepatitis B core antigen (HBcAg) ( Fig. 17.14A ) may be detected by IHC and correlates with active replication of the virus. However, immunohistochemical stains for surface ( Fig. 17.14B ) and core antigens (HBV and HCV) are rarely helpful or required in daily practice.

Differential Diagnosis

The histologic differential diagnosis of chronic viral hepatitis primarily includes AIH, primary biliary disorders, Wilson’s disease, α1AT deficiency, DILI, and low-grade lymphoproliferative disorders. Serologic and PCR-based testing are essential in distinguishing these entities. Ground-glass hepatocytes are associated with chronic HBV infection but are only present in the setting of active viral replication. Similar-appearing cytoplasmic inclusions (“pseudo-ground-glass change”) have been described in other conditions, such as cyanamide toxicity, type IV glycogen storage disease (GSD). Lafora disease, uremia, transplant recipients, patients taking numerous medications, and immunosuppressed patients. Extensive plasma cell inflammatory infiltrates and more extensive interface activity with concurrent lobular necroinflammatory activity favor AIH.

Like chronic viral hepatitis, the early stages of PBC and PSC show portal-based inflammation and fibrosis. Elevated serum ALP, positive antimitochondrial antibodies (AMAs) (in PBC), or endoscopic retrograde cholangiopancreatography (ERCP) (in the case of PSC) help distinguish these entities from chronic viral hepatitis.

Wilson’s disease usually affects young individuals and can be clinically excluded by the serum ceruloplasmin level, 24-hour urine copper levels, and quantitative copper on liver tissue analysis. A1AT deficiency is characterized by the accumulation of PAS-positive, diastase-resistant cytoplasmic globules in hepatocytes.

Drug-induced liver injury (discussed later in this chapter) must also be considered; medication history is key to diagnosis. Rarely, lymphoproliferative disorders, in particular low-grade B-cell lymphomas, can mimic chronic hepatitis. Monotonous or expansile lymphoid infiltrates should raise suspicion for lymphoma. Immunohistochemical stains and flow cytometry help differentiate lymphoma from chronic hepatitis.

Clinical Features

Autoimmune hepatitis is an immune-mediated hepatitis characterized by a combination of clinical, laboratory, and histologic findings of hepatitis that predominantly affects young to middle-aged women. It is an a priori chronic form of hepatitis with phases of acute exacerbations. The presenting symptoms are highly variable and include anorexia, jaundice, hepatomegaly, and abdominal pain. However, the diagnosis should be considered in any patient with elevated transaminases of any duration. Between 10% and 20% of patients present with acute liver failure, but presentation with clinical features of an acute or chronic hepatitis is far more common.

Transaminase elevation is a consistent feature of AIH, and nearly all patients exhibit elevated serum immunoglobulin (Ig) G levels at the time of diagnosis. Autoantibodies including anti–smooth muscle antibodies (ASMAs) and antinuclear antibodies (ANAs), can be detected in most patients but are not required for the diagnosis. Anti-LKM1 are most often seen in young female patients (including adolescents and children). These autoantibodies are not specific and can be present in other conditions including alcoholic liver disease, NAFLD, PBC, and PSC, among others. Hepatitis C antibodies can also be falsely positive in patients with AIH and remain positive after effective HCV treatment; for this reason, confirmatory RNA testing is used to confirm or exclude HCV infection. Hyperbilirubinemia and ALP elevations may be seen in patients with severe hepatitis and extensive hepatocyte injury and in the setting of AIH–PBC overlap.

Given the multiple elements (clinical, serologic, and histologic) that contribute to the diagnosis, a detailed scoring system for diagnosing AIH was established by the International Autoimmune Hepatitis Group and later simplified by Hennes et al. ( Table 17.3 ). Rapid response to immunosuppression is typical.

