This chapter examines two of the most commonly encountered patterns of hepatic pathology. Fatty change (or, in its Greek version, steatosis) designates the excess accumulation of lipids, primarily triglycerides, within hepatocytes. Basically denoting some imbalance in normal fat processing and storage, it occurs in a wide variety of conditions, both hepatic and extrahepatic, and, by itself, provides little etiologic or diagnostic leverage.

A distinctive pattern of hepatocellular injury and inflammation occasionally develops within a background of fatty change. The prototypic example of this pattern, well known by all pathologists, is caused by chronic ethanol abuse and is referred to as alcoholic hepatitis. However, the same histologic pattern is seen in the absence of alcohol abuse, and the need thus arises for a more general designation that does not presuppose etiology. Several terms, including steatohepatitis, fatty liver hepatitis, and steatonecrosis, have been advanced, but none is entirely satisfactory: They all emphasize fatty change, which is an inconsistent and often minor feature of pattern. The term steatohepatitis has nonetheless gained common currency and will be used here. Based on the clinical history, steatohepatitis can thus be separated into alcoholic and nonalcoholic groups.

The diagnosis of fatty change or steatohepatitis is based primarily on pathologic grounds: The clinical and laboratory features lack specificity and, furthermore, correlate poorly with the the extent or severity of the disease. Therefore, even when clinical suspicion is high, liver biopsy is necessary for a reliable assessment.

Fatty change is identified in routine histologic sections by the appearance of empty vacuoles within the hepatocyte cytoplasm. Based on the size of these vacuoles, two basic patterns of steatosis have traditionally been recognized: macrovesicular fatty change and microvesicular fatty change.

These two patterns have broadly different clinical and differential diagnostic implications. Macrovesicular fatty change is the standard variety, found in a wide spectrum of conditions, but, by itself, is generally an innocuous lesion, whereas microvesicular fatty change is affiliated with a narrower group of disorders and carries a more serious connotation.

This distinction, although useful as a descriptive categorization, does not signify any inherent pathogenetic differences between the two groups, but instead relates to the tempo of lipid exchange and processing by the hepatocyte. Fat initially accumulates in the form of small vacuoles, and with time and continued accretion, these progressively coalesce into larger and larger globules.¹ Macrovesicular steatosis therefore implies a stable, equilibrated excess in hepatic triglycerides, while microvesicular fat suggests ongoing, active lipid turnover. Depending on the cause and time course of the fatty change, a combination of droplet sizes may be present.

The pathogenesis of fatty change focuses on the normal physiology of lipid metabolism and storage. Fatty acids derived by hydrolysis from dietary or adipocyte triglycerides are transported to the liver, where they may be oxidized for energy, converted to other substances such as phospholipids, or esterified back into triglycerides. The triglycerides, in turn, may be cached within the hepatocyte or packaged into very low-density lipoproteins and exported into the blood, in this way transferring triglycerides back to adipose tissue reserves. There is thus a net circulation of fatty acids between the liver and adipose tissue, maintaining a balance between the triglyceride reservoirs of each. A disturbance in the commerce or processing of fatty acids can lead to an accumulation of hepatic triglycerides; when this exceeds 5% of liver weight, steatosis can be appreciated histologically.

Fatty change can therefore be produced by several mechanisms, including increased mobilization of lipid from adipose tissue, impaired removal or increased synthesis of fatty acids by the liver, and reduced formation or secretion of lipoproteins. Depending on the particular cause, one or more factors may be responsible. In obesity, for example, the steatosis results primarily from increased lipolysis of peripheral fat reserves, whereas with alcohol ingestion, all the mechanisms have been implicated to some degree.^1,14

This commonplace and readily recognized pattern is distinguished by a preponderance of large droplet steatosis, in which a single, bulky fat vacuole distends the hepatocyte and pushes the nucleus and cytoplasm to the side (Figure 7-1).

The causes are many, with alcohol abuse, obesity, and diabetes mellitus accounting for most cases.¹⁸ Fatty change is a direct consequence of acute ethanol ingestion: It rapidly appears following even moderate exposure and disappears after three or four weeks of abstinence.^6,10,17 This basic pharmacologic response is additionally modified by such factors as nutritional status and gender, although their precise contributions remain controversial. Nevertheless, fatty change is noted in 80% to 90% of liver biopsy specimens from alcoholic patients. Obesity and diabetes are also major etiologic considerations, but, because of their common coexistence, their relative roles are difficult to determine; some 50% to 90% of such patients will demonstrate fatty change on biopsy.^3,19,20

Other causes include persistent nutrition alterations such as may result from kwashiorkor, hyperalimentation, or jejunoileal bypass surgery, and a variety of drugs and toxins including corticosteroids, methotrexate, asparaginase, mithramycin, chlorinated hydrocarbons, and phosphorus. Macrovesicular fat can also be found, usually in minor quantities, in normal individuals and in patients hospitalized with many febrile or systemic diseases. In addition, it may also represent a secondary histologic component in other conditions, including steatohepatitis, various infections including acute and chronic hepatitis C, and several inherited metabolic diseases such Wilson's disease and galactosemia. In some instances, a cause cannot be definitively identified.

