Alcoholic Liver DiseaseAlcoholic Liver Disease

Presentation: Dr. Sundar Karki Presentation: Dr. Sundar Karki

Introduction Introduction Chronic and excessive alcohol ingestion is one Chronic and excessive alcohol ingestion is one

of the major causes of liver disease. The of the major causes of liver disease. The pathology of alcoholic liver disease comprises pathology of alcoholic liver disease comprises three major lesions, with the injury rarely three major lesions, with the injury rarely existing in a pure form: (1) fatty liver, (2) existing in a pure form: (1) fatty liver, (2) alcoholic hepatitis, and (3) cirrhosis. alcoholic hepatitis, and (3) cirrhosis.

Fatty liver is present in >90% of binge and Fatty liver is present in >90% of binge and chronic drinkers. A much smaller percentage chronic drinkers. A much smaller percentage of heavy drinkers will progress to alcoholic of heavy drinkers will progress to alcoholic hepatitis, thought to be a precursor to cirrhosis. hepatitis, thought to be a precursor to cirrhosis.

Risk Factors Risk Factors

Quantity and duration of alcohol intake are the Quantity and duration of alcohol intake are the most important risk factors involved in the devmost important risk factors involved in the development of alcoholic liver disease. The roles elopment of alcoholic liver disease. The roles of beverage type(s), i.e. wine, beer, or spirits, aof beverage type(s), i.e. wine, beer, or spirits, and pattern of drinking are less clear .nd pattern of drinking are less clear .

Progress of the hepatic injury beyond the fatty Progress of the hepatic injury beyond the fatty liver stage seems to require additional risk factliver stage seems to require additional risk factors that remain incompletely defined. ors that remain incompletely defined.

Risk factors Risk factors

In general, the time it takes to develop liver disease is dIn general, the time it takes to develop liver disease is directly related to the amount of alcohol consumed. It is irectly related to the amount of alcohol consumed. It is useful in estimating alcohol consumption to understand useful in estimating alcohol consumption to understand that one beer, four ounces of wine, or one ounce of 80% that one beer, four ounces of wine, or one ounce of 80% spirits all contain ~12 g of alcohol. spirits all contain ~12 g of alcohol.

The threshold for developing alcoholic liver disease in The threshold for developing alcoholic liver disease in men is an intake of >60–80 g/d of alcohol for 10 years, men is an intake of >60–80 g/d of alcohol for 10 years, while women are at increased risk for developing similawhile women are at increased risk for developing similar degrees of liver injury by consuming 20–40 g/d. Ingesr degrees of liver injury by consuming 20–40 g/d. Ingestion of 160 g/d is associated with 25–fold increased risk tion of 160 g/d is associated with 25–fold increased risk of developing alcoholic cirrhosis. of developing alcoholic cirrhosis.

Risk Factors Risk Factors Quantity: In men, 40–80 g/d of ethanol produces fatty Quantity: In men, 40–80 g/d of ethanol produces fatty

liver; 160 g/d for 10–20 years causes hepatitis or cirrhliver; 160 g/d for 10–20 years causes hepatitis or cirrhosis. Only 15% of alcoholics develop alcoholic liver diosis. Only 15% of alcoholics develop alcoholic liver disease.sease.

Gender: Women exhibit increased susceptibility to alcGender: Women exhibit increased susceptibility to alcoholic liver disease at amounts >20 g/d.oholic liver disease at amounts >20 g/d.

Hepatitis C: HCV infection concurrent with alcoholic lHepatitis C: HCV infection concurrent with alcoholic liver disease is associated with younger age for severity,iver disease is associated with younger age for severity, more advanced histology, decreased survival. Even m more advanced histology, decreased survival. Even moderate alcohol intake of 20–50 g/d increases the risk ooderate alcohol intake of 20–50 g/d increases the risk of cirrhosis and hepatocellular cancer in HCV-infected if cirrhosis and hepatocellular cancer in HCV-infected individuals.ndividuals.

Risk Factors Risk Factors

Genetics: Alcoholism is more common in monozygotGenetics: Alcoholism is more common in monozygotic than dizygotic twins. However, polymorphisms in tic than dizygotic twins. However, polymorphisms in the genes involved in alcohol metabolism, such as aldhe genes involved in alcohol metabolism, such as aldehyde dehydrogenase (ALD), have yet to be linked to ehyde dehydrogenase (ALD), have yet to be linked to alcoholic liver disease.alcoholic liver disease.

