Temitope Foster, MD, MSCR and Ryan M. Ford, MD
What are the different types of alcohol-induced liver disease?
Bland reversible steatosis, transaminitis, steatohepatitis, acute alcoholic hepatitis (AAH), and alcohol-induced cirrhosis.
What are the primary risk factors for alcoholic liver disease?
The amount and duration of alcohol consumption are the most important. Neither the pattern of drinking nor the beverage type is necessarily a risk factor. Genetic factors, environmental factors, and other medical comorbidities also portend risk of chronic liver disease from alcohol.
What percentage of the U.S. population suffers from either alcohol abuse or alcohol dependence?
Approximately 7%–8%.
What percentage of patients with chronic alcoholism in the United States go on to develop cirrhosis of the liver?
Approximately 20%–25%.
How is a standard drink of alcohol in the United States defined?
0.6 fluid ounces of ethanol, which is found in a 12-fluid ounce beer, a 5-fluid ounce glass of wine, or a 1.5-fluid ounce shot of 80-proof spirit. It is important to note that a standard drink is different in different parts of the world (alcohol by volume, etc).
Describe what is meant by “first-pass” metabolism of ethanol and how it may vary among individuals.
The stomach contains alcohol dehydrogenase (ADH) and may account for up to 10% of “first-pass” metabolism, or oxidation of ethanol before systemic absorption occurs. The dose of ethanol, concomitant food ingestion, and gastric emptying time may affect first-pass gastric metabolism. Also, women, Native Americans, Asians, and the elderly have lower levels of gastric ADH and therefore may absorb more ethanol systemically.
What are the two major pathways of ethanol metabolism in the liver?
ADH and the microsomal ethanol oxidizing system (MEOS)/cytochrome P450 pathway (CYP2E1).
What are the negative effects of acetaldehyde, a toxic metabolite of ethanol?
It causes formation of reactive oxygen species and depletes glutathione stores, both of which contribute to ongoing cellular and DNA damage.
What are the threshold levels of daily consumption of alcohol in males and females that may lead to significant liver disease?
Twenty grams of ethanol per day in women and 80 g of ethanol per day in men.
What countries in the world have the highest daily amount intake of ethanol per adult?
Russia and Ukraine.
What percentage of individuals with alcoholic liver disease also has antibody positivity to hepatitis C virus (HCV)?
40%.
What three factors must be present for a diagnosis of alcohol dependence (“alcoholism”)?
Physiological dependence, loss of control, and social/physical impairment.
True/False: Alcohol abuse is the same as alcoholism.
False. “Alcoholism” refers to alcohol dependence as defined by Diagnostic and Statistical Manual-Fourth Edition-Text Revision (DSM-IV-TR) criteria. Alcohol abuse refers to problematic drinking with consequences.
What tools are available to help a physician screen someone for alcoholism?
Detailed history, CAGE questions, and Michigan Alcohol Screening Test (MAST). The “CAGE” criteria consist of four questions referring to events occurring within a patient’s lifetime. It is a commonly used and practical means of screening for alcoholism and consists of the following questions: have you ever had to “cut-down” on drinking?; have you ever been “annoyed” when people ask about your drinking?; have you ever felt “guilty” about your drinking?; and, have you ever had an “eye-opener” or had to drink alcohol in the morning to avoid feeling badly?
What diseases are associated with nonalcoholic steatohepatitis (NASH)?
Dyslipidemia, insulin resistance, diabetes mellitus, hypertension, obesity, and the metabolic syndrome.
What commonly prescribed medication can result in the histologic picture of NASH?
Drugs are responsible for less than 2% of all cases of steatohepatitis. Amiodarone has been shown to independently cause steatohepatitis. Tamoxifen, corticosteroids, and estrogens have also been associated with steatohepatitis, although a causal relationship has not been clearly established and the mechanism is likely through the exacerbation of NASH risk factors.
True/False: Cirrhosis caused by alcoholic liver disease can occur in the absence of necroinflammation, that is, alcoholic hepatitis.
True.
What is the current hypothesis for the development of alcoholic cirrhosis in the absence of inflammation?
Ethanol metabolites (ie, acetaldehyde) and products of lipid peroxidation are involved.
What is the most important microsomal ethanol oxidizing enzyme related to the pathogenesis of both alcoholic liver disease and NASH?
Cytochrome P450 2E1.
True/False: Patients with AAH may show clinical signs of chronic liver disease, despite not having cirrhosis.
True. Acute hepatic congestion and stellate cell activation can lead to transient portal hypertension. As a result, patients can develop hepatosplenomegaly, ascites, encephalopathy, and/or varices.
True/False: Patients with alcoholic liver disease are at increased risk for acetaminophen toxicity.
True, due to a lack of glutathione stores and an upregulated cytochrome P450 (CyP2E1) system.
True/False: Ethanol causes only microsteatosis of the liver.