The degree of macrovesicular fatty change varies considerably among biopsies. In severe cases, entire lobules may be affected; with lesser involvement, fat may be found in single hepatocytes or small clusters of cells. The distribution may follow lobular zones; the centrilobular area is often favored, but a predilection for periportal hepatocytes is also seen, particularly in settings such as kwashiorkor, total parenteral nutrition, or methotrexate therapy (Figure 7-2).^2,23 There are many exceptions, however, and such differences therefore have no great diagnostic or etiologic implications.

Focal fatty change is noted in occasional instances; the fat-laden hepatocytes are gathered into a circumscribed nodule surrounded by minimal or no steatosis, rather than being allocated uniformly across the liver (Figure 7-3). Noted in up to 3% of autopsies, the resulting yellow nodules range between 0.5 and 4 cm in diameter and are commonly located in the subcapsular region. They may mimic neoplasms on gross examination or radiographic imaging studies.^4,7,24

A variety of secondary histologic changes may accompany macrovesicular steatosis. Occasionally noted are reactive lobular changes of minor degree, including prominent Kupffer cells or a sparse mononuclear cell infiltrate. Glycogenated nuclei can be conspicuous in diabetes-associated cases but are neither a sensitive nor specific etiologic marker. Distended fat-laden hepatocytes may rupture, producing small fat cysts and subsequently prompting a local inflammatory response and lipogranuloma formation (Figure 7-4). Lipogranulomas consist of an extracellular lipid pool encircled by a loose aggregate of macrophages and histiocytes with occasional lymphocytes, eosinophils, plasma cells, or multinucleated giant cells.^5,11 They most often reside in the lobules but may also appear within portal tracts, presumably because of the transfer of parenchymal fat to portal areas.⁸ (Note, however, that lipogranulomas need not be associated with steatosis, as they may also be caused by mineral oil deposits.^9,22) Although most lipogranulomas vanish without sequelae, some may become confluent and fibrotic; whether these small fibrotic foci contribute to chronic liver disease is not clear.

Most patients with fatty livers are asymptomatic, although, in severe cases, complaints of abdominal fullness or tenderness might be present. On physical examination, the liver is often enlarged and smooth. Modest biochemical test abnormalities are common but inconsistent and do not correlate well with the histologic severity.^12,18 Steatosis is nonetheless a common reason for unexplained elevations in serum aminotransferase levels.^13,21

Macrovesicular fatty change is generally a benign and harmless lesion with few functional consequences. However, an enigmatic association between sudden death and severe alcoholic steatosis has been reported.¹⁶ Typically, the fat departs once its cause is removed, and, even if persistent, it does not usually lead to progressive disease unless other abnormalities supervene.^15,18

In this uncommon pattern, many small fat vacuoles are diffusely dispersed throughout the hepatocyte cytoplasm with the nucleus remaining centrally placed (Figure 7-5). This is easily identified when the vacuoles are discrete and sharply defined, but, in some cases, the lipid is so finely partitioned that the hepatocytes appear swollen rather than burdened with fat; then the appearances may be mistaken for ballooning degeneration or glycogen accumulation. In this situation, frozen sections stained for fat with oil red-O or Sudan black stains can assist in confirming the nature of the change.

Microvesicular fatty change is a more ominous finding than its large-droplet counterpart. It occurs in a diverse group of conditions, many of which display severe systemic manifestations and have an appreciable mortality (Table 7-1). Many features of these disorders suggest that widespread metabolic disruption involving mitochondria or intermediary fat metabolism may be central events.⁶⁷

Acute Fatty Liver of Pregnancy.^61,64 This is an uncommon and mysterious complication of late pregnancy associated with severe, and often fatal, liver failure. The prevalence is estimated at one case per about 13,300 deliveries, although many mild cases are probably not recognized.⁵⁹ The onset is usually between 30 and 40 weeks of gestation, with a peak occurrence at 35 weeks. Any pregnancy may be affected, but an increased prevalence is noted with primigravida, twin gestations, and male offspring.

