Alcoholic Liver Disease : Etiology, Pathogenesis and Treatment

Alcoholic Liver Disease
Chronic and excessive alcohol ingestion is one of the major causes of liver disease. The pathology of alcoholic liver disease comprises three major lesions, with the injury rarely existing in a pure form: (1) fatty liver, (2) alcoholic hepatitis, and (3) cirrhosis. Fatty liver is present in more than 90% of binge and chronic drinkers. A much smaller percentage of heavy drinkers will progress to alcoholic hepatitis, thought to be a precursor to cirrhosis. The prognosis of severe alcoholic liver disease is dismal; the mortality of patients with alcoholic hepatitis concurrent with cirrhosis is nearly 60% at 4 years. Although alcohol is considered a direct hepatotoxin, only between 10 and 20% of alcoholics will develop alcoholic hepatitis. The explanation for this apparent paradox is unclear but involves the complex interaction of facilitating and comorbid factors such as gender, heredity, and immunity.

Etiology and Pathogenesis
Quantity and duration of alcohol intake are the most important risk factors involved in the development of alcoholic liver disease (Table 301-1). The roles of beverage type(s), i.e. wine, beer, or spirits, and pattern of drinking are less clear. Progress of the hepatic injury beyond the fatty liver stage seems to require additional risk factors that remain incompletely defined. Women are more susceptible to alcoholic liver injury when compared to men. They develop advanced liver disease with substantially less alcohol intake. Hispanic men have a much higher age-adjusted death rate in the United States from alcoholic cirrhosis than do non-Hispanic whites and blacks. In general, the time it takes to develop liver disease is directly related to the amount of alcohol consumed. It is useful in estimating alcohol consumption to understand that one beer, four ounces of wine, or one ounce of 80% spirits all contain ~12 g of alcohol. The threshold for developing alcoholic liver disease in men is an intake of more than 60–80 g/d of alcohol for 10 years, while women are at increased risk for developing similar degrees of liver injury by consuming 20–40 g/d. Ingestion of 160 g/d is associated with 25–fold increased risk of developing alcoholic cirrhosis. Gender-dependent differences result from poorly understood effects of estrogen and the metabolism of alcohol. Social, immunologic, and heritable factors have all been postulated to play a part in the development of the pathogenic process.
Table 301-1 Risk Factors for Alcoholic Liver Disease
Risk Factor
In men, 40–80 g/d of ethanol produces fatty liver; 160 g/d for 10–20 years causes hepatitis or cirrhosis. Only 15% of alcoholics develop alcoholic liver disease.
Women exhibit increased susceptibility to alcoholic liver disease at amounts more than 20 g/d; two drinks per day probably safe.
Hepatitis C
HCV infection concurrent with alcoholic liver disease is associated with younger age for severity, more advanced histology, decreased survival.
Gene polymorphisms may include alcohol dehydrogenase, cytochrome P4502E1, and those associated with alcoholism (twin studies).
Alcohol injury does not require malnutrition, but obesity and fatty liver from the effect of carbohydrate on the transcriptional control of lipid synthesis and transport may be factors. Patients should receive vigorous attention to nutritional support.

Chronic infection with hepatitis C (HCV)  is an important comorbidity in the progression of alcoholic liver disease to cirrhosis in chronic and excessive drinkers. Even moderate alcohol intake of 20–50 g/d increases the risk of cirrhosis and hepatocellular cancer in HCV-infected individuals. Patients with both alcoholic liver injury and HCV infection develop decompensated liver disease at a younger age and have poorer overall survival. Increased liver iron stores and, rarely, porphyria cutanea tarda can occur as a consequence of the overlapping injurious processes secondary to alcohol abuse and HCV infection. In addition, alcohol intake of more than 50 g/d by HCV-infected patients decreases the efficacy of interferon-based antiviral therapy.
Our understanding of the pathogenesis of alcoholic liver injury is incomplete. Alcohol is a direct hepatotoxin, but ingestion of alcohol initiates a variety of metabolic responses that influence the final hepatotoxic response. The initial concept of malnutrition as the major pathogenic mechanism has been replaced by the understanding that the hepatic metabolism of alcohol initiates a pathogenic process involving production of toxic protein-aldehyde adducts, endotoxins, oxidative stress, immunologic activity, and pro-inflammatory cytokine release (Fig. 301-1). The complex interaction of intestinal and hepatic cells is crucial to alcohol-mediated liver injury. Tumor necrosis factor  (TNF-) and intestine-derived endotoxemia facilitate hepatocyte apoptosis and necrosis. Stellate cell activation and collagen production are key events in hepatic fibrogenesis. The resulting fibrosis determines the architectural derangement of the liver following chronic alcohol ingestion.
Figure 301-1
Biomedical and cellular pathogenesis of liver injury secondary to chronic ethanol ingestion. MAA, malondialdehyde-acetaldehyde; TNF, tumor necrosis factor; TGF, transforming growth factor; IL, interleukin; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor.