Pathologic Features

Microscopic Findings

Autoimmune hepatitis most commonly presents a chronic hepatitis pattern of injury followed by acute hepatitis and cholestatic hepatitis patterns. The classic histologic findings include a chronic hepatitis with well-developed interface hepatitis and lobular necroinflammatory activity. Most cases reveal dense portal lymphoplasmacytic infiltrates, often with plasma cell aggregates. Prominent plasma cells are a frequent but not required feature. Interface hepatitis is often prominent in untreated AIH ( Fig. 17.15A ). The lobules demonstrate several foci of necroinflammatory activity, including perivenular plasma cell–rich inflammatory cell infiltrates and hepatocyte necrosis. Acidophil bodies may be frequent, and patients experiencing an acute exacerbation may show diffuse hepatocyte swelling with lobular disarray ( Fig. 17.15B ). Kupffer cell hyperplasia can be seen, but well-formed epithelioid granulomas are not a feature of AIH. A panel of pathology experts recently published a set of criteria to aid in the histologic diagnosis of AIH. In this publication (Lohse et al., 2022), portal or lobular lymphoplasmacytic infiltrates along with more than mild interface activity and portal based fibrosis remain importan features in the diagnosis.

Bile duct injury, if present, tends to be patchy, mild, and most commonly associated with lymphocytic injury. Destructive bile duct lesions or “florid duct lesions” are not a feature of AIH and, if present, should raise concern for an AIH–PBC overlap syndrome, DILI, or other forms of liver disease. Portal-based fibrosis is often present at initial presentation.

In a subset of cases, an acute hepatitis or acute-on-chronic hepatitis pattern of injury predominates. In these biopsies, the lobular inflammation and injury predominates, with prominent hepatocellular swelling, lobular disarray, and regenerative changes, including hepatocellular rosettes ( Fig. 17.15C ) and bile ductular proliferation. In severe cases, extensive necroinflammatory activity leads to bridging necrosis and even massive hepatic necrosis with parenchymal collapse ( Fig. 17.15D ). Transformation of hepatocytes into syncytial multinucleated giant cells (acute hepatitis with giant cell transformation) can also be present. Hepatocanalicular cholestasis may be seen in the acute phase of exacerbation and present as an acute cholestatic hepatitis pattern of injury.

Autoimmune Hepatitis—Pathologic Features

Gross Findings

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  Cases of acute fulminant disease may show massive hepatic necrosis

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  In end-stage disease, the liver shows evidence of cirrhosis

Microscopic Findings

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  Chronic hepatitis pattern of injury

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  Usually well-established interface hepatitis and lobular necroinflammatory activity in untreated disease

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  Plasma cells may be prominent in portal tracts and perivenular locations

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  Variable fibrosis, from portal expansion to portal–portal or portal–central bridging and cirrhosis

Genetics

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  Genetic predisposition associated with human leukocyte antigen A1-B8-DR haplotype

Differential Diagnosis

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  Viral hepatitis (especially hepatitis B and C)

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  Primary biliary cholangitis and primary sclerosing cholangitis

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  Drug-induced liver injury

These histologic changes may be significantly reduced or even absent after immunosuppressive therapy.

Differential Diagnosis

The differential diagnosis for AIH includes chronic viral hepatitis, DILI, and early stages of primary biliary disorders, among others. Viral serologies and PCR-based testing are used to exclude chronic viral hepatitis, which often shows less extensive interface hepatitis and lobular necroinflammatory activity than AIH. As opposed to PBC, AIH exhibits only minimal bile duct injury without duct destruction and a hepatitic rather than cholestatic pattern of liver enzyme abnormalities.

Drugs can cause an AIH-like clinical and histologic picture with autoantibodies and hypergammaglobulinemia at any time after initiating the medication. Drugs associated with an AIH-like pattern of injury include nitrofurantoin, minocycline, diclofenac, infliximab, atorvastatin, and other statins and hydralazine, methyldopa, and anti–tumor necrosis factor-α (anti–TNF-α) agents, among others. DILI is a diagnosis of exclusion and requires clinical correlation. The LiverTox website is a helpful database to search for medications known to induce liver injury. Wilson’s disease can rarely present with features of AIH; however, clinical and laboratory findings are helpful in separating these entities.