The early manifestations include nausea, vomiting, malaise, and abdominal pain. These symptoms are usually followed within one or two weeks by evidence of liver dysfunction, including jaundice and, in severe instances, acute hepatic failure leading to coagulopathy, ascites, and hepatic encephalopathy with confusion, somnolence, or coma. This classic picture describes the more extreme end of the incompletely-described clinical spectrum of the disorder; at the other end are patients who are asymptomatic and identified only because of biochemical abnormalities.^26,62

Pertinent laboratory findings include elevated levels of serum bilirubin and alkaline phosphatase together with generally modest increases in serum aminotransferases. Hypoglycemia, hyperuricemia, leukocytosis, or thrombocytopenia may be noted, and circulating normoblasts are often found in the peripheral blood.³⁰ Also frequently present is preeclampsia, manifest by proteinuria and hypertension, and some have suggested that acute fatty liver of pregnancy represents the severe form of a spectrum that includes preeclampsia and the so-called HELLP syndrome of hemolysis, elevated liver enzymes, and low platelet count.^52,59,62 The diagnosis may be suggested by ultrasonography or computed tomography.³¹

Death in acute fatty liver of pregnancy is usually precipitated by one of its many complications, including hepatic failure, disseminated intravascular coagulation, bleeding, pancreatitis, and renal failure. Rupture of the liver has also been reported, although it is more common in toxemia of pregnancy.⁵³ Treatment consists of rapid termination of the pregnancy and conscientious supportive care. With delivery, hepatic function improves, and, in the successful case, gradual and complete recovery follows. In the past, the high mortality rate of this disorder -- in the range of 75% to 85% for both mother and child -- has been emphasized, but recent series indicate a more favorable prognosis, probably because of the recognition of earlier and milder cases and prompt, aggressive management. Currently, the maternal mortality averages about 15% to 25% and the fetal mortality 35% to 40%.^26,30,59 Surviving mothers are at low risk of recurrence with subsequent pregnancies.

The histologic hallmark is microvesicular fatty change, which may affect the centrilobular zone alone or spread to the entire lobule (Figure 7-6). Several additional lesions can amend this basic pattern. In some instances, inflammatory infiltration by lymphocytes and plasma cells is conspicuous within the lobules and, to a lesser degree, the portal tracts. The appearances may then be confused with acute hepatitis.^30,63 Parenchymal loss is sometimes substantial, resulting in a small shrunken liver on gross examination; this loss is principally in the form of lytic necrosis and is recognized by finding closely approximately portal tracts and central veins with replacement of hepatocytes by aggregates of activated Kupffer cells.

Canalicular cholestasis is often present, sometimes accompanied by proliferated bile ductules and attendant neutrophils. Extramedullary hematopoiesis may be noted in some instances, and fibrin deposition along the sinusoids -- similar to the lesion of preeclampsia -- has been occasionally demonstrated.^30,62,63 In patients who survive, the fat rapidly remits, disappearing within a few weeks of convalescence, and normal hepatic histology is restored.⁴⁰

The etiology and pathogenesis are not known. Several observations suggest that mitochondrial injury is a prime ingredient of the disorder. Upon ultrastructural examination, for example, the mitochondria are frequently enlarged, irregularly shaped, and inclusion-bearing, and deficiencies of certain mitochondrial urea cycle enzymes have been reported in some cases.^30,63 Such changes, however, do not appear to be specific, and they likely represent secondary phenomenon. The presence of fatty change implies some abnormality in lipid metabolism, but, again, this need not be a primary pathogenetic occurrence. Nonetheless, in one instance, biochemical assays demonstrated high levels of free fatty acids within the affected liver; these are markedly cytotoxic compounds that can disrupt cell membranes and mitochondrial function and may possibly contribute to the hepatocellular injury.⁴¹

Reye's Syndrome.^36,44 This is an acute and potentially life-threatening disorder characterized by fatty change and encephalopathy of varying degree. Described in 1963 by the Australian pathologist R.D.K. Reye, it occurs primarily in infants and children under 17 years, with an average age at onset of about six years, but occasional cases are also reported in adults.⁵¹ The syndrome has a worldwide distribution and is more frequent in rural and suburban areas, but its incidence is noticeably declining; reported cases in the United States have dropped from a peak of 555 cases in 1980 to 25 cases in 1989.^32,33 Although hepatic dysfunction is a major and defining feature, the course and outcome of Reye's syndrome are dominated by the neurologic manifestations, the consequence of progressive cerebral edema.

