On physical exam, signs of fatty liver can range from mild hepatomegaly, with blunting of the normally sharp liver edge, to massive hepatomegaly (Table 8.1). In patients with alcoholic hepatitis , hepatomegaly (80–90 % of cases), jaundice (40–60 %), and fever (23–56 %) are very common. If the injury is severe, the patients will have ascites, hepatic encephalopathy, splenomegaly, evidence of muscle wasting, and sometimes gastrointestinal hemorrhage with portal hypertensive gastropathy or gastroesophageal varices [11, 12].

Patients with compensated cirrhosis often have hepatomegaly with hard liver consistency and a nodular surface. They may also have splenomegaly and, less often, right upper quadrant pain. Less common findings include gynecomastia and testicular atrophy [13], amenorrhea, parotid enlargement [14], cutaneous spider angioma [15], Dupuytren’s contractures [16], digital clubbing [17] (found especially in patients with hypoxemia related to hepatopulmonary syndrome), palmar erythema, and nail changes.

Patients with decompensated cirrhosis may also have mental changes of hepatic encephalopathy with variable degrees of confusion, with or without asterixis, jaundice, ascites, and peripheral edema. Some patients will have evidence of gastrointestinal bleeding or other organ damages, including alcoholic gastritis or pancreatitis, alcoholic neuropathy, or, less commonly, alcoholic cardiomyopathy. Signs of alcohol withdrawal are common in patients with alcoholic hepatitis who have recently discontinued alcohol.

Patients with ALD should have a complete blood count, international normalization ratio (INR), comprehensive metabolic panel, and GGT. Because there is the risk of overlapping viral hepatitis, serologies for current infection or past exposure to hepatitis A, B, and C are advised. Patients who are not immune should be vaccinated against hepatitis A and B. If the ALT is elevated, a full workup for other causes of liver disease and cirrhosis is also advisable because other immune or metabolic causes may be uncovered.

Common hematologic findings include anemia, macrocytosis, leukopenia, lymphocytopenia, and thrombocytopenia. Macrocytosis is often due to alcohol toxicity to the bone marrow, but is important to assess for folic acid and/or vitamin B12 deficiency. In patients with alcoholic hepatitis without cirrhosis, thrombocytopenia frequently reverses with rebound thrombocytosis after 1–3 weeks [18]. In cirrhotic patients, thrombocytopenia persists as evidence of portal hypertension. An elevated INR is a marker of the severity of the disease, but can also signal a nutritional deficiency; hence, vitamin K repletion can be helpful in clarifying the situation by eliminating the nutritional deficiency component.

The comprehensive metabolic panel helps to identify electrolyte imbalances that need prompt correction. Similarly, measurements of magnesium, zinc, and phosphorous in plasma can be useful. We frequently supplement with magnesium (magnesium oxide 400 mg/day) and zinc (zinc sulfate 220 mg/day) to treat muscle cramps. Patients with alcoholic hepatitis and with decompensated cirrhosis are very susceptible to kidney injury, and creatinine elevated above the patient’s usual “baseline” requires prompt attention and intervention to avoid progression of acute kidney injury and development of hepatorenal syndrome.

Consumption of alcohol in excess of 50 g per day causes elevation of AST (sensitivity 50 %, specificity 82 %) and ALT (sensitivity 35 %, specificity 86 %) [19]. The elevation of AST is typically higher than that of ALT, and 79 % of patients with alcoholic hepatitis have an AST–ALT ratio >2. Patients with alcoholic hepatitis with ALT > AST frequently have overlapping causes, such as superimposed viral hepatitis or drug injury (most often acetaminophen); the same is true if the AST or ALT is higher than 300 units/L, because this threshold is not likely to be surpassed by alcohol injury alone. Elevated GGT is more sensitive for alcohol abuse (56–73 %) but less specific (53–70 %) than CDT or MCV [20]. Using a combination of these tests may be warranted. Elevated bilirubin, in the absence of biliary obstruction, is a marker of the severity of the alcoholic liver injury and is very important as a component of the Maddrey discriminant function , MELD score, Glasgow alcoholic hepatitis score, the Lille model, and the Child–Turcotte–Pugh calculator index (discussed subsequently).