Clinical Features

Nonalcoholic fatty liver disease refers to steatosis and steatohepatitis occurring in the absence of significant alcohol use and attributed to metabolic factors that are associated with increased risk of cardiovascular disease and death known as the metabolic syndrome: abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, and prothrombotic or proinflammatory states. NAFLD is common in developed countries and has also been recognized as an emerging health problem in the pediatric population. Patients are usually asymptomatic and often incidentally discovered because of mildly elevated transaminase levels. Many patients who were previously diagnosed with “cryptogenic cirrhosis” likely had cirrhosis secondary to end-stage NAFLD.

Pathologic Features

Gross Findings

In severe steatosis, the liver is grossly enlarged, yellow, and greasy ( Fig. 17.16 ).

Microscopic Findings

Nonalcoholic fatty liver disease encompasses a range of histologic findings, including mild steatosis to steatohepatitis (NASH) and even end-stage cirrhosis.

Steatosis is a key feature of NAFLD. A minimum of 5% macrovesicular steatosis (large or small droplets) ( Fig. 17.17A ), often exclusively or predominantly macrovesicular ( Fig. 17.17B ) or mixed, should be present for the diagnosis. Microvesicular steatosis is less common and is characterized by very small fat vacuoles that impart a granular or “fluffy” appearance to the hepatocyte cytoplasm ( Fig. 17.17C ). Microvesicular steatosis may be present as scattered cells or in contiguous patches in NAFLD. Steatosis is classified as none (<5%), mild (5%–33%), moderate (34%–66%), or severe (>66%).

Nonalcoholic steatohepatitis can be distinguished from steatosis by the presence of ballooning hepatocyte degeneration (a key diagnostic feature) and inflammation ( Fig. 17.17D ). Ballooned hepatocytes ( Fig. 17.17E ) stand out from the background hepatocytes because of their large size and pale, irregular wispy or clumpy cytoplasm and disrupted cell membranes. They tend to be most prominent in zone 3, where they are associated with perisinusoidal fibrosis and steatotic hepatocytes. Classic ballooned hepatocytes may contain Mallory-Denk bodies, although this is not a required feature. Mallory-Denk bodies (also termed Mallory bodies or Mallory hyaline ) are abnormally folded intermediate filaments recognized histologically as eosinophilic ropy or globular structures in hepatocyte cytoplasm. Mallory-Denk bodies are not specific to NASH and can be seen in a variety of settings, including alcoholic liver disease, chronic cholestatic conditions, Wilson’s disease, and some tumors.

The inflammation seen in NASH includes a mixture of neutrophils, lymphocytes, plasma cells, and macrophages in the hepatic lobules and/or portal tracts ( Figs. 17.17F and G ). Whereas lobular inflammation is usually more prominent in adults, children may exhibit predominantly or exclusively portal inflammation (see later discussion). Lobular neutrophils are often present but are not required for the diagnosis of steatohepatitis. Portal inflammation is inconspicuous in most cases and is usually composed of mature lymphocytes and rare plasma cells. Greater portal inflammation occurring in the absence of chronic hepatitis (e.g., hepatitis C) has been linked to faster progression of disease, especially in pediatric patients, and with more severe disease in adults. If portal inflammation exceeds the extent of lobular inflammation, the possibility of coexisting chronic hepatitis or other liver disease should be considered, particularly when interface activity is seen. Megamitochondria, patchy glycogenosis, glycogenated nuclei, and lipogranulomas may also be seen in patients with steatohepatitis, although these features are not required for diagnosis.