The clinical findings typically follow a biphasic pattern: A prodromal febrile illness, usually an upper respiratory infection or varicella, is followed after three to five days by the abrupt onset of vomiting and neurologic alterations. These alterations initially consist of lethargy and irritability, but they may progress through delirium, agitation, obtundation, and seizures to deepening coma and death. Focal neurologic signs are absent, except with brain stem herniation, and the cerebrospinal fluid contains normal levels of glucose and protein and only sparse leucocytes. The degree of encephalopathy is an important prognostic indicator and has been incorporated into various clinical staging classifications.³⁹ About three-fourths of the patients suffer only mild disease and do not develop further deterioration.^45,50

Other than mild hepatomegaly, clinical evidence of hepatic disease is often missing, and jaundice and splenomegaly are rare. Abnormal laboratory tests are the chief manifestation of liver dysfunction: Serum aminotransferase levels are elevated, usually between three and 30 times normal, the serum ammonia is variably increased, and the prothrombin time may be modestly prolonged. The serum bilirubin is generally normal. Hypoglycemia is occasionally identified, particularly in infants, and increased quantities of amino acids, free fatty acids, or uric acid can be identified in the serum. A metabolic acidosis and respiratory alkalosis may complicate the clinical picture.

A presumptive diagnosis of Reye's syndrome can be rendered on clinical and laboratory criteria alone, although a similar picture can be produced by several inborn errors of ureagenesis or fatty acid metabolism.^43,65 Liver biopsy can serve a confirmatory role, but whether it is essential for the diagnosis continues to be debated.⁴²

The treatment consists of general supportive measures directed at controlling increased intracranial pressure and correcting any metabolic abnormalities. The overall mortality rate approximates 30%, with death usually consequent to cerebral edema and its complications. Children who survive the acute illness generally recover uneventfully with a gradual improvement in their neurologic function after two or three days. A small percentage, however, experience long-term neurologic sequelae resulting from cerebral hypoxia; the risk relates to the depth and duration of coma. Diagnosis and treatment before irreversible brain damage develops is accordingly important in reducing morbidity and mortality.

The fundamental histologic finding is diffuse, panlobular microvesicular fatty change unadorned by other lesions.²⁸ The steatosis is most evident during the first three or four days of the illness, but, in early biopsies, its small-droplet nature may not be apparent (Figure 7-7). In this circumstance, appropriately stained frozen sections may be of diagnostic assistance, but these need to be correlated with clinical data since stainable microvesicular fat may be found at autopsy in other settings including acute trauma, for example.²⁷

Inflammation and hepatocyte injury are typically absent or minimal. Occasionally, a mild portal infiltrate of neutrophils and lymphocytes may be seen, and, in some cases, swelling or even necrosis of periportal liver cells may supervene.^25,29 Markedly depletion of glycogen is a regular finding, and cholestasis is uncommon.

By electron microscopy, the mitochondria reveal striking and distinctive changes. They are variably enlarged, swollen, and pleomorphic, sometimes with bizarre or ameboid forms, and display lucent flocculent matrix, disrupted and fragmented cristae, and loss of matrical dense bodies; in advanced disease, mitochondrial numbers are reduced. These changes tend to become more extensive and prominent with increasing disease severity.^34,27,56,58

Although much remains to be learned about the pathogenesis of this disorder, the probable primary target is the mitochondria. Mitochondrial injury is a fundamental feature, evident morphologically and demonstrated biochemically by reduced activities of mitochondrial enzymes involved in urea formation, the citric acid cycle, and glucogeneogenesis.⁴⁴ Current speculations suggest that the underlying process is an alteration in the chemical microenvironment of the mitochondria that depletes local ATP levels and interferes with intramitochondrial enzyme processing.^35,72 In any event, the consequent failure of mitochondrial metabolic processes produces a multitude of derangements in carbohydrate, amino acid, and fatty acid metabolism that lead to hyperammonemia, free fatty acidemia, lactic acidosis, and dicarboyxlic acidemia; these abnormalities may be directly responsible for many manifestations of the disease and could additionally potentiate mitochondrial damage.

The factors that initiate the mitochondrial injury remain obscure. An antecedent viral infection is an almost invariable component of the disorder, but its contribution remains unexplained. Another intriguing but controversial aspect is the role of salicylate exposure. This association was first raised by epidemiologic investigations that demonstrated an association between recent aspirin ingestion and Reye's syndrome; in one well-designed investigation, for example, 96% of patients with Reye's syndrome had received aspirin compared with only 38% of controls.⁴⁶ The widespread publicity about this correlation led to a decreased use of salicylates in treating children with febrile illnesses, and this has coincided with a declining incidence of Reye's syndrome.^32,60 Although aspirin may act as a predisposing factor, a causal connection is not proved and the mechanisms of its contribution are not defined.