False. Ethanol can cause both a macrosteatosis and a microsteatosis. Ethanol classically causes a potentially reversible macrosteatosis, but a more serious microsteatosis can develop in the setting of mitochondrial toxicity.
True/False: Mallory’s hyaline is pathognomonic for alcohol-induced liver disease.
False. Mallory’s hyaline can be seen with other inflammatory hepatitides, including NASH.
True/False: AAH is more likely to occur in first-time drinkers.
False. AAH is more likely to occur in habitual drinkers of alcohol.
True/False: AAH is a self-limiting disease with a good prognosis.
False. AAH is a serious medical condition that can be fatal.
In addition to abstinence, what is the most important therapy for patients with AAH?
Optimal nutritional support and supplementation.
What is an important prognostic formula to calculate in patients who present with AAH?
Maddrey discriminant function, which is calculated as follows: 4.6 × (PT-control) + serum bilirubin (mg/dL). A value > 32 is associated with a worse prognosis.
Other than the Maddrey discriminant function, what are some prognostic scoring systems to predict mortality with alcoholic hepatitis?
Child-Pugh score, model for end-stage liver disease (MELD) score, Lille model, and the Glasgow score.
True/False: A typical patient with AAH will have aminotransferase levels > 400 U/L.
False. Transaminase levels are almost never elevated above 400 U/L in the setting of AAH alone. Additionally, aspartate aminotransferase (AST) levels generally exceed alanine aminotransferase (ALT) levels in AAH.
True/False: Corticosteroids can improve mortality in some patients with AAH.
True, in selected groups. A number of clinical trials and meta-analyses have shown benefit in a selected group of patients with AAH.
In which patients should corticosteroids be considered in the treatment of AAH?
Patients with a Maddrey discriminant function >32 and no evidence of active infection. Those with encephalopathy may also benefit. The presence of renal failure or GI bleeding may be a relative contraindication to steroids.
What dose and what type of corticosteroid should be used?
Prednisolone 40 mg daily for 4 weeks. Methylprednisolone may also be used at a dose of 32 mg per day. Prednisone 40 mg daily may also be acceptable. Steroids should be tapered down prior to discontinuation.
What is another medication that has been shown to improve mortality and prevent renal failure in severe AAH?
Pentoxifylline.
True/False: Alcoholic cirrhosis is a risk factor for hepatocellular carcinoma (HCC).
True. Patients with alcoholic cirrhosis should be screened for HCC every 6 months.
In chronic alcoholics, which epidemiological characteristics have been identified as independent risk factors for HCC?
Cirrhosis, age greater than 50, male sex, hepatitis B surface antigen positivity, and anti-HCV positivity.
True/False: Alcoholic cirrhosis is currently the second most common indication for liver transplant in the United States.
True. Hepatitis C is the most common and nonalcoholic fatty liver disease (NAFLD) is the third most common.
How long does a patient need to be abstinent before he/she can be considered for a liver transplant?
Although controversial, many transplant centers require 6 months of abstinence; however, this is not universal and somewhat arbitrary.
What length of sobriety more accurately indicates a low risk of recidivism?
5–7 years, although the longer the better.
What are some risk predictors of alcohol relapse?
Family history of alcoholism, concomitant substance abuse, prior history of relapse, coexisting psychiatric disease, poor social support/structure, noncompliance, and concomitant personality disorder.
What three variables independently increase the risk of progression of alcohol-related hepatic steatosis to cirrhosis?
Continued alcohol consumption, severity of initial histologic injury, and female gender.
True/False: Patients who undergo liver transplant for alcohol cirrhosis have a lower overall survival than patients who are transplanted for other reasons.
False.
What is the approximate relapse rate of any alcohol use after liver transplant for patients with alcohol liver disease?
5%–20%.
True/False: Acetaminophen can be safely given to patients with alcohol cirrhosis. What about nonsteroidal anti-inflammatory drugs (NSAIDs)?
True. In the setting of abstinence, acetaminophen remains the initial drug of choice to treat pain in patients with alcohol cirrhosis. Generally, the dose should not exceed more than 2–3 g/day. Aspirin and NSAIDs should be avoided due to increased risk of GI bleeding and acute kidney injury.
What other general classes of drugs should be avoided in patients with end-stage liver disease?
The most important group of drugs to avoid is aminoglycosides as they can precipitate renal failure.
What are the clinical signs/symptoms of alcohol withdrawal or delirium tremens?
Alcohol withdrawal syndrome is defined by autonomic hyperactivity, manifested by tachycardia, hypertension, diaphoresis, dilated pupils, and anxiety. Delirium tremens is a severe form of withdrawal that includes extreme agitation with delusions or hallucinations. Seizures may also be precipitated in alcohol withdrawal.
What risk factors are associated with delirium tremens?
Male sex, age >30, 5- to 15-year drinking history, history of withdrawal seizures, and previous history of delirium tremens.
What are some other neurologic syndromes that can occur in alcoholics?