Fibrosis in adult patients with NASH begins in the centrilobular region ( Fig. 17.17H ). In the early stages, delicate pericellular fibrosis is best highlighted by the trichrome stain. With progressive disease, portal and periportal fibrosis develops, and fibrous septa form between portal tracts and central veins or between portal tracts with subsequent evolution to cirrhosis. “Burned-out” steatohepatitis presenting in the cirrhotic stage ( Fig. 17.17I ) often shows only focal residual features of steatohepatitis and may be difficult to recognize histologically. Many cases of “cryptogenic cirrhosis” likely represent end-stage NAFLD.

Pediatric Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease is the leading cause of liver disease in children. Some children show a similar histologic picture as seen in adults (type 1 pediatric NAFLD), whereas others have a distinct pattern of injury termed type 2 pediatric NAFLD and characterized by zone 1–predominant steatosis, portal inflammation, and portal or periportal scarring. Some children may show a combination of these patterns. The minimal diagnostic criteria for recognizing children at greatest risk of progressive disease are unclear, and some pathologists have used the term borderline, zone 1, steatohepatitis to indicate potentially progressive disease in biopsies exhibiting zone 1–predominant or panacinar steatosis, portal inflammation (usually mild) ( Fig. 17.18A ), and portal fibrosis ( Fig. 17.18B ) but little or no ballooning or Mallory bodies.

In 2005, the semiquantitative “NAFLD Activity Score” (NAS; Table 17.5 ) was published by the NASH Clinical Research Network (CRN). This score was intended for use in research trials to standardize reporting and assess changes in component features that might be seen in serial biopsies. The NAS represents the unweighted sum of steatosis, lobular inflammation, and hepatocyte ballooning scores. As in chronic hepatitis, grade is reported separately from stage (extent of fibrosis).

Differential Diagnosis

Because of the histologic similarities, NAFLD cannot be reliably distinguished from alcoholic liver disease on the basis of biopsy findings alone; this distinction is made clinically. That said, there are some differences between these entities. For example, steatosis is an important feature of NASH but is not always seen in alcoholic liver disease. Furthermore, canalicular cholestasis, bile ductular proliferation, veno-occlusive lesions, sclerosing hyaline necrosis, and alcoholic foamy degeneration (pure microvesicular steatosis) are features of alcoholic liver disease and are not commonly seen in NAFLD.

Drug reaction should also be considered in the differential diagnosis. Many medications, including estrogens, tamoxifen, and glucocorticoids, can cause steatosis, and amiodarone toxicity, for example, can cause a pattern of injury similar to ASH with frequent Mallory bodies.

Autoimmune hepatitis is sometimes considered in the clinical differential diagnosis of NAFLD, and nonspecific elevation of autoantibodies (ANA, SMA, AMA) can be identified in up to 20% of individuals with NAFLD. When autoantibodies are detected in the presence of prominent portal inflammation, a careful search for diagnostic features of coexisting chronic liver diseases such as AIH or PBC is warranted. Chronic HBV or HCV can coexist with NAFLD and should also be excluded clinically.

Clinical Features

Excess alcohol consumption is a leading cause of liver failure in the United States and worldwide. Significant alcohol use has been variably defined for research purposes. The National Institutes of Health–funded NASH CRN defined a limit of 20 g/day for men and 10 g/day for women for inclusion in their studies on NAFLD. Risk for severe hepatic injury correlates with daily intake, with 80 g/day of alcohol being a risk factor for severe hepatic injury. However, only 10% to 15% of people with alcoholism develop cirrhosis.

Like NAFLD, alcoholic liver disease can present as steatosis, alcoholic hepatitis, or cirrhosis. Hepatic steatosis presents with hepatomegaly and mild elevation of serum liver test results (in particular AST > ALT in a >2:1 ratio). Steatosis resolves with cessation of alcohol intake. Acute alcoholic hepatitis (acute alcoholic intoxication) may be life threatening. Patients often present with malaise, anorexia, weight loss, jaundice, and altered sensorium. In this setting, hyperbilirubinemia may be seen in addition to more pronounced elevation of transaminases. The clinical presentation of alcoholic cirrhosis is similar to other forms of cirrhosis.