Alcoholic Foamy Degeneration.^54,71 This term refers to a syndrome of microvesicular steatosis associated with ethanol abuse. It is an uncommon condition, found in 0.8% to 14% of biopsy specimens from chronic alcoholics. Patients typically present with jaundice and hepatomegaly, often together with anorexia, weight loss, nausea, or vomiting, but some individuals are asymptomatic and discovered because of biochemical abnormalities. Manifestations of decompensated liver disease such as encephalopathy or portal hypertension are usually absent. The laboratory findings include moderately increased serum aminotransferases, alkaline phosphatase, bilirubin, and cholesterol levels. These clinical and biochemical abnormalities rapidly resolve following the discontinuance of alcohol ingestion, although hepatic failure and death are the outcome in singular cases.⁵⁵

Histologically, microvesicular fat, usually most prominent in the centrilobular zone, is accompanied by varying degrees of large-droplet steatosis (Figure 7-8). Canalicular cholestasis and focal hepatocyte necrosis are also commonly found. Other alcohol-related lesions, including those of alcoholic hepatitis may also be present, including megamitochondria, Mallory bodies, neutrophil infiltration, and fibrosis in perivenular, pericellular, or periportal distributions. With resolution, the microvesicular fatty change disappears, although macrovesicular fat can persist.

Other Causes. Several drugs other than ethanol can produce microvesicular fatty change; among those implicated are valproic acid, parenteral tetracycline, and salicylates.^57,68,73 The exotic condition known as Jamaican vomiting sickness is caused by a toxin, hypoglycin A, which is found in unripe akee fruit.⁶⁹

Several inborn errors of metabolism are variably accompanied by a mixture of microvesicular and macrovesicular fat. These include disorders of the urea cycle (particularly ornithine transcarbamylase deficiency and carbamyl phosphate synthetase deficiency) and disturbances in fatty acid oxidation (such as carnitine deficiency and acyl-CoA-dehydrogenase deficiency). Ultrastructural examination may aid in distinguishing these cases from Reye's syndrome since they lack the distinctive mitochondrial alterations of that disorder.^48,70 Multiple small lipids vacuoles are also noted with deficiency of lysosomal acid lipases, characteristic of Wolman's disease and cholesterol ester storage disease, but this alteration affects Kupffer cells and macrophages as well as hepatocytes.³⁸

In addition, a miscellany of intense hepatic insults may be associated with microvesicular fatty change, including acute hepatitis D, fatal exertional heatstroke, and septic diseases such as toxic shock syndrome.^47,49,66

Alcoholic hepatitis signifies the hepatocyte injury and inflammation that arises as a complication of chronic alcohol ingestion. The term was first applied to a clinical syndrome, but, because many affected patients do not demonstrate the classic clinical picture, it is better employed in a histologic sense to specify cases of alcohol-related steatohepatitis. By this defintion, alcoholic hepatitis encompasses a wide spectrum of clinical and pathologic disease, ranging from a mild or inapparent condition to a severe, progressive, and potentially life-threatening disorder with cirrhosis as the end-stage consequence.

Given the overall prevalence of alcoholism in modern societies, alcoholic hepatitis constitutes a major health problem and an important cause of morbidity and mortality. Its precise incidence is difficult to define because the diagnosis requires histologic confirmation, but it is discovered in some 20% to 40% of chronic alcoholics who undergo liver biopsy, having progressed to cirrhosis in over half these cases.^6,85,122

The pathogenesis of alcoholic hepatitis remains a controversial and contentious subject despite extensive inquiry and a correspondingly immense literature.^14,112,145 Alcohol-induced hepatotoxicity must nevertheless be assigned a major pathogenetic role, as suggested by several lines of evidence. Epidemiologic studies, for example, show a correlation between the amount and duration of alcohol consumption and the development of alcoholic hepatitis and cirrhosis: Most affected patients have ingested at least 60 to 80 grams of ethanol daily over a period of five to ten years, and increased ingestion is associated with a greater risk of disease.^120,155