Malnutrition: Alcohol injury does not require malnutMalnutrition: Alcohol injury does not require malnutrition, but obesity and fatty liver from the effect of carition, but obesity and fatty liver from the effect of carbohydrate on the transcriptional control of lipid syntrbohydrate on the transcriptional control of lipid synthesis and transport may be factors. Patients should rehesis and transport may be factors. Patients should receive vigorous attention.ceive vigorous attention.

Metabolism of Alcohol Metabolism of Alcohol Alcohol is metabolised almost exclusively by the Alcohol is metabolised almost exclusively by the

liver via one of two main pathways.liver via one of two main pathways. Eighty per cent of alcohol is metabolised to acetaEighty per cent of alcohol is metabolised to aceta

ldehyde by the mitochondrial enzyme, alcohol deldehyde by the mitochondrial enzyme, alcohol dehydrogenase (ADH). Acetaldehyde forms adducthydrogenase (ADH). Acetaldehyde forms adducts with cellular proteins in hepatocytes which actis with cellular proteins in hepatocytes which activate the immune system, leading to cell injury. Avate the immune system, leading to cell injury. Acetaldehyde is then metabolised to acetyl-CoA acetaldehyde is then metabolised to acetyl-CoA and acetate by ALD. This generates NADH from nd acetate by ALD. This generates NADH from NAD (nicotinamide adenine dinucleotide), which NAD (nicotinamide adenine dinucleotide), which changes the redox potential of the cell. changes the redox potential of the cell.

Metabolism of Alcohal Metabolism of Alcohal The remaining 20% is metabolised by the mixed function oxidasThe remaining 20% is metabolised by the mixed function oxidas

e enzymes of the smooth endoplasmic reticulum. Cytochrome Ce enzymes of the smooth endoplasmic reticulum. Cytochrome CYP2E1 is an enzyme which oxidises ethanol to acetate. It is indYP2E1 is an enzyme which oxidises ethanol to acetate. It is induced by alcohol, and during metabolism of ethanol it releases oxuced by alcohol, and during metabolism of ethanol it releases oxygen free radicals, leading to lipid peroxidation which can inducygen free radicals, leading to lipid peroxidation which can induce mitochondrial damage. The CYP2E1 enzyme also metabolises e mitochondrial damage. The CYP2E1 enzyme also metabolises acetaminophen and hence chronic alcoholics are more susceptibacetaminophen and hence chronic alcoholics are more susceptible to hepatotoxicity from low doses of paracetamol. le to hepatotoxicity from low doses of paracetamol.

It is thought that pro-inflammatory cytokines may also be involvIt is thought that pro-inflammatory cytokines may also be involved in inducing hepatic damage in alcoholic hepatitis, since endoted in inducing hepatic damage in alcoholic hepatitis, since endotoxin is released into the blood because of increased gut permeaboxin is released into the blood because of increased gut permeability, leading to release of TNF-α, IL-1, IL-2 and IL-8 from immility, leading to release of TNF-α, IL-1, IL-2 and IL-8 from immune cells. All of these cytokines have been implicated in the patune cells. All of these cytokines have been implicated in the pathogenesis of liver fibrosis. hogenesis of liver fibrosis.

PathologyPathology

Alcohol can produce a wide spectrum of liver Alcohol can produce a wide spectrum of liver disease from fatty change to hepatitis and cirrhdisease from fatty change to hepatitis and cirrhosis. osis.

Pathology- Fatty liver Pathology- Fatty liver The metabolism of alcohol invariably produces fat in the liver. The metabolism of alcohol invariably produces fat in the liver.

This is minimal with small amounts of alcohol, but with larger This is minimal with small amounts of alcohol, but with larger amounts, the cells become swollen with fat amounts, the cells become swollen with fat (steatosis(steatosis) giving e) giving eventually, a Swiss-cheese effect on haematoxylin and eosin staventually, a Swiss-cheese effect on haematoxylin and eosin stain. Steatosis can also be seen in obesity, diabetes, starvation anin. Steatosis can also be seen in obesity, diabetes, starvation and occasionally in chronic illness . There is d occasionally in chronic illness . There is no liver cell damageno liver cell damage.. The fat disappears on stopping alcohol. The fat disappears on stopping alcohol.

