Alcoholic Fatty Liver Disease

Question 1

Discuss the natural history of alcoholic liver disease.

Answer 1

Alcohol abuse may lead to steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Hepatic steatosis is seen in approximately 90 percent of heavy drinkers and is typically macrovesicular. It may be seen within two weeks of regular alcohol ingestion and resolves rapidly with abstinence. It has been estimated that a third of patients with steatosis will develop hepatic inflammation (steatohepatitis) if they continue to drink.

Once steatohepatitis has developed, the risk of cirrhosis is increased compared with simple steatosis. In one study, over a five-year period, cirrhosis developed in 16 percent of patients with steatohepatitis and in 7 percent of patients with simple steatosis. Higher rates of progression to cirrhosis are seen among patients with steatohepatitis who continue to drink or who present with symptomatic alcoholic hepatitis (up to 50 percent for both groups). Overall, it is estimated that 8 to 20 percent of patients with steatosis will eventually progress to cirrhosis.

Hepatic decompensation is common among patients with alcoholic cirrhosis. In a population-based study from Denmark that included 446 patients with alcoholic cirrhosis, the risk of complications (ascites development, variceal bleeding, or hepatic encephalopathy) was approximately 25 percent after one year and 50 percent after five years. Once hepatic decompensation develops, the expected five-year transplant-free survival rate is 60 percent for those who stop drinking alcohol and 30 percent for those who continue to drink alcohol.

Question 2

Outline the spectrum of clinical manifestations of alcoholic liver disease.

Answer 2

The clinical manifestations of alcoholic liver disease depend on the severity of disease. Patients with simple steatosis are often asymptomatic, patients with alcoholic hepatitis typically present with jaundice, and patients who have developed cirrhosis may have peripheral stigmata of liver disease or signs of hepatic decompensation.

Question 3

What are some symptoms related to AFLD?

Answer 3

Patients with alcoholic fatty liver are typically asymptomatic. Patients who have developed cirrhosis may report jaundice, weakness, peripheral edema, abdominal distension, or symptoms of gastrointestinal bleeding, such as hematemesis or melena. Patients with hepatic encephalopathy may note disturbances in their sleep pattern and confusion.

Question 4

What are some signs related to AFLD?

Answer 4

Physical examination findings in patients with alcoholic liver disease range from a normal physical examination to evidence of cirrhosis with hepatic decompensation. Patients with steatosis may have a normal examination or hepatomegaly. Patients who have developed cirrhosis may have stigmata of chronic liver disease (eg, spider angiomata, palmar erythema, gynecomastia). With hepatic decompensation, patients may develop ascites, peripheral edema, or hepatic encephalopathy.

Patients with alcoholic liver disease often have coexisting dysfunction in other organs and may have signs of cardiomyopathy, neuropathies, pancreatic dysfunction, and skeletal muscle wasting.

Question 5

Make a general comment on lab investigations in AFLD.

Answer 5

There are several characteristic laboratory abnormalities in patients with alcoholic liver disease, but none are diagnostic. The classic finding is moderately elevated transaminases, with an aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio >1 (and often >2).

Question 6

Write short notes on the LFT in the presence of AFLD.

Answer 6

Serum aminotransferase levels may be normal or moderately elevated in the setting of alcoholic fatty liver disease and alcoholic cirrhosis [30,31]. The AST elevation is usually less than eight times the upper limit of normal, and the ALT elevation is typically less than five times the upper limit of normal. The degree of elevation does not correlate with the severity of the underlying liver disease.

An AST to ALT ratio >1 is occasionally seen in patients with nonalcoholic steatohepatitis and is frequently seen in patients who have developed nonalcoholic cirrhosis. However, if the ratio is greater than two, the transaminase elevations are likely due to alcoholic liver disease since values greater than two are rarely seen in other forms of liver disease. In a study of 271 patients with biopsy-confirmed liver disorders, more than 90 percent of the patients whose AST to ALT ratio was ≥2 had alcoholic liver disease. The percentage increased to greater than 96 percent when the ratio was ≥3.

The gamma-glutamyl transpeptidase (GGT) is often elevated in patients with alcoholic liver disease. However, GGT elevations are not specific for alcoholic liver disease.