In addition, numerous biochemical, cell culture and animal model studies demonstrate that ethanol and its metabolites can directly cause liver injury.^14,123 The cellular basis of this injury is not clearly established, although a multitude of possibilities have been advanced. A prime culprit is acetaldehyde, the major product of ethanol oxidation, which is an extremely reactive compound capable of binding covalently to proteins and other macromolecules. A wide range of consequences may then ensue, including inhibition of enzyme activities, interference with tubulin polymerization and intracellular protein traffic, disruption of the mitochondrial electron transport chain, and formation of free radicals with subsequent lipid peroxidation.^123,176

Ethanol metabolism can provoke several other potentially injurious effects in hepatocytes: The intracellular redox state is altered; the cellular oxygen consumption increases, potentially resulting in hypoxia; the composition and fluidity of cell membranes are affected; and a specific form of microsomal cytochrome P-450 is activated, which may, in turn, generate free radicals or enhance the hepatotoxicity of other agents.^91,123,176 In addition, immunologic mechanisms of various types have been incriminated in the production or perpetuation of liver injury, and cytokines such as tumor necrosis factor and interleukin-1 have been proferred as mediators of hepatic and extrahepatic tissue damage.^119,166,183 Any of these changes may be further exacerbated by ethanol's capability for depressing hepatocellular regeneration and stimulating collagen synthesis by Ito cells.¹²⁸ Which of these myriad actions, if any, are the prime injurious agents and which are simply secondary effects remain uncertain.

The hepatotoxicity of ethanol cannot be the complete pathogenetic story, however. Only a minority of individuals who chronically abuse alcohol -- even at high doses -- ever develop alcoholic hepatitis. Furthermore, prospective epidemiologic studies suggest that the disease is not simply a function of cumulative ethanol exposure, implying that ethanol exerts a permissive rather than dose-related effect.^156,157 Additional pathogenetic factors must therefore act in concert with ethanol hepatoxicity, although their precise nature and contribution are not defined.

Differences in host susceptibility have been examined, including such variables as genetic background, metabolic handling of ethanol, comcomitant infection with hepatitis viruses, and concurrent exposure to therapeutic drugs or other chemical agents. The most significant of such factors, however, is female sex: Women are clearly more susceptible to alcoholic hepatitis than are men, although the reason is obscure.¹¹⁴

Major attention has also focused on the pathogenetic contribution of nutritional factors. This is the subject of long-standing debate, and the opposing arguments span the extremes; nutritional impairment has been held both primarily responsible for and completely irrelevant to the development of alcoholic hepatitis. The dispute cannot be completely adjudicated, but both clinical and experimental investigations suggest that dietary manipulations can modify the development and progression of alcohol-induced liver disease.^89,132,167 The pathogenesis of alcoholic hepatitis is therefore best described as multifactorial, the combination of various acquired and genetic factors conspiring with excess alcohol ingestion, although certainly many questions remain unanswered.

Clinical Features^127,130

Alcoholic hepatitis may first present at any stage in its evolution, and it therefore exhibits a broad and varied clinical spectrum. Common manifestations include such nonspecific complaints of anorexia, nausea, vomiting, fatigue, and abdominal tenderness, sometimes accompanied by hepatomegaly, jaundice, or fever. However, some patients are asymptomatic and show little clinical indication of liver disease, whereas those at the opposite extreme can present with evidence of hepatic dysfunction including encephalopathy, ascites, or coagulopathy.^82,108,125 Portal hypertension manifest by splenomegaly or esophageal varices is variably noted, particularly when cirrhosis has supervened, but it also may appear in noncirrhotic cases, presumably because of sinusoidal fibrosis or compression by enlarged hepatocytes.^79,105 Other clinical features reflect, in part, the extrahepatic effects of alcohol abuse and chronic liver disease: palmar erythema, spider angiomas, testicular atrophy, myopathies, and parotid gland enlargement.

The laboratory abnormalities commonly include moderate elevations of serum aminotransferase levels. Specifically, the aspartate aminotransferase is generally increased three- to eight-fold -- unlike the more marked increase seen, for example, in acute hepatitis -- but the alanine aminotransferase is only modestly increased and may be normal. The ratio of the two aminotransferase levels therefore often exceeds two; this is a helpful, but not infallible, clue to alcoholic hepatitis.^87,177 The serum bilirubin and alkaline phosphatase vary widely, and hypoalbumenia, hyperglobulinemia, or prolonged prothrombin times are noted in advanced disease. In some patients, alkaline phosphatase levels are sufficiently increased to cause confusion with biliary obstruction.¹⁴⁷ The peripheral blood often shows leukocytosis and, because of concurrent folate deficiency, macrocytosis. Unfortunately, neither the clinical nor the laboratory findings correlate well with the histologic abnormalities.

