ACUTE ALCOHOLIC HEPATITIS

ACUTE ALCOHOLIC HEPATITIS
By Dr Langlet Philippe, Hepato-gastroenterology department, Brugmann University Hospital, Brussels.
Summary
1.Clinical presentation2.Investigations3.Prognosis4.Therapy5.Conclusions

1. CLINICAL PRESENTATION
Epidemiology
Alcoholic liver disease (ALD) is one of the major medical complications of alcohol abuse and a major health economic problem in the western world.Alcohol is the major cause of liver cirrhosis in the Western world whereas alcoholic cirrhosis is responsible for approximately 44% of the 26000 death cirrhosis in the United States each years.
Safe limits for alcohol intake
The safe limits for alcohol intake are controversial but it is generally advised a weekly limit of 21 units (210g) of alcohol in men and 14 units in women.Although there is steep dose dependent increase in ALD risk above this threshold with increasing alcohol intake, there is an heterogeneity of the patient population with regard to disease severity and individual susceptibility to alcohol-related liver injury.

Factors increasing susceptibility to ALD
- Women at any given level of intake. - Lifetime intake of alcohol - Genetic factors - Drinking without food - Binge drinking - High concentration alcoholic drinks (spirits,…) - Drinking multiple different alcoholic beverages
It is estimated ,as shown in Figure 1, that although 90-100% of heavy drinkers show evidence of fatty liver, only 10-35% develop alcoholic hepatitis and 8-20% develop cirrhosis.


Figure 1.
Progression of alcoholic liver diseasein heavy drinkers.

Spectrum of liver disease
The three most widely recognised forms of ALD are alcoholic fatty liver (steatosis), acute alcoholic hepatitis, and alcoholic cirrhosis.
Steatosis appears invariably if consumption exceeds 80 g of alcohol per day. In this pathology, cytoplasm of affected hepatocytes is occupied by a single large triglyceride occlusion. Liver function is often normal and steatosis is reversible with abstinence.
Acute Alcoholic hepatitis
In alcoholic hepatitis , the typical histologic picture includes hepatocellular necrosis and ballooning degeneration, alcoholic Mallory's hyaline bodies and an inflammatory reaction with many polymorphonuclear leukocytes (sattelitosis). It is estimated that 15-20 years of excessive drinking is necessary to develop alcoholic hepatitis. Cholestasis is prominent. It is more severe in females and also in Nothern Europeans and unrelated to pattern of drinking or type of alcohol drink. High mortality rates are seen (30-60%) and patients often deteriorate after hospital admission despite abstinence. Alcoholic hepatitis has been established as an important precursor to the formation of cirrhosis.
Cirrhosis
The most severe form of alcoholic liver injury and usually of the micronodular type. The risk is increased in continuous drinkers. Survival for patients is 60%-70% at one year and 35%-50% at five years.
Pathogenesis
Most evidence indicates that the principal cause of alcohol-induced liver injury is cellular toxicity resulting from acetaldehyde.Ethanol is oxidised to acetaldehyde in the mitochondria by alcohol dehydrogenase, which in turn is oxidised to acetate by acetaldehyde dehydrogenase. These oxydation reactions alter the cellular metabolism with harmful effects on lipid and carbohydrate metabolism- for example, steatosis. Oxygen derived free radicals may cause direct hepatocyte injury by lipid peroxydation whereas acetaldehyde binds covalently to proteins forming adducts and may serve as neoantigens. This binding initiates harmful humoral and/or cellular immune responses, which leads to tissue injury.
The expression of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-a), transforming growth factor-beta (TGF-ß), interleukin (IL)-1ß and IL-6 are increased in alcoholic liver injury while the anti-inflammatory cytokine, IL-4 is decreased. These cytokines stimulate stellate cells which produce collagen leading to liver fibrosis. Moreover, in patients with alcoholic hepatitis, malnutrition leads to a reduction of the antioxydant defence mechanisms and contribute to the development of alcohol induced injury.
Clinical presentation
The clinical presentation of alcoholic hepatitis varies greatly with the severity of disease. Common symptoms are weakness, anorexia, weight loss, nausea, vomiting and diarrhea. Patients with alcoholic hepatitis are often malnourished and pyrexial. Pain in the right upper quadrant, jaundice, and fever may be present and can wrongly lead to a diagnosis of biliary tract disease. On physical examination, there is often marked hepatomegaly which is tender on palpation. Hepatic bruits may be heard. Splenomegaly is uncommon. Ascites and hepatic encepalopathy are common in severe disease but varices are not common.
Upper gastrointestinal bleeding does occur but is usually due to gastric erosions or peptic ulceration on a backgroung of coagulopathy Infections are very common.Often patients have co-existence of alcoholic hepatitis and cirrhosis with clinical features such as spider telangiectasia, parotid enlargement, gynecomastia.