Wernicke’s encephalopathy (nystagmus, ataxia, and confusion), Korsakoff’s syndrome (dementia with confabulation due to mamillary body destruction), and peripheral neuropathy. These problems relate to thiamine deficiency.
What is the principal collagen-producing cell in the liver?
Stellate cell.
True/False: The prevalence of antibody to HCV increases with the severity of underlying alcoholic liver disease.
True. While there is a 20% prevalence of antibody to HCV in patients with alcoholic hepatitis and 40% in patients with alcoholic cirrhosis, it is found in only 2% of alcoholic patients with normal liver biopsies.
True/False: In aggregate, trials of parenteral and enteral nutritional support indicate that restricted intake of nutrients is associated with a poor prognosis in patients hospitalized with alcoholic liver disease.
True. Feed the hospitalized alcoholic, especially those with AAH. Enteral nutrition is preferred over parenteral nutrition.
True/False: When faced with a patient with steatosis who drinks some amount of alcohol and who has elevated liver tests, there is a score that can help differentiate between alcohol- and nonalcohol-induced steatohepatitis.
True. The Mayo alcoholic liver disease/nonalcoholic liver disease index (ANI) score can be useful and uses the variables of age, gender, AST, ALT, mean corpuscular volume (MCV), and body mass index (BMI). The ANI score is most useful in patients with a MELD score less than 20.
What is the typical profile of a NASH patient?
Middle-aged female with obesity, non-insulin-dependent diabetes mellitus, with or without hyperlipidemia.
Which cytokines have been implicated in the development of NASH?
Pro-inflammatory cytokines, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6), have been shown to play a major role in the development of NASH. Levels of TNF-α and IL-6 are elevated in the liver and blood of patients with NASH, and inhibition of these cytokines has improved liver tests in animal models.
True/False: Currently available imaging modalities are relatively insensitive and nonspecific for NASH.
True. Although a number of noninvasive imaging techniques and scoring systems have been evaluated, liver biopsy remains the gold standard for confirming a clinical suspicion of NASH.
True/False: NASH is histologically indistinguishable from alcohol-induced liver disease.
True. NASH is, therefore, a diagnosis made after carefully excluding excessive alcohol use defined as greater than 20 g/day in females and 30 g/day in males.
What treatments can be recommended to patients with NASH?
Treatment consists of modifying the factors that are commonly associated with NASH—vigorous exercise with or without weight loss, actual weight loss, reduction in serum lipids and glucose, and cessation of responsible medications. Medical therapy with vitamin E as well as statin drugs have shown some promise.
What counseling can be given to patients with NAFLD about their overall prognosis?
The majority of patients with NAFLD have a benign fatty infiltrate that is considered to be nonprogressive. However, it is estimated that up to 10%–25% of those with NAFLD (or 2%–7% of the entire population) will have NASH, a combination of necroinflammation and fibrosis. About 10%–29% of those with NASH will go on to develop cirrhosis over 10 years.
Define focal fatty liver, or fatty sparing.
An important difference between NAFLD and the above named lesion is that NAFLD is diffuse. Focal fatty liver is incidentally found as a result of improved abdominal imaging techniques. This is not a pathologic diagnosis, needs no treatment, and often regresses.
What are the histologic features of NASH?
Steatosis in the presence of lobular inflammation and hepatocyte ballooning.
What are the leading causes of increased mortality in patients with NAFLD?
Currently, the number one cause of mortality is cardiovascular disease followed by nonliver malignancy, then liver-related deaths.
True/False: Patients with NASH can develop HCC in the absence of cirrhosis.
True. There is now increasing evidence of NASH patients with only stage 1 or 2 fibrosis developing HCC.
What ethnic group in the United States has the highest prevalence of NAFLD?
Hispanics, followed by Caucasians, then African-Americans.
What gene is associated with the ethnic variation seen in the prevalence of NAFLD?
Patatin-like phospholipase domain containing 3 gene (PNPLA3) also called adiponutrin. PNPLA3 accounts for approximately 70% of the variation in the prevalence of NAFLD among Hispanics, African-Americans, and Caucasians. The physiological role of PNPLA3 and the mechanism by which it influences fatty liver are not yet known.
How much daily alcohol consumption would make a diagnosis of NAFLD less likely?
More than 20 g/day in females and 30 g/day in males.
True/False: Patients with NASH typically have elevated transaminases.
False. Most patients with steatohepatitis have normal liver function tests.
True/False: More than 70% of patients with diabetes have evidence of NAFLD.
True.
• • • SUGGESTED READINGS • • •
Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011;332(6037):1519-1523.
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274-285.
Menon KV, Gores GJ, Shah VH. Pathogenesis, diagnosis, and treatment of alcoholic liver disease. Mayo Clin Proc. 2001 Oct;76(10): 1021-1029.
Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009 Jun. 25;360(26):2758-2769.
Dunn W, Jamil LH, Brown LS, et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology. 2005;41(2): 353-358.