The course of the disease is extremely variable, and overall five-years survival rates accordingly ranging between 50% and 80% in different series.^75,152 Many patients suffer rapid deterioration and death within months after presentation, particularly when decompensated hepatic function is present, as manifest, for example, by pronounced serum bilirubin elevation, prolonged prothrombin time, encephalopathy, or ascites.¹⁴⁴ Further limiting the long-term prognosis is the development of cirrhosis with its attendant complications. In prospective studies, this progression occurs in roughly 5% to 10% of cases per year, depending, in part, on subsequent alcohol consumption.^129,146,157 Continued drinking generally results in persistent and often progressive disease, whereas abstinence is often -- but not invariably -- followed by improvement. In addition, women are especially at risk for cirrhosis, even with cessation of drinking. Once cirrhosis has evolved, death typically results from bleeding esophageal varices, hepatic coma, infections or other intercurrent diseases. Hepatocellular carcinoma is a well-established hazard of alcoholic cirrhosis, but whether ethanol plays a greater role in carcinogenesis than simply causing cirrhosis is subject to debate.^124,135

The management of alcoholic hepatitis consists primarily of encouraging abstinence together with nutrtional replenishment and supportive care. A variety of medical therapies have been tried, including corticosteroids, propylthiouracil, colchicine, anabolic steroids, and insulin-glucagon infusions, but their efficacy is debated and none is of generally proven benefit. Liver transplantation remains the treatment of last resort for end-stage alcoholic hepatitis. Although the results are generally favorable, this is a controversial subject surrounded by medical, moral, social, and economic issues.¹⁵⁴

Pathologic Features^{77,90,112,126}

Histologically, alcoholic hepatitis is distinguished by a combination of hepatocyte injury and necrosis, inflammation, and fibrosis, usually in a setting of fatty change. These basic changes vary greatly in their severity, extent, and relative proportion from case to case. The early changes principally involve the centrilobular regions (Figure 7-9), but as the disease progresses, the process extends across the lobule, eventually destroying the normal hepatic architecture, with cirrhosis as the ultimate outcome.¹⁰⁰ The morphologic picture of alcoholic hepatitis therefore covers a wide spectrum, extending from minor involvement of the centrilobular areas at one end to advanced cirrhosis at the other.

The hepatocyte injury of alcoholic hepatitis is characterized primarily by ballooning degeneration; focal hepatocyte necrosis and acidophilic bodies are also noted, but usually in sparse numbers. The ballooned cells are enlarged, swollen, and pale with finely granular or reticulated cytoplasm and large distinct nucleoli (Figure 7-10).

The most arresting feature of these cells, however, is the distinctive intracytoplasmic inclusions known as alcoholic hyaline or Mallory bodies (Figure 7-11). These are discrete masses of dense eosinophilic material, often perinuclear in location, that range from short, irregular clumps to the classic elongated, serpiginous structures. They are negative with PAS, but range from gray to blue with Masson's trichrome and appear blue in Luxol fast blue, chromotrope-analine blue, or toluidine blue preparations, although special stains are not usually necessary for their identification.¹⁴⁸ Ultrastructurally, they are composed of filaments of 5 to 20 nm thickness, usually haphazardly clustered but also in parallel arrays, together with obscuring granular or amorphous electron-dense material in some instances.¹⁸⁰

Although a hallmark of alcoholic hepatitis, Mallory bodies are neither an invariable nor specific feature. They are noted in 40% to over 80% of cases in various series, tending to be more prevalent in cases of greater severity.^80,82,85,98 On the other hand, they have been identified in an ever-growing list of other conditions, including nonalcoholic steatohepatitis, chronic cholestatic conditions such as primary biliary cirrhosis and primary sclerosing cholangitis, Wilson's disease, various benign and malignant hepatocellular neoplasms, and a miscellany of disorders including Indian childhood cirrhosis and abetalipoproteinemia.^97,99

Since their first description in 1911, Mallory bodies have been a subject of great fascination and study.^96,97,178 They are now known to consist largely of aggregated cytokeratins, the intermediate filament component of the hepatocyte cytoskeleton. The cytokeratins found in Mallory bodies differ from their normal counterparts in several ways: alterations in conformational and antigenic structure, modifications in phenotypic subtype, including the appearance of bile duct cytokeratins, and conjugation with ubiquitin, one of the so-called heat shock proteins important in the cellular response to stress.^{107,118,141,173} Although the precise mechanism of Mallory body formation is not clearly understood, these aberrations imply a disruption in the normal assembly, organization, or distribution of intermediate filaments within liver cells. Several pathogenetic hypotheses, none of them completely satisfactory, have been advanced to explain this disruption: inadequate microtubule function, a deficiency of hepatic vitamin A, and the unveiling of a preneoplastic state.^96,178