The liver has a limited repertoire in response to injury. Fatty liver is the initial and most common histologic response to hepatotoxic stimuli, including excessive alcohol ingestion. The accumulation of fat within the perivenular hepatocytes coincides with the location of alcohol dehydrogenase, the major enzyme responsible for alcohol metabolism. Continuing alcohol ingestion results in fat accumulation throughout the entire hepatic lobule. Despite extensive fatty change and distortion of the hepatocytes with macrovesicular fat, the cessation of drinking results in normalization of hepatic architecture and fat content within the liver. Alcoholic fatty liver has traditionally been regarded as entirely benign, but similar to the spectrum of nonalcoholic fatty liver disease, the appearance of steatohepatitis and certain pathologic features such as giant mitochondria, perivenular fibrosis, and macrovesicular fat may be associated with progressive liver injury.
The transition between fatty liver and the development of alcoholic hepatitis is blurred. The hallmark of alcoholic hepatitis is hepatocyte injury characterized by ballooning degeneration, spotty necrosis, polymorphonuclear infiltrate, and fibrosis in the perivenular and perisinusoidal space of Disse. Mallory bodies are often present in florid cases but are neither specific nor necessary to establishing the diagnosis. Alcoholic hepatitis is thought to be a precursor to the development of cirrhosis. However, like fatty liver, it is potentially reversible with cessation of drinking. Cirrhosis is present in up to 50% of patients with biopsy-proven alcoholic hepatitis and its regression is uncertain, even with abstention.

Clinical Features
The clinical manifestations of alcoholic fatty liver are subtle and characteristically detected as a consequence of the patient's visit for a seemingly unrelated matter. Previously unsuspected hepatomegaly is often the only clinical finding. Occasionally, patients with fatty liver will present with right upper quadrant discomfort, tender hepatomegaly, nausea, and jaundice. Differentiation of alcoholic fatty liver from nonalcoholic fatty liver is difficult unless an accurate drinking history is ascertained. In every instance where liver disease is present, a thoughtful and sensitive drinking history should be obtained. Standard, validated questions accurately detect alcohol-related problems. Alcoholic hepatitis is associated with a wide gamut of clinical features. Cytokine production is thought to be responsible for the systemic manifestations of alcoholic hepatitis. Fever, spider nevi, jaundice, and abdominal pain simulating an acute abdomen represent the extreme end of the spectrum, while many patients will be entirely asymptomatic. Portal hypertension, ascites, or variceal bleeding can occur in the absence of cirrhosis. Recognition of the clinical features of alcoholic hepatitis is central to the initiation of an effective and appropriate diagnostic and therapeutic strategy. It is important to recognize that patients with alcoholic cirrhosis often exhibit clinical features identical to other causes of cirrhosis.