Elevated bilirubin levels are frequently seen in patients with decompensated cirrhosis from any cause, including alcoholic liver disease. Elevation of the bilirubin in a patient who does not have cirrhosis should raise concern for alcoholic hepatitis. Patients who are malnourished or who have cirrhosis may have low albumin levels.

Question 7

Write short notes on the haematological abnormalities (on FBC and INR) in AFLD.

Answer 7

Hematologic findings in patients with alcoholic liver disease may include thrombocytopenia, anemia, an elevated mean corpuscular volume (MCV), a decreased lymphocyte count, an elevated erythrocyte sedimentation rate (ESR), and an elevated international normalized ratio (INR). Macrocytosis suggests longstanding disease and may result from vitamin B12 or folate deficiency, alcohol toxicity, or increased lipid deposition in red cell membranes. Similarly, thrombocytopenia may result from primary bone marrow hypoplasia (which can be due to alcohol and is usually brief) or splenic sequestration (due to portal hypertension and an enlarged spleen).

In one study that included 40 patients with alcoholic liver disease, the following mean laboratory test results were noted:
●ESR: 25.9
●INR: 1.6

Question 8

Hepatic and haematological abnormalities aside, what other problems might be noted on routine bloods in patients with AFLD?

Answer 8

Additional laboratory findings that may be seen in patients who have progressed to cirrhosis include hyponatremia and an elevated creatinine in patients with hepatorenal syndrome.

Question 9

What is the role of imaging in the diagnosis of AFLD?

Answer 9

Liver imaging may provide evidence of hepatic steatosis or cirrhosis, but it is not able to differentiate alcoholic liver disease from other causes. Ultrasound is always indicated to confirm that the liver is homogeneous and to exclude other causes of abnormal liver tests (eg, biliary obstruction, hepatic masses). More detailed liver imaging (eg, computed tomography [CT] or magnetic resonance imaging [MRI]) is obtained for patients with suspected cirrhosis or ultrasound evidence of biliary tract obstruction (eg, jaundice, elevation of liver tests in a cholestatic pattern).

Question 10

Provide an outline to making the diagnosis of AFLD.

Answer 10

Alcoholic liver disease may be suspected in a patient with a compatible history who has elevated serum transaminases, a suggestion of fatty liver on imaging tests, or is found to have steatosis on liver biopsy. Liver tests are generally normal or modestly elevated, and jaundice is unusual. The diagnosis is established after excluding other causes of fatty liver or cirrhosis.

Question 11

Describe the diagnostic evaluation of a patient with suspected AFLD.

Answer 11

The evaluation includes:
●Obtaining a very detailed history to quantify alcohol use and drinking patterns and to identify other potential sources of hepatic injury. This should be supplemented by use of either the CAGE or AUDIT questionnaires to establish the likelihood of problem alcohol drinking or abuse
●Performing a physical examination to identify stigmata of chronic liver disease.
●Obtaining laboratory tests to look for signs of hepatitic inflammation and to assess hepatic synthetic function, including:
•Liver blood tests – transaminases, bilirubin, alkaline phosphatase, gamma-glutamyl transaminase;
•Complete blood count;
•Serum albumin level;
•Coagulation studies – prothrombin time, international normalized ratio (INR).
●Obtaining laboratory tests to identify other causes of chronic hepatic injury, including:
•Hepatitis B surface antigen, anti-hepatitis B core IgG;
•Antibodies to hepatitis C virus (HCV);
•Serum ferritin and transferrin saturation for hemochromatosis;
•Total IgG or gamma-globulin level, antinuclear antibody, anti-smooth muscle antibody, anti-liver/kidney microsomal-1 (anti-LKM-1) antibodies for autoimmune hepatitis.

Clinical and laboratory features are often adequate for establishing the diagnosis of alcoholic liver disease in a patient with a history of significant alcohol use, provided the patient does not have risk factors for other causes of liver disease and testing for other common causes of liver disease is negative.

Liver imaging may provide evidence of hepatic steatosis or cirrhosis, but it is not able to differentiate alcoholic liver disease from other causes.

A liver biopsy may be required if the diagnosis remains uncertain following a noninvasive evaluation. In addition, it can establish the severity of liver disease.