Pathologic Features

Gross Findings

The liver in patients with steatosis and alcoholic hepatitis is often enlarged, yellow, soft, and greasy. In alcoholic cirrhosis, the liver is enlarged initially, with a finely granular capsular surface and firm texture ( Fig. 17.19 ).

Microscopic Findings

Alcoholic steatosis is commonly macrovesicular and zone 3 in distribution. With abstinence, steatosis may rapidly disappear, but residual foci lobular inflammation and lipogranulomas may be observed.

The diagnosis of alcoholic hepatitis (also known as alcoholic steatohepatitis has overlapping histologic features with NASH: steatosis with lobular inflammation and liver cell injury (ballooned hepatocytes and acidophil bodies), often with Mallory-Denk bodies ( Fig. 17.20A ). The degree of steatosis is variable. The lobular inflammation may be neutrophil rich with neutrophils in clusters around ballooned hepatocytes containing Mallory-Denk bodies (“satellitosis”) ( Fig. 17.20B ). In cases with pronounced hepatocellular injury, there is evidence of hepatocellular dropout, readily highlighted by the reticulin stain. Most cases show only mild or complete absence of mononuclear cell inflammatory infiltrate within the portal tracts.

Zone 3 pericellular and perisinusoidal fibrosis is a characteristic feature of alcoholic hepatitis. Collagen surrounds individual hepatocytes in a “chicken wire” pattern ( Fig. 17.20C ). As fibrosis progresses, central–central and central–portal fibrous bridges form, eventually resulting in micronodular cirrhosis. Scoring systems specifically designed for alcoholic liver disease (e.g., the system by Altamirano et al., 2014) are not widely used in clinical practice.

Although similarity between ASH and NASH exists, some patterns of injury described in alcoholic liver disease do not occur in NASH: (1) cholestatic steatohepatitis ( Figs. 17.20D ), (2) alcoholic foamy degeneration, and (3) sclerosing hyaline necrosis. Patients with cholestatic disease are often jaundiced with elevated ALP and gamma-glutamyl transferase (GGT). Biopsy shows prominent canalicular and hepatocellular cholestasis with or without bile ductular proliferation, mimicking bile duct obstruction. Alcoholic foamy degeneration is characterized by marked centrilobular microvesicular steatosis, often with prominent megamitochondria and cholestasis. Macrovesicular steatosis and neutrophilic inflammation is usually absent. Sclerosing hyaline necrosis is characterized by marked centrilobular hepatocellular necrosis and dropout. These patients later develop confluent fibrosis that obliterates the central veins (veno-occlusive lesions).

Alcoholic Liver Disease—Pathologic Features

Gross Findings

• ■

  Steatosis: liver is enlarged, yellow, and greasy because of lipid accumulation

• ■

  Alcoholic hepatitis: liver may be enlarged; yellow discoloration and firm consistency with progressive fibrosis

Microscopic Findings

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  Steatosis: macrovesicular steatosis, predominantly centrilobular but can be panlobular

• ■

  Alcoholic steatohepatitis: hepatocyte ballooning degeneration, Mallory-Denk bodies, variable steatosis, neutrophilic inflammation, zone 3 pericellular and perisinusoidal fibrosis, progressing to central–portal bridging fibrosis

• ■

  Alcoholic cirrhosis: delicate central–portal fibrous septa in early stages form micronodules, later mixed macronodular and micronodular cirrhosis pattern

Differential Diagnosis

• ■

  Nonalcoholic fatty liver disease

• ■

  Drug-induced liver injury

• ■

  Chronic cholestatic conditions

• ■

  Wilson’s disease

Differential Diagnosis

Nonalcoholic fatty liver disease is the major differential diagnosis for alcoholic liver disease, and frequently NASH and ASH cannot be differentiated based on histologic features alone. In general, neutrophilic-rich infiltrates, prominent Mallory’s hyaline, cholestasis, and conspicuous pericellular sinusoidal fibrosis should favor the diagnosis of alcohol-induced injury over NASH.