Laboratory Features
Patients with alcoholic liver disease are often identified through routine screening tests. The typical laboratory abnormalities seen in fatty liver are nonspecific and include modest elevations of the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and -glutamyl transpeptidase (GGTP), accompanied by hypertriglyceridemia, hypercholesterolemia, and occasionally hyperbilirubinemia. In alcoholic hepatitis and in contrast to other causes of fatty liver, the AST and ALT are usually elevated two- to sevenfold. They are rarely more than 400 IU, and the AST/ALT ratio more than 1 (Table 301-2). Hyperbilirubinemia is common and is accompanied by modest increases in the alkaline phosphatase level. Derangement in hepatocyte synthetic function indicates more serious disease. Hypoalbuminemia and coagulopathy are common in advanced liver injury. Ultrasonography is useful in detecting fatty infiltration of the liver and determining liver size. The demonstration by ultrasound of portal vein flow reversal, ascites, and intraabdominal collaterals indicates serious liver injury with less potential for complete reversal of liver disease.
Table 301-2 Laboratory Diagnosis of Alcoholic Fatty Liver and Alcoholic Hepatitis
Increased two- to sevenfold, less than 400 U/L, greater than ALT
Increased two- to sevenfold, less than 400 U/L
Usually more than 1
Not specific to alcohol, easily inducible, elevated in all forms of fatty liver
May be markedly increased in alcoholic hepatitis despite modest elevation in alkaline phosphatase
If more than5500/L, predicts severe alcoholic hepatitis when discriminant function more than 32

Note: AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGTP, gamma-glutamyl transpeptidase; PMN, polymorphonuclear cells.

                      Critically ill patients with alcoholic hepatitis have short-term (30 day) mortality rates more than 50%. Severe alcoholic hepatitis is heralded by coagulopathy (prothrombin time more than 5 s), anemia, serum albumin concentrations less than25 g/L (2.5 mg/dL), serum bilirubin levels more than 137 mol/L (8 mg/dL), renal failure, and ascites. A discriminant function calculated as 4.6 x [prothrombin time control (seconds)] + serum bilirubin (mg/dL) can identify patients with a poor prognosis (discriminant function more than 32). The presence of ascites, variceal hemorrhage, deep encephalopathy, or hepatorenal syndrome predicts a dismal prognosis. The pathologic stage of the injury can be helpful in predicting prognosis. Liver biopsy should be performed whenever possible to confirm the diagnosis, to establish potential reversibility of the liver disease, and to guide the therapeutic decisions.

Alcoholic Liver Disease: Treatment
                      Complete abstinence from alcohol is the cornerstone in the treatment of alcoholic liver disease. Improved survival and the potential for reversal of histologic injury regardless of the initial clinical presentation are associated with total avoidance of alcohol ingestion. Referral of patients to experienced alcohol counselors and/or alcohol treatment programs should be routine in the management of patients with alcoholic liver disease. Attention should be directed to the nutritional and psychosocial states during the evaluation and treatment periods. Because of data suggesting that the pathogenic mechanisms in alcoholic hepatitis involve cytokine release and the perpetuation of injury by immunologic processes, glucocorticoids have been extensively evaluated in the treatment of alcoholic hepatitis. Patients with severe alcoholic hepatitis, defined as a discriminant function more than  32, were given prednisone, 40 mg/d, or prednisolone, 32 mg/d, for 4 weeks followed by a steroid taper (Fig. 301-2). Exclusion criteria included active gastrointestinal bleeding, sepsis, renal failure, or pancreatitis. Women with encephalopathy from severe alcoholic hepatitis may be particularly good candidates for glucocorticoids
Figure 301-2
Effect of glucocorticoid therapy of severe alcoholic hepatitis on short-term survival: the result of a meta-analysis of individual data from three studies. Prednisolone, solid line; placebo, dotted line.

                         Newer understanding of the role of TNF- expression and receptor activity in alcoholic liver injury has led to an examination of TNF inhibition as an alternative to glucocorticoids for severe alcoholic hepatitis. The nonspecific TNF inhibitor, pentoxifylline, recently demonstrated improved survival in the therapy of severe alcoholic hepatitis (Fig. 301-3). Preliminary trials of neutralizing monoclonal antibody specific for TNF have been disappointing because of increased deaths secondary to infection. Because of inordinate surgical mortality and the high rates of recidivism following transplantation, patients with alcoholic hepatitis are not candidates for immediate liver transplantation. The transplant candidacy of these patients should be reevaluated after a defined period of sobriety.          
Fig. 301-3 algorithm for alcoholic hepatitis. As identified by a calculated discriminant function more than 32 (see text), patients with severe alcoholic hepatitis, without the presence of gastrointestinal bleeding or infection, would be candidates for either glucocorticoids or pentoxifylline administration.

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