Question 12

Provide an example of which questions should be asked on history. Include:

• Definition of a standard drink
• What constitutes significant alcohol consumption
• Risk factors for other hepatic diseases

Answer 12

• A standard drink in the United States (12 oz [360 mL] of beer, 5 oz [150 mL] of wine, 1.5 oz [45 mL] of 80-proof spirits) contains approximately 14 grams of alcohol (figure 1), so the limits below roughly translate to >15 drinks per week for men and >10 drinks per week for women.
• Several definitions have been proposed for what constitutes significant alcohol consumption. We define significant alcohol consumption as an average consumption of >210 grams of alcohol per week in men or >140 grams of alcohol per week in women over at least a two-year period.
• To identify risk factors for other causes of liver disease, the patient should also be carefully questioned about medication use (including herbal supplements and over-the-counter medications), possible parenteral exposures to viral hepatitis (including transfusions, intravenous and intranasal drug use, tattoos, and sexual activity), occupational exposures to hepatotoxins, family history of liver disease, and whether the patient has a history of diseases that may be associated with liver disease (such as the metabolic syndrome, celiac disease, or autoimmune disorders).

Question 13

In terms of testing for other liver diseases, what needs to be remembered about the interpretation of tests for hereditary haemochromatosis?

Answer 13

Ferritin production and the plasma ferritin concentration are increased in the absence of iron overload in certain liver diseases, including alcoholic liver disease and acute or subacute hepatitis (from any cause). As a result, in patients with acute or subacute hepatitis testing should be deferred until the patient has recovered from the acute episode. In addition, the serum transferrin saturation in alcoholic liver disease may reach or exceed 60 percent, perhaps because alcohol suppresses liver transferrin synthesis. As a result, if ferritin levels or the transferrin saturation are high, additional testing for hemochromatosis is indicated.

Question 14

What are typical radiographic findings of AFLD:

• on US?
• on CT?

Answer 14

• Ultrasound can detect hepatic steatosis, but will miss many patients with <30 percent steatosis. Ultrasonography in patients with fatty liver may reveal a liver with a hyperechoic texture. In patients with fibrosis, the ultrasound may reveal a coarse echo pattern. If cirrhosis has developed, nodules may be seen, causing an irregular outline of the liver surface.
• CT findings in patients with cirrhosis may include atrophy of the right lobe of the liver, hypertrophy of the caudate lobe, hypertrophy of the lateral segment of the left lobe, parenchymal nodularity, attenuation of hepatic vasculature, splenomegaly, venous collaterals, and ascites. In some cases, the liver may be diffusely atrophic or hepatomegaly may be seen.

Question 15

List the indications for liver biopsy in patients with AFLD.

Answer 15

The decision to perform a biopsy should consider the confidence of the clinical diagnosis and the role that the biopsy findings would have in guiding therapeutic options. As a general rule, a biopsy may be indicated in:
●Any patient with serum aminotransferase elevations that persist for more than six months without a clear explanation, even if the patient is asymptomatic.
●Patients who have elevated aminotransferases and evidence of clinically significant hepatic dysfunction (eg, abnormal prothrombin time, hypoalbuminemia). If a coagulopathy is present, transjugular biopsy is usually safer than percutaneous biopsy.
●Patients in whom the diagnosis of alcoholic liver disease is uncertain based on clinical and laboratory findings.
●Patients who may have more than one type of liver disease (such as alcohol and hepatitis C) in whom a liver biopsy may help determine the relative contribution of these factors.
●Patients in whom a more detailed understanding of prognosis is desired.

Question 16

What are the typical histologic findings in AFLD?

Answer 16

Early changes in patients with alcoholic liver disease seen under the electron microscope include accumulation of membrane-bound large droplet (macrovesicular) steatosis, proliferation of smooth endoplasmic reticulum, and gradual distortion of mitochondria. This is most often seen in the pericentral region of hepatic lobules (zone 3). Fat accumulation can be seen easily by light microscopy; inflammatory changes are minimal at this stage apart from occasional lipogranulomata in pericentral zones.

Question 17

Which conditions should be considered in the differential diagnosis of AFLD?