Validated self-reported questionnaires are superior to biochemical tests in detecting alcohol abuse. Biochemical tests can be utilized in situations where the suspicion of alcohol abuse is high but the patient denies alcohol abuse. Carbohydrate-deficient transferrin (CDT) is elevated in alcohol abuse but is a less useful marker in females [21, 22] and in patients with cirrhosis [23]. Combinations of CDT, MCV, and/or GGT can help improve sensitivity and specificity [24–26] for heavy alcohol consumption.

For patients with alcohol abuse who have significant fat in the liver (≥30 % fat), ultrasound will detect diffuse hyperechoic texture, with a sensitivity of 91 % and a specificity of 93 %. The sensitivity is only 64 % with fatty infiltration less than 30 % [27]. CT scan without contrast is highly predictive of fatty liver when the liver-to-spleen attenuation ratio is more than ten Hounsfield units [28]. MRI is the best tool but is more expensive, with a sensitivity of 95 % and specificity of 98 % [29]. When trying to identify advanced fibrosis or cirrhosis, ultrasound has lower sensitivity (50–70 %) with specificity of 88 % [30]. Multiphase CT scan and MRI are superior in identifying cirrhosis and its complications, including collateral circulation, vascular thrombosis, hepatocellular carcinoma, or other focal liver lesions. Ultrasound is the most commonly used initial imaging technique, helpful in identifying biliary dilation in a patient with jaundice and in the detection of ascites.

In the presence of a history of alcohol abuse associated with typical liver enzyme elevations, diagnosis is very reliable with sensitivity of 91 % and specificity of 97 % [31], and liver biopsy is often not performed in the clinical (non-research) setting. Patients with atypical presentation or who have markers of other types of liver disease (autoimmune hepatitis, hemochromatosis, viral hepatitis, etc.) are good candidates for liver biopsy. Liver biopsy helps to clarify the diagnosis and will give the stage of disease, which is useful in deciding if surveillance for hepatocellular carcinoma is needed. Liver biopsy also differentiates simple steatosis from steatohepatitis but is rarely needed for this purpose. The histologic findings of alcoholic steatohepatitis include centrilobular steatosis, hepatocyte ballooning, Mallory bodies, perivenular fibrosis, pericellular fibrosis, and mixed inflammatory infiltration of neutrophils and lymphocytes. Megamitochondria are often seen in cases of recent alcohol abuse. Patients with cirrhosis frequently have micronodular changes and bile duct proliferation. Less often, patients have mixed macro- and micronodular cirrhosis.

The phenotypical manifestation of alcohol consumption in the liver, and general health status of an individual, is determined by a complex interplay of varying elements such as drinking habits (duration and quantity of alcohol consumption), environmental agents, and individual factors, as discussed previously [107]. Chronic alcohol consumption can lead to a spectrum of liver injuries which can occur sequentially, separately, or simultaneously in the same patient [108].

Alcoholic steatosis is the most common and initial manifestation of alcoholic liver disease. This lesion is pathologically characterized by both microvesicular and macrovesicular fat accumulation within the hepatocytes, with minimal inflammatory response or hepatic fibrosis [109]. Patients with steatosis are usually asymptomatic and are often diagnosed incidentally on abdominal imaging (usually in the form of transabdominal ultrasound or computed tomography (CT) scan). Patients typically have normal to very mild elevations of their liver enzymes, such as gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Serum bilirubin and other markers of hepatic function (international normalized ratio (INR), albumin levels) also tend to be normal. Alcoholic steatosis is a relatively benign condition which is reversible with abstinence; however, it has the potential to progress to alcoholic hepatitis or cirrhosis in an accelerated fashion in a minority of patients who continue to drink heavily [110].