In some cases collagen is laid down around the central hepatic In some cases collagen is laid down around the central hepatic veins (perivenular fibrosis) and this can sometimes progress to veins (perivenular fibrosis) and this can sometimes progress to cirrhosis without a preceding hepatitis. Alcohol directly affects cirrhosis without a preceding hepatitis. Alcohol directly affects stellate cells, transforming them into collagen-producing myofstellate cells, transforming them into collagen-producing myofibroblast cells. Cirrhosis might then develop if there is an imbaibroblast cells. Cirrhosis might then develop if there is an imbalance between degradation and production of collagen. lance between degradation and production of collagen.

Pathology- Alcoholic Hepatitis Pathology- Alcoholic Hepatitis

In addition to fatty change there is infiltration by polyIn addition to fatty change there is infiltration by polymorphonuclear leucocytes and hepatocyte necrosis. Dmorphonuclear leucocytes and hepatocyte necrosis. Dense cytoplasmic inclusions called ense cytoplasmic inclusions called Mallory bodiesMallory bodies are are sometimes seen in hepatocytes and sometimes seen in hepatocytes and giant mitochondrigiant mitochondriaa are also a feature. are also a feature.

Mallory bodies are suggestive of, but not specific for, Mallory bodies are suggestive of, but not specific for, alcoholic damage as they can be found in other liver dalcoholic damage as they can be found in other liver disease, such as Wilson's disease and Primary Biliary isease, such as Wilson's disease and Primary Biliary Cirrhosis. If alcohol consumption continues,alcoholic Cirrhosis. If alcohol consumption continues,alcoholic hepatitis may progress to cirrhosis. hepatitis may progress to cirrhosis.

Pathology- Alcoholic Cirrhosis Pathology- Alcoholic Cirrhosis

This is classically of the micronodular type, buThis is classically of the micronodular type, but a mixed pattern may also be seen accompanyit a mixed pattern may also be seen accompanying fatty change, and evidence of pre-existing ang fatty change, and evidence of pre-existing alcoholic hepatitis may be present. lcoholic hepatitis may be present.

Clinical Features- Fatty liver Clinical Features- Fatty liver

There are often no symptoms or signs. Vague There are often no symptoms or signs. Vague abdominal symptoms of nausea, vomiting and abdominal symptoms of nausea, vomiting and diarrhoea are due to the more general effects odiarrhoea are due to the more general effects of alcohol on the gastrointestinal tract. f alcohol on the gastrointestinal tract.

Hepatomegaly, sometimes huge, can occur togHepatomegaly, sometimes huge, can occur together with other features of chronic liver diseasether with other features of chronic liver disease. e.

Clinical Features- Alcoholic HepatitisClinical Features- Alcoholic Hepatitis The clinical features vary in degree: The clinical features vary in degree: The patient may be well, with few symptoms, the hepatitis only The patient may be well, with few symptoms, the hepatitis only

being apparent on the liver biopsy in addition to fatty change. being apparent on the liver biopsy in addition to fatty change. Mild to moderate symptoms of ill-health, occasionally with milMild to moderate symptoms of ill-health, occasionally with mil

d jaundice, may occur. Signs include all the features of chronic d jaundice, may occur. Signs include all the features of chronic liver disease. Liver biochemistry is deranged and the diagnosis liver disease. Liver biochemistry is deranged and the diagnosis is made on liver histology. is made on liver histology.

In the severe case, usually superimposed on patients with alcohIn the severe case, usually superimposed on patients with alcoholic cirrhosis, the patient is ill, with jaundice and ascites. Abdoolic cirrhosis, the patient is ill, with jaundice and ascites. Abdominal pain is frequently present, with a high fever associated wminal pain is frequently present, with a high fever associated with the liver necrosis. On examination there is deep jaundice, heith the liver necrosis. On examination there is deep jaundice, hepatomegaly, sometimes splenomegaly, and ascites with ankle opatomegaly, sometimes splenomegaly, and ascites with ankle oedema. edema.

Clinical Features- Alcoholic cirrhosisClinical Features- Alcoholic cirrhosis

This represents the final stage of liver disease fThis represents the final stage of liver disease from alcohol abuse. Nevertheless, patients can rom alcohol abuse. Nevertheless, patients can be very well with few symptoms. On examinatbe very well with few symptoms. On examination, there are usually signs of chronic liver dision, there are usually signs of chronic liver disease. The diagnosis is confirmed by liver biopsease. The diagnosis is confirmed by liver biopsy. y.