Answer 17

The differential diagnosis of hepatic steatosis includes:
●Nonalcoholic liver disease
●Hepatitis C (particularly genotype 3)
●Wilson disease
●Lipodystrophy
●Starvation
●Parenteral nutrition
●Abetalipoproteinemia
●Medications (amiodarone, tetracycline, methotrexate, tamoxifen, glucocorticoids, valproate, anti-retroviral agents for HIV)
●Reye syndrome
●Acute fatty liver of pregnancy
●HELLP (hemolytic anemia, elevated liver enzymes, low platelet count) syndrome
●Inborn errors of metabolism (LCAT deficiency, cholesterol ester storage disease, Wolman disease)

Question 18

It can be difficult to distinguish NAFLD from alcoholic liver disease based upon clinical or histologic features. How does one differentiate between AFLD and NAFLD?

Answer 18

Nonalcoholic fatty liver disease (NAFLD) is the primary consideration in patients who deny alcohol abuse but have clinical features suggestive of alcoholic liver disease (such as elevated aminotransferases in the absence of serum markers of viral hepatitis).

The presence of obesity does not help differentiate alcoholic from NAFLD. While obesity is a known risk factor for NAFLD, it can also increase the risk of developing steatosis in heavy drinkers.

A predictive model (the alcoholic liver disease to NAFLD index [ANI]) has been proposed to distinguish alcoholic from nonalcoholic liver disease. The model is based upon aminotransferase levels, mean corpuscular volume (MCV), body mass index (BMI), and sex:

ANI = -58.5 + 0.637 (MCV) + 3.91 (AST/ALT) – 0.406 (BMI) + 6.35 for men

An ANI greater than zero favors a diagnosis of alcoholic liver disease, whereas an ANI less than zero favors a diagnosis of NAFLD. The probability of the patient having alcoholic liver disease rather than NAFLD is then calculated using the value obtained for the ANI:

Probability = eANI/(1+eANI)

The ability of the model to accurately categorize patients ranged from good to excellent in validation cohorts.

Question 19

Outline the general approach to the management of AFLD patients.

Answer 19

• Management of alcoholic liver disease centers on alcohol abstinence. In patients who have not yet progressed to cirrhosis, abstinence may allow for reversal of the hepatic changes induced by alcohol. In patients with cirrhosis, alcohol abstinence decreases the risk of hepatic decompensation and improves survival. Abstinence is more likely among patients who receive treatment for alcohol abuse or dependence.
• Patients with alcoholic cirrhosis also require nutritional therapy and measures to prevent superimposed hepatic injury (eg, vaccination for hepatitis A and B).
• Patients with decompensated cirrhosis are managed the same as patients with other forms of end-stage liver disease and require treatment for complications such as ascites, variceal bleeding, and hepatic encephalopathy. In some cases, liver transplantation may be required.

Question 20

Describe nutritional therapy for AFLD. Cover:

• Deficiencies encountered.
• Indications for
• “Cirhhotic diet”
• Benefits of

Answer 20

Alcoholism is associated with nutritional deficiencies including protein calorie malnutrition and deficiencies of vitamins and trace minerals, including vitamin A, vitamin D, thiamine, folate, pyridoxine, and zinc. In patients with alcoholic cirrhosis, protein calorie malnutrition increases the risk of major complications, such as infection, encephalopathy, and ascites.

All patients with alcoholic liver disease should undergo a nutritional assessment. Nutritional therapy is indicated for patients with alcoholic fatty liver who are malnourished or who have evidence of vitamin or mineral deficiencies. Patients with alcoholic fatty liver who are not malnourished and do not have evidence of vitamin or mineral deficiencies should be encouraged to eat a healthy, balanced diet.

For patients with alcoholic cirrhosis, general nutritional therapy is indicated because protein, carbohydrate, and lipid metabolism are all affected by liver disease. Patients with alcoholic cirrhosis should eat multiple times per day, including breakfast and a nighttime snack. The diet should consist of higher amounts of protein (1.2 to 1.5 g/kg) and total calories (35 to 40 kcal/kg) than are recommended in a standard healthy diet.

While nutritional therapy has not been shown to improve mortality in most randomized trials, a systematic review that included 13 studies with 319 patients with alcoholic cirrhosis suggests that it improves nitrogen balance and albumin levels, decreases hospitalization rates, and decreases the frequency of complications related to cirrhosis (encephalopathy, gastrointestinal bleeding, ascites).