Early studies by Dr. Charles Lieber in volunteers demonstrated the relative ease with which alcohol consumption causes fatty liver [111, 112]. In the first study, five volunteer subjects with a history of alcoholism were fed alcohol in a clinical research setting. All subjects had previously abstained from alcohol for 2–5 months. The study lasted 18 days. Patients were given 25 % of calories as protein (high), 25 % of calories as fat (low), and 50 % as carbohydrates. Alcohol was substituted for carbohydrates and was slowly increased so that after 8 days on the study, subjects were receiving 46 % of total calories as alcohol. Some subjects had interval liver biopsies during this study, and two had liver biopsies performed 1 month after alcohol was discontinued. Alcohol consumption caused histologic and biochemical fatty liver and ultrastructural changes in the liver. This occurred in spite of the fact that subjects received a nutritious diet. This highlighted the fact that alcohol itself is hepatotoxic in spite of a nutritious diet. In a second study, healthy volunteers who were never drinkers were given alcohol anywhere from 2 days to 2 weeks. Four different regimens of alcohol feeding were administered. One group received alcohol for only 2 days in addition to a standard diet, and another group received alcohol for 2 days in addition to a high-protein/low-fat diet. Importantly, both groups developed hepatic steatosis. Longer duration of feeding involved isocaloric substituting of alcohol for carbohydrates. Again, all subjects developed fatty liver on liver biopsy. These results clearly demonstrate that normal nonalcoholic subjects who regularly consume alcohol even for a relatively short period of time can develop fatty liver, and histologic changes were independent of nutritional factors.

The paramount histologic finding determining the natural history of alcoholic liver disease is alcoholic hepatitis. This is a necroinflammatory process characterized by predominant neutrophilic infiltration, ballooning degeneration of hepatocytes, and hepatocyte necrosis [113]. The development of this key clinical and histologic entity represents a “fork in the road” in relation to the natural history of ALD, with important short-term and long-term implications. Acutely, the development of alcoholic hepatitis is associated with a significant increase in proximal mortality and the potential to develop portal hypertension and its complications, even without the development of major fibrosis [114]. In the long term, for those who survive, this disease process is associated with an accelerated course of fibrosis progressing to cirrhosis in 40 % of cases [115]. These distinctions in the natural progression of alcoholic liver disease also have therapeutic implications, explaining why a subset of alcoholics with inflammatory features are candidates for treatment with anti-inflammatory agents (i.e., corticosteroids and pentoxifylline) in an attempt to reduce proximal mortality, whereas patients without these inflammatory features may be better candidates for treatment geared toward reducing long-term hepatic injury/cell death and hepatic dysfunction or possibly enhancing liver regeneration.

Due to the important acute prognostic implication of alcoholic hepatitis , multiple scoring systems have been developed to assess the severity of liver disease in terms of patient survival in order to stratify patients to proven treatment modalities. The Child–Turcotte–Pugh (CTP) , the oldest scoring system, incorporates the serum bilirubin level, albumin level, PT, and the severity of ascites and hepatic encephalopathy in assigning a numerical score that is used to categorize patients (class A = scores 1–6, class B = scores 7–9, class C = scores 10–15), with a higher score denoting more severe disease [116]. This scoring system has fallen out of favor in grading alcoholic hepatitis due to subjectivity in grading among other things. Since 2002, the United Network for Organ Sharing (UNOS) has utilized the MELD score to grade the severity of liver disease in patients awaiting liver transplant. This represents a more objective analysis, utilizing only the serum bilirubin, creatinine, and INR [117]. The use of this scoring system is a reflection of the reason for which this scoring system was initially intended to assess—the short-term prognosis of cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedures [118]. The use of this scoring system has been validated in multiple studies to accurately predict the 3-month mortality of patients with liver disease, especially those patients awaiting liver transplantation [119].