Drug-induced liver injury is an important consideration if a history of alcohol use cannot be established. Amiodarone toxicity causes phospholipidosis and prominent Mallory-Denk bodies, which can mimic alcoholic hepatitis.

Cholestatic ASH, large duct obstruction, and other chronic cholestatic conditions can show overlapping histologic features; however, the clinical history of alcohol use and clinical exclusion of large duct obstruction should be helpful in sorting this differential. In young patients, Wilson’s disease should be also considered as a potential cause and should be distinguished using clinical and ancillary laboratory tests.

Prognosis and Therapy

The long-term prognosis depends on the severity of liver injury and alcohol abstinence. Alcoholic steatosis tends to resolve within 1 to 3 months of stopping alcohol consumption. On the other hand, alcoholic hepatitis can progress to cirrhosis. Sclerosing hyaline necrosis carries a poor prognosis and often leads to portal hypertension and ascites. Treatment includes alcohol cessation and nutritional interventions and, for patients with more severe disease, prednisolone or pentoxifylline. Liver transplantation is an option for patients who achieve abstinence.

Cholestatic Pattern of Injury

A cholestatic pattern of injury can be seen in disease processes that affect parts of the biliary tree. The clinical presentation depends on the underlying disease, but in general, patients present with pruritus and fatigue, and laboratory testing reveals elevation of ALPH, bilirubin, and GGT. Clinically, cholestasis is associated with certain signs and symptoms that correspond, at least in part, to elevated serum levels of bilirubin, bile acids, and cholesterol. However, pathologically, it is defined by morphologic consequences of biliary retention and injury to the biliary tree. It is important to note that cholestasis by itself is quite nonspecific and does not necessarily indicate a primary cholestatic disorder. It can be seen in many other conditions, including drug injury, viral hepatitis, Wilson’s disease, and alcoholic liver disease.

Cholestasis may be classified by time frame (acute vs chronic cholestasis) or by the pattern and location of cholestasis: bland cholestasis, canalicular cholestasis, ductular cholestasis, ductal cholestasis, or ductular reaction or proliferation.

Acute Versus Chronic Cholestasis

Acute cholestasis often results from acute biliary obstruction but can also occur in sepsis and DILI. Histologic features of acute biliary obstruction include portal stromal edema, bile ductular proliferation with accompanying neutrophils. The lobules show canalicular cholestasis and bile plugs. Portal edema is a more specific histologic feature; however, it is uncommon and lacks sensitivity. Occasionally, bile infarcts and bile lakes are identified, and their presence indicates large bile duct obstruction.

Chronic cholestatic conditions such as chronic biliary obstruction, PBC, PSC, drugs or toxins, total parenteral nutrition (TPN) toxicity, sarcoidosis, graft-versus-host disease, bile transporter mutations, IgG4 cholangitis, and ischemic cholangitis, among others, show histologic features of chronic cholestasis. A key feature is periportal “cholate stasis” caused by accumulation of bile salts in hepatocytes, imparting a rarefied, feathery appearance to the cytoplasm of periportal hepatocytes. Intracytoplasmic copper accumulation within periportal hepatocytes can be highlighted by rhodanine and orcein stains, and periportal Mallory-Denk bodies are often seen. Other features include feathery degeneration of hepatocytes, hepatocyte rosette formation, and ductular proliferation. Over time, scarring progresses to a biliary-type cirrhosis, which exhibits a characteristic low-power appearance of irregular, serpiginous, or “jigsaw-shaped” nodules and periportal cholate stasis.

Patterns and Manifestations of Cholestasis

Bland cholestasis is defined by the presence of lobular canalicular and hepatocellular cholestasis in the absence of inflammation and hepatocyte injury. Bland cholestasis is typically related to DILI ( Fig. 17.21A ). Medications associated with bland cholestasis include androgenic steroids, estrogen, azathioprine, and others. Less frequently, bland cholestasis occurs in benign recurring intrahepatic cholestasis, thyroid disorders, or intrahepatic cholestasis of pregnancy and as a paraneoplastic syndrome.

