Overall Bottom Line
- AH represents a clinicopathologic spectrum of liver disease, ranging from mild to a severe, life-threatening injury in patients who drink to excess.
- AH is typically characterized by fever, hepatomegaly, jaundice and characteristic laboratory abnormalities, including moderate elevations of AST and ALT (<500 U/L) with AST > ALT.
- The disease may present with liver failure in patients who already have cirrhosis.
- Patients are at high risk for progressive liver injury, renal failure, infection and death.
- Corticosteroids may improve survival in appropriately selected patients.
- The key to long-term treatment success is abstinence from alcohol, usually require ongoing behavioral intervention or alcohol abuse counseling.
Section 1: Background
Definition of disease
- AH is a clinicopathologic syndrome of significant inflammatory liver disease in patients who have high-risk or excessive alcohol ingestion. The diagnosis can be strongly suspected based on clinical and laboratory features indicating liver injury in the setting of heavy ethanol use, with AST and ALT elevations (AST > ALT but both <500 U/L), and further established by liver biopsy demonstrating Mallory’s hyaline, pericentral injury, steatosis and neutrophil infiltration.
- The disease may be classified in terms of severity based on a discriminant function formula or the MELD score (see Section 6).
Incidence/prevalence
- The overall prevalence of alcohol-related disorders has been estimated at 4.65% in the USA by the NIAAA 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (see http://www.niaaa.nih.gov/Resources/DatabaseResources/QuickFacts/AlcoholDependence/Pages/abusdep1.aspx)
- Alcoholic liver disease accounts for up to 20% of all liver transplants in the USA, alone or in conjunction with HCV (www.unos.org).
- Up to 44% of all deaths from liver disease may be attributable to alcohol. Moreover, current prevalence data probably underestimate the true burden of disease.
- In the European Union (see EU Alcohol and Health Forum http://ec.europa.eu/health/alcohol/forum/index_en.htm):
- Fifty-five million adults are estimated to drink at harmful levels in the EU (more than 40 g of alcohol, i.e. four drinks per day for men and over 20 g, i.e. two drinks per day for women). Drinking more than this amount is known to carry a health risk.
- Harmful alcohol consumption is estimated to account for approximately 195 000 deaths a year in the EU due to, e.g. accidents, liver disease, cancers, etc.
- Harmful alcohol use is the third biggest cause of early death and illness in the EU, behind tobacco and high blood pressure.
- Fifty-five million adults are estimated to drink at harmful levels in the EU (more than 40 g of alcohol, i.e. four drinks per day for men and over 20 g, i.e. two drinks per day for women). Drinking more than this amount is known to carry a health risk.
Economic impact
- Alcoholic liver disease exacts a substantial cost exceeding $185 million/year in the USA.
- The cost of alcohol-related harm to the EU’s economy has been estimated at €125 billion for 2003, equivalent to 1.3% of GDP. This estimate includes losses due to underperformance at work, work absenteeism and premature death.
- The actual spending on alcohol-related problems in the EU is estimated at about €66 billion, e.g. on crime, traffic accidents, health and disease treatment and prevention.
Etiology/pathogenesis
- Only about a third of patients with high-risk drinking histories will develop significant liver disease, but the reasons for this variable risk are not fully understood. In fact, the evidence for alcohol-induced liver disease is primarily epidemiologic, not biochemical.
- There are at least five potential pathogenic pathways that contribute to the development of AH:
- LPS from leaky gut, with Kupffer cell activation – the intestinal wall becomes edematous and increased amounts of LPS from gut bacteria leak into the portal blood. Upon arrival in the liver LPS activates Kupffer cells, or resident macrophages, which secrete a number of inflammatory and fibrogenic cytokines including TNF-alpha, transforming growth factor beta 1 and interleukin 1. Direct activation of fibrogenic cells (activated stellate cells) by LPS via TLR4 also contributes to a fibrogenic response.
- Centrilobular hypoxia – as ethanol is metabolized, oxygen is consumed, leading to relative hypoxemia in the region of the hepatic sinusoid furthest from oxygenated blood, which is the central vein. This hypoxemia is compounded by the fact that normally the blood that enters the liver is already hypo-oxygenated, since it is derived primarily from the portal vein.
- Leukocyte infiltration – the infiltration of neutrophils is relatively unique to alcoholic liver disease and these inflammatory cells are a potent source of injurious enzymes and free radicals that damage cells in the liver.
- Lipid peroxidation – alternate pathways of ETOH metabolism – chronic exposure of liver cells to ethanol induces a key alternative pathway to metabolize ethanol through cytochrome P450 2E1 (Cyp2E1). Unlike ethanol metabolism by ADH, Cyp2E1-mediated ethanol metabolism generates free radicals that are injurious to liver cells.
- Acetaldehyde adduct formation – metabolism of ethanol to acetaldehyde allows this reactive metabolite to link with proteins on liver cells to generate neo-antigens. These neo-antigens elicit an immunologic reaction by antibodies and lymphocytes that may attack native proteins on resident liver cells.