Alcohol-induced cirrhosis often presents with Alcohol-induced cirrhosis often presents with a serious complication such as variceal haemora serious complication such as variceal haemorrhage or ascites.rhage or ascites.

Laboratory Investigation Laboratory Investigation The typical laboratory abnormalities seen in fatty liveThe typical laboratory abnormalities seen in fatty live

r are nonspecific and include modest elevations of the r are nonspecific and include modest elevations of the aspartate aminotransferase (AST), alanine aminotransaspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase ferase (ALT), and gamma-glutamyl transpeptidase (GGTP), accompanied by hypertriglyceridemia, hype(GGTP), accompanied by hypertriglyceridemia, hypercholesterolemia, and occasionally hyperbilirubinemircholesterolemia, and occasionally hyperbilirubinemia. a.

In alcoholic hepatitis and in contrast to other causes oIn alcoholic hepatitis and in contrast to other causes of fatty liver, the AST and ALT are usually elevated twf fatty liver, the AST and ALT are usually elevated two- to sevenfold. They are rarely >400 IU, and the ASo- to sevenfold. They are rarely >400 IU, and the AST/ALT ratio >1 T/ALT ratio >1

Laboratory Investigation Laboratory Investigation Hyperbilirubinemia is common and is accompanied bHyperbilirubinemia is common and is accompanied b

y modest increases in the alkaline phosphatase level. y modest increases in the alkaline phosphatase level. Derangement in hepatocyte synthetic function indicatDerangement in hepatocyte synthetic function indicates more serious disease. Hypoalbuminemia and coagues more serious disease. Hypoalbuminemia and coagulopathy are common in advanced liver injury. lopathy are common in advanced liver injury.

Ultrasonography is useful in detecting fatty infiltratioUltrasonography is useful in detecting fatty infiltration of the liver and determining liver size. The demonstn of the liver and determining liver size. The demonstration by ultrasound of portal vein flow reversal, ascitration by ultrasound of portal vein flow reversal, ascites, and intraabdominal collaterals indicates serious lives, and intraabdominal collaterals indicates serious liver injury with less potential for complete reversal of lier injury with less potential for complete reversal of liver disease. ver disease.

ManagementManagement

Complete abstinence from alcohol is the cornerstone iComplete abstinence from alcohol is the cornerstone in the treatment of alcoholic liver disease. Improved sn the treatment of alcoholic liver disease. Improved survival and the potential for reversal of histologic injurvival and the potential for reversal of histologic injury regardless of the initial clinical presentation are asury regardless of the initial clinical presentation are associated with total avoidance of alcohol ingestion. sociated with total avoidance of alcohol ingestion.

Referral of patients to experienced alcohol counselors Referral of patients to experienced alcohol counselors and/or alcohol treatment programs should be routine iand/or alcohol treatment programs should be routine in the management of patients with alcoholic liver disen the management of patients with alcoholic liver disease. ase.

Management Management

Attention should be directed to the nutritional and psyAttention should be directed to the nutritional and psychosocial states during the evaluation and treatment pchosocial states during the evaluation and treatment periods. Because of data suggesting that the pathogenic eriods. Because of data suggesting that the pathogenic mechanisms in alcoholic hepatitis involve cytokine remechanisms in alcoholic hepatitis involve cytokine release and the perpetuation of injury by immunologic lease and the perpetuation of injury by immunologic processes, glucocorticoids have been extensively evalprocesses, glucocorticoids have been extensively evaluated in the treatment of alcoholic hepatitis. uated in the treatment of alcoholic hepatitis.

Patients with severe alcoholic hepatitis, defined as a dPatients with severe alcoholic hepatitis, defined as a discriminant function > 32, were given prednisolone, 3iscriminant function > 32, were given prednisolone, 32 mg/d, for 4 weeks followed by a steroid taper .2 mg/d, for 4 weeks followed by a steroid taper .

Management Management

Pentoxifylline, which has a weak anti-TNF action, maPentoxifylline, which has a weak anti-TNF action, may also be beneficial and is alternative to the corticostey also be beneficial and is alternative to the corticosteroid in severe alcoholic hepatitis. It appears to reduce roid in severe alcoholic hepatitis. It appears to reduce the incidence of hepatorenal failure and its use is not the incidence of hepatorenal failure and its use is not complicated by sepsis.complicated by sepsis.