Canalicular cholestasis refers to bile within the bile canaliculi, which are not visible on routine H&E in the normal liver. Hepatocellular cholestasis indicates bile accumulation within hepatocyte cytoplasm. Hepatocellular and canalicular cholestasis often coexist ( hepatocanalicular cholestasis ) (see Fig. 17.19B ).

Ductal cholestasis is uncommon and indicates the presence of bile within the lumen of a native interlobular bile duct. Ductular cholestasis indicates the presence of bile plugs within the lumens of proliferating bile ductules (see later). Also termed cholangitis lenta ( Fig. 17.21C ), this finding can be seen in patients with sepsis. Ductular reaction or proliferation is a nonspecific finding that can be seen in a broad array of settings, including biliary obstruction, as a regenerative phenomenon in the setting of hepatocyte injury, with drug-induced injury, sepsis, parenteral nutrition, advanced hepatic fibrosis, and others.

Clinical Features

The clinical diagnosis of large duct obstruction is based on imaging studies. Mechanical blockage of extrahepatic (large) intrahepatic ducts in the setting of biliary lithiasis is usually manifested by colicky right upper quadrant abdominal pain and elevated ALP, GGT, and serum bilirubin levels. In cases of malignant obstruction, patients often present with painless jaundice. Fever is only present when there is superimposed ascending bacterial cholangitis.

Radiologic Features

Imaging studies remain the gold standard for diagnosing of large duct obstruction. Ultrasonography may show dilated intrahepatic and extrahepatic bile ducts above the level of obstruction as well as biliary stones. Endoscopic ultrasonography or ERCP is more helpful in the setting of malignant obstruction because this procedure provides information on the exact site of obstruction and allows clinicians to obtain biopsy samples to place stents or dilate strictures. Compared with ERCP, magnetic resonance cholangiopancreatography (MRCP) is noninvasive; superior in visualizing the bile ducts proximal to a site of obstruction; and provides additional information regarding hepatic parenchyma, vascular structures, and lymph nodes.

Pathologic Features

Microscopic Findings

Liver biopsy does not play a major role in the work-up and diagnosis of large duct obstruction because the histologic features are largely nonspecific, and the diagnosis of large duct obstruction is generally based on imaging studies. Portal tract abnormalities appear as early as 4 to 5 days after obstruction and include mixed portal inflammation, bile duct proliferation, and portal stromal edema ( Fig. 17.22A ). The portal inflammation consists of numerous neutrophils (secondary to bile ductular proliferation) and scattered lymphocytes and plasma cells ( Fig. 17.22B ). Canalicular cholestasis and bile plugs may be present. When present, bile infarcts and bile lakes are very specific for large duct obstruction ( Figs. 17.22C and D ). Some patients may develop superimposed ascending cholangitis with numerous intraluminal neutrophils within bile ducts, portal edema, and bile ductular proliferation.

With prolonged biliary obstruction, periportal hepatocytes show cholate stasis, copper accumulation, and Mallory hyaline inclusions. Mild periductal fibrosis may occur but bile duct loss is unusual in large duct obstruction. Advanced fibrosis with prominent bile ductular proliferation may develop in the setting of chronic biliary obstruction ( Fig. 17.22E ).

Large Duct Obstruction—Pathologic Features

Gross Findings

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  Intrabiliary stones

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  Bile lakes and infarcts

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  Strictures or thickening of the bile duct wall

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  Biliary-type cirrhosis with green discoloration

Microscopic Findings

Early Findings

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  Canalicular and hepatocellular cholestasis

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  Portal tract edema, more pronounced around interlobular bile ducts

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  Variable portal mixed inflammatory infiltrates

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  Bile ductular reaction accompanied by neutrophils

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