The practical implication is that Mallory bodies can be demonstrated immunohistochemically using antibodies directed against cytokeratins and other Mallory body-related antigens (Figure 7-12).^78,149,182 This provides a more sensitive means of detection than standard histology, although it is not routinely required. In addition, minimally injured hepatocytes that aberrantly express cytokeratins can be identified with these methods; these cells are considered to be precursors of the cells harboring overt Mallory bodies.

Neutrophils are the principal inflammatory cell of alcoholic hepatitis. They gather around the injured hepatocytes and within adjacent sinusoids; in conspicuous instances, they encircle Mallory body-bearing hepatocytes in an phenomenon colorfully termed satellitosis and may even migrate into these cells and aid in their destruction (Figure 7-13).^164,168 Mononuclear cells, including lymphocytes and macrophages, are present in varying numbers and sometimes predominate, particularly with resolving or less active disease (Figure 7-14).^80,98 In mild cases, the inflammatory infiltrate may be sparse or absent, but other associated findings permit a diagnosis of alcoholic hepatitis.

Fatty change is almost universally present, customarily in a macrovesicular form, but, depending on the timing of the biopsy, it may be negligible or absent.

Fibrosis is a regular feature of alcoholic hepatitis, occurring in almost all cases but varying in degree from minimal to extensive. The earliest alterations develop primarily in the centrilobular regions and comprise two basic histologic patterns, pericellular fibrosis and perivenular fibrosis.

Pericellular fibrosis extends along the sinusoids and surrounds swollen hepatocytes, either individually or in small groups, to produce a "chicken-wire" network of collagenous fibers (Figure 7-15). This appearance is best appreciated with trichrome stains, which highlight even minor foci of involvement. Ultrastructural and immunohistochemical studies show that the collagen accumulates within the space of Disse, together with other basal lamina components such as fibronectin and laminin.^106,109 The cells responsible for this deposition are apparently fibroblasts derived from transformed perisinusoidal lipocytes (Ito cells).^110,133,142 The obliteration of the space of Disse, sometimes referred to as capillarization of the sinusoids, has certain functional consequences; it interferes with the metabolic interchange between hepatocytes and blood and, by increasing sinusoidal resistance, may also contribute to portal hypertension.¹⁴⁵

Fibrosis additionally develops in and around the walls of central veins. Initially this so-called perivenular fibrosis (or phlebosclerosis) exaggerates the connective tissue cuff that surrounds the vein (Figure 7-16), and, although mild mural thickening is occasionally seen in normal livers, the lesions in alcoholic hepatitis tend to be more marked and diffuse. By quantitative criteria, the venular walls should exceed 3 μm to 4 μm in thickness, as compared with the normal value of about 2 μm.^84,137,138 As the disease advances, the width and extent of the perivenular scarring increases, and the venular lumens are progressively compressed and eventually obliterated (Figure 7-17).⁹² Consequently, with routine stains, the central veins may not be readily discerned within the fibrotic zone, although their remnants can be detected with elastic tissue or other connective tissue stains. In addition, the veins may occasionally demonstrate a lymphocytic phlebitis or may develop intimal proliferation and fibrosis that resembles the lesions of veno-occlusive disease.^83,105

Megamitochondria are distinctive intracytoplasmic adornments found with varying frequency in all types of alcoholic liver disease. They appear under light microscopy as discrete eosinophilic bodies, 3 μm to 10 μm in diameter, with rounded or, less often, needle-like shapes (Figure 7-21). Visible as pink to red masses with hematoxylin-and-eosin staining, they are bright red on trichrome stains and are negative with PAS stains. They most often reside in centrilobular hepatocytes, but may be found anywhere in the lobule.^81,116,169 Megamitochondria are identified in alcoholic liver disease with a prevalence that ranges in different series anywhere from 25% to 93%.^158,181 They have also been identified, however, in a variety of other hepatic conditions (as well as in histologically normal livers) and are therefore not a specific marker of alcohol-associated injury, although they are typically more numerous and have a uniformly rounded appearance in that setting.^116,158 Their clinical significance is not well defined; some studies relate them to heavy alcohol ingestion with the preceding 30 days, while, in other studies, they connote a mild clinical course and favorable long-term survival.^81,86