In the acute presentation of alcoholic liver disease it iIn the acute presentation of alcoholic liver disease it is also important to identify and anticipate alcohol wits also important to identify and anticipate alcohol withdrawal and Wernicke's encephalopathy, which need hdrawal and Wernicke's encephalopathy, which need treating in parallel with the liver disease treating in parallel with the liver disease

Management Management

Treatment for complications of cirrhosis, such Treatment for complications of cirrhosis, such as variceal bleeding, encephalopathy and ascitas variceal bleeding, encephalopathy and ascites, may also be needed. es, may also be needed.

A trial of abstention to establish if liver disease A trial of abstention to establish if liver disease can improve is mandatory, but transplantation can improve is mandatory, but transplantation should not be denied if the patient continues to should not be denied if the patient continues to deteriorate. deteriorate.

Liver Transplantation Liver Transplantation

The role of liver transplantation in the management of The role of liver transplantation in the management of alcoholic liver disease remains controversial. In many alcoholic liver disease remains controversial. In many centres, however, alcoholic liver disease is a common centres, however, alcoholic liver disease is a common indication for liver transplantation. The challenge is tindication for liver transplantation. The challenge is to identify patients with an unacceptable risk of returnio identify patients with an unacceptable risk of returning to harmful alcohol consumption. ng to harmful alcohol consumption.

Many programmes require a 6-month period of abstinMany programmes require a 6-month period of abstinence from alcohol before a patient is considered for trence from alcohol before a patient is considered for transplantation ansplantation

Liver TransplantationLiver Transplantation

Although this relates poorly to the incidence of alcohAlthough this relates poorly to the incidence of alcohol relapse after transplantation, liver function may imol relapse after transplantation, liver function may improve to the extent that transplantation is no longer neprove to the extent that transplantation is no longer necessary.cessary.

The outcome of transplantation for alcoholic liver disThe outcome of transplantation for alcoholic liver disease is good (if the patient remains abstinent) because ease is good (if the patient remains abstinent) because minimal immunosuppression is often required and theminimal immunosuppression is often required and there is no risk of disease recurrence.re is no risk of disease recurrence.

Transplantation for alcoholic hepatitis has a poorer oTransplantation for alcoholic hepatitis has a poorer outcome than for complications of alcoholic cirrhosis. utcome than for complications of alcoholic cirrhosis.

Prognosis Prognosis

Critically ill patients with alcoholic hepatitis have shoCritically ill patients with alcoholic hepatitis have short-term (30 day) mortality rates >50%. Severe alcoholrt-term (30 day) mortality rates >50%. Severe alcoholic hepatitis is heralded by coagulopathy (prothrombin ic hepatitis is heralded by coagulopathy (prothrombin time > 5 s), anemia, serum albumin concentrations <2time > 5 s), anemia, serum albumin concentrations <25 g/L (2.5 mg/dL), serum bilirubin levels > 137 mol/5 g/L (2.5 mg/dL), serum bilirubin levels > 137 mol/L (8 mg/dL), renal failure, and ascites. L (8 mg/dL), renal failure, and ascites.

A A discriminant functiondiscriminant function calculated as 4.6 x [prothro calculated as 4.6 x [prothrombin time control (seconds)] + serum bilirubin (mg/dmbin time control (seconds)] + serum bilirubin (mg/dL) can identify patients with a poor prognosis (discriL) can identify patients with a poor prognosis (discriminant function > 32). minant function > 32).

Prognosis Prognosis

The presence of ascites, variceal hemorrhage, The presence of ascites, variceal hemorrhage, deep encephalopathy, or hepatorenal syndrome deep encephalopathy, or hepatorenal syndrome predicts a dismal prognosis. The pathologic stapredicts a dismal prognosis. The pathologic stage of the injury can be helpful in predicting prge of the injury can be helpful in predicting prognosis ognosis

Liver biopsy should be performed whenever pLiver biopsy should be performed whenever possible to confirm the diagnosis, to establish possible to confirm the diagnosis, to establish potential reversibility of the liver disease, and to otential reversibility of the liver disease, and to guide the therapeutic decisions. guide the therapeutic decisions.

ReferencesReferences

Harrison’s Principle of Internal Medicine 17Harrison’s Principle of Internal Medicine 17 thth edition edition

Davidson’s Principle and Practice of Medicine Davidson’s Principle and Practice of Medicine 2121stst edition edition

Kumar and Clark Clinical Medicine 6Kumar and Clark Clinical Medicine 6 thth edition edition