- LPS from leaky gut, with Kupffer cell activation – the intestinal wall becomes edematous and increased amounts of LPS from gut bacteria leak into the portal blood. Upon arrival in the liver LPS activates Kupffer cells, or resident macrophages, which secrete a number of inflammatory and fibrogenic cytokines including TNF-alpha, transforming growth factor beta 1 and interleukin 1. Direct activation of fibrogenic cells (activated stellate cells) by LPS via TLR4 also contributes to a fibrogenic response.
Predictive/risk factors
- Amount and duration of intake.
- Gender: females > males.
- Concurrent liver disease: iron overload, HBV, HCV.
- Obesity.
- Genetic factors: determine both risk of alcoholism and likelihood of liver injury after heavy drinking (e.g. PNPLA3 gene variants).
- Family history of alcoholism.
Section 2: Prevention
Bottom Line
- The key to prevention is abstinence:
- Abstinence is the single most important determinant of outcome in patients diagnosed with AH.
- Multiple studies indicate that in patients with alcoholic liver injury, continued alcohol ingestion guarantees that the disease will progress.
- A major responsibility of health professionals caring for patients with alcoholic liver disease is to encourage participation in alcohol abstinence programs.
- Abstinence is the single most important determinant of outcome in patients diagnosed with AH.
Screening
- Screening strategies to identify individuals at risk for high-risk drinking and alcohol abuse are important complements to abstinence efforts in those already diagnosed with alcohol dependence disorders.
- The CAGE screening questions (see next section) are widely used in the USA.
- The AUDIT questionnaire is a more detailed questionnaire developed by the WHO that has 92% sensitivity and specificity of 94%.
Primary and secondary prevention
- Primary prevention is directed at identifying high risk drinking behavior before end-organ damage has occurred. In addition to the CAGE and AUDIT instruments, the National Institute of Alcohol Abuse and Alcoholism has a valuable web tool to educate the public in identifying such behaviors (see http://rethinkingdrinking.niaaa.nih.gov/).
- Enrolment in an alcohol rehabilitation program is an essential step in preventing continued alcohol abuse. Among these, Alcoholics Anonymous and related 12-step programs have the highest rate of long-term success (∼ 50%).
Section 3: Diagnosis
Bottom Line
- Patients with suspected alcoholic liver disease typically underestimate or may even deny alcohol consumption.
- The presence of moderate elevations of AST and ALT (<500 U/L) in which AST > ALT should raise the concern for AH.
- If AH is suspected based on history, yet AST and ALT greatly exceed 500 U/L, then additional etiologies must be considered, especially concurrent acetaminophen usage or viral hepatitis.
- Liver biopsy may be necessary in cases where the diagnosis is in doubt or additional etiologies are suspected. Evidence of Mallory’s hyaline, neutrophil infiltration and a centrizonal distribution of injury are consistent with alcoholic liver injury, but may also be seen in patients with NASH (see Differential diagnosis table that follows).
Differential diagnosis
- Although typical features of alcoholic liver injury are not difficult to identify, the disease may co-exist with other liver diseases, especially viral hepatitis or NAFLD.
| Differential diagnosis | Features |
|---|---|
| NASH | This may be difficult to distinguish from alcoholic liver disease and both may co-exist. A formula (ALD/NAFLD Index – ANI) to distinguish the two may be useful: ANI Score = −58.5 + 0.637(MCV) + 3.91 (AST/ALT) − 0.406 (BMI) + 6.35 for male gender
|
| Viral hepatitis | Evidence of serologic markers or viremia, consistent with viral liver disease Liver biopsy evidence of periportal, not pericentral, mononuclear leukocyte infiltration |
| Amiodarone hepatotoxicity | History of amiodarone use Liver biopsy with characteristic lamellar lysosomal inclusion bodies |
| Autoimmune hepatitis | Presence of serum autoimmune markers and elevated gamma globulin Liver biopsy with plasma cell infiltration and immune cells |
Typical presentation
- The typical patient with alcoholic liver disease is asymptomatic for long periods despite sustained high-risk drinking behavior before coming to medical attention. In such a patient, the diagnosis only becomes apparent following review of standard liver chemistry studies demonstrating characteristic abnormalities. It is not unusual for patients to deny heavy alcohol use or underestimate their intake, which is why instruments such as the CAGE and AUDIT questions are so valuable.
- As liver disease becomes more symptomatic, patients may present with anorexia, RUQ discomfort, jaundice, coagulopathy, and stigmata of liver disease. Fever may be present, and infection must be excluded in such patients.
Related posts:
24: Portopulmonary Hypertension
25: Pregnancy-Related Liver Disease
38: Liver Transplantation: A Pediatric Perspective
36: Approach to Jaundice in Infancy
53: Recurrent Disease Post-Liver Transplantation: Autoimmune Diseases, Hepatitis B and NASH
34: Diagnosis and Management of Acute Liver Failure: A Pediatric Perspective
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