2. INVESTIGATIONS
Laboratory findings
Table 1.Common laboratory findings in alcoholic hepatitis
Leukocytosis with shift to the left AST 2 to 3 times higher than ALT (ALT usually < 100 IU/L) Increased serum bilirubin level; correlates with severityProlonged prothrombin time; correlates with severity Decreased serum albumin level Increased serum IgA and IgG levelsDecreased serum cholesterol levelDecreased serum triiodothyronine level
-Serum transaminases levels are often not greatly raised in ALD and values greater than five times the upper limit of the normal reference range should lead to consideration of other diagnoses such as viral or autoimmune hepatitis.- Hyperbilirubinemia reflects the severity of the hepatitis and could be greatly increased in alcoholic hepatitis.- Prolongation of the prothrombin time and hypoalbuminemia reflect poor hepatic synthetic function.- Leukocytosis is common and a count of polymorphonuclear leukocytes greater than 5500/mm3 could be associated with a better response to the corticotherapy.
Ultrasonography
Ulrasound scanning can help eliminate the possibility of biliary tract disease in jaundiced and febrile patients.An irregular shrunken liver suggests severe cirrhosis while additional signs such as ascites, varices and splenomegaly.
Liver biopsy
Liver biopsy is necessary to confirm the diagnosis, to assess the extend of liver injury and to provide a prognostic guide.The coagulopathy often associated to severe alcoholic hepatitis may necessitate using the transjugular venous route for performing the biopsy.

3. PROGNOSIS
In patients with severe disease, the 30-day mortality rate approaches 50% but in all patients with alcoholic hepatitis the overall 30-day mortality rate is about 15%.
The Maddrey's discriminant function following the below formula has the best correlation and the highest positive predictive value to predict the 30-day mortality. Discriminant function: (4,6 X ptothrombin time prolongation in seconds) + bilirubin (mg/dL).Values above 32 indicate severe disease. The prognostic value of this formula has been prospectively confirmed and appears to be the most clinically helpful for therapeutic decisions when severity of illness determines treatment.
Others factors that correlate with poor prognosis include older age, impaired renal function, encephalopathy, and a rise in the white blood cell count in the first 2 weeks of hospitalization.





4. THERAPY
The most important aspect of treatment is abstinence from alcohol
Mild disease
Patients with mild to moderate disease usually survive this stage of their illness as long as they abstain from alcohol use.
Severe disease
Patients with severe alcoholic hepatitis (Maddrey's score above 32) require active, specific treatment to alter the grim, high short-mortality rate.
As shown in table 2, there have been a number of therapeutic agents that have undergone clinical testing for alcoholic hepatitis. Among all of these therapies, only corticosteroids and total enteral nutrition have clearly shown benefit.

Table 2
Propylthiouaril Colchicine Corticosteroids Insulin/glucagon (intravenous Anabolic steroids) Testosterone OxandroloneTotal enteral nutrition Antioxydants ?
Corticosteroids
Corticosteroids have been the most controversial therapy in alcoholic hepatitis. More than 40 studies have been conducted to test the effect of this treatment. Recent two meta-analyses of 11 randomized control trials are more in favor of corticosteroid therapy for patients with severe disease and spontaneous hepatic encephalopathy. However steroids seems to have a beneficial effect on short term survival but not on long-term survival. Recent study has shown that enteral nutrition was associated with a better long-term outcome compared with corticosteroids. Actually no single therapy had had universally miraculous success.
Nutritional support
Because patients with alcoholic hepatitis often have protein-calorie malnutrition, nutritional support has been a tempting therapeutic option. Recent data have clearly shown that total enteral nutrition (20-30 kcal/kg/day) is actually the treatment of choice because of the beneficial effect on long-term outcome with a decrease of the infections rate.
Liver transplantation
Orthotopic liver transplantation has been shown to be the chief therapeutic option for patients with end-stage alcoholic liver disease. An abstinence of 3 to 6 months before operation is required to have a low rate of alcohol abuse recidivism after transplantation.


5. CONCLUSIONS
Alcoholic hepatitis is a necrotizing, inflammatory process often leading to cirrhosis or death. The diagnosis of this severe condition necessitates to perform liver biopsy.
The pathogenesis is not fully understood although significant progress has been achieved recently. The prognosis is poor in severe disease when alterations of prothombin time and serum bilirubin levels are marked. Abstinence from alcohol and appropriate total enteral nutrition are probably the most effective current treatment.
There is renewed interest in the use of corticosteroids in severe disease. Orthotopic liver transplantation is appropriate for some patients with end-stage liver disease.