Alcoholic liver disease  by dr. sundar karki
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Alcoholic liver disease

Alcoholic liver disease

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Alcoholic liver disease  by dr. sundar karki Alcoholic liver disease by dr. sundar karki Presentation Transcript

  • Alcoholic Liver DiseaseAlcoholic Liver Disease Presentation: Dr. Sundar KarkiPresentation: Dr. Sundar Karki
  • IntroductionIntroduction  Chronic and excessive alcohol ingestion is oneChronic and excessive alcohol ingestion is one of the major causes of liver disease. Theof the major causes of liver disease. The pathology of alcoholic liver disease comprisespathology of alcoholic liver disease comprises three major lesions, with the injury rarelythree 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 andFatty liver is present in >90% of binge and chronic drinkers. A much smaller percentagechronic drinkers. A much smaller percentage of heavy drinkers will progress to alcoholicof heavy drinkers will progress to alcoholic hepatitis, thought to be a precursor to cirrhosis.hepatitis, thought to be a precursor to cirrhosis.
  • Risk FactorsRisk Factors  Quantity and duration of alcohol intake are theQuantity and duration of alcohol intake are the most important risk factors involved in themost important risk factors involved in the development of alcoholic liver disease. Thedevelopment of alcoholic liver disease. The roles of beverage type(s), i.e. wine, beer, orroles of beverage type(s), i.e. wine, beer, or spirits, and pattern of drinking are less clear .spirits, and pattern of drinking are less clear .  Progress of the hepatic injury beyond the fattyProgress of the hepatic injury beyond the fatty liver stage seems to require additional riskliver stage seems to require additional risk factors that remain incompletely defined.factors that remain incompletely defined.
  • Risk factorsRisk factors  In general, the time it takes to develop liver disease isIn general, the time it takes to develop liver disease is directly related to the amount of alcohol consumed. Itdirectly related to the amount of alcohol consumed. It is useful in estimating alcohol consumption tois useful in estimating alcohol consumption to understand that one beer, four ounces of wine, or oneunderstand that one beer, four ounces of wine, or one ounce of 80% spirits all contain ~12 g of alcohol.ounce of 80% spirits all contain ~12 g of alcohol.  The threshold for developing alcoholic liver diseaseThe threshold for developing alcoholic liver disease in men is an intake of >60–80 g/d of alcohol for 10in men is an intake of >60–80 g/d of alcohol for 10 years, while women are at increased risk foryears, while women are at increased risk for developing similar degrees of liver injury bydeveloping similar degrees of liver injury by consuming 20–40 g/d. Ingestion of 160 g/d isconsuming 20–40 g/d. Ingestion of 160 g/d is associated with 25–fold increased risk of developingassociated with 25–fold increased risk of developing alcoholic cirrhosis.alcoholic cirrhosis.
  • Risk FactorsRisk Factors  Quantity: In men, 40–80 g/d of ethanol produces fattyQuantity: In men, 40–80 g/d of ethanol produces fatty liver; 160 g/d for 10–20 years causes hepatitis orliver; 160 g/d for 10–20 years causes hepatitis or cirrhosis. Only 15% of alcoholics develop alcoholiccirrhosis. Only 15% of alcoholics develop alcoholic liver disease.liver disease.  Gender: Women exhibit increased susceptibility toGender: Women exhibit increased susceptibility to alcoholic liver disease at amounts >20 g/d.alcoholic liver disease at amounts >20 g/d.  Hepatitis C: HCV infection concurrent with alcoholicHepatitis C: HCV infection concurrent with alcoholic liver disease is associated with younger age forliver disease is associated with younger age for severity, more advanced histology, decreased survival.severity, more advanced histology, decreased survival. Even moderate alcohol intake of 20–50 g/d increasesEven moderate alcohol intake of 20–50 g/d increases the risk of cirrhosis and hepatocellular cancer in HCV-the risk of cirrhosis and hepatocellular cancer in HCV- infected individuals.infected individuals.
  • Risk FactorsRisk Factors  Genetics: Alcoholism is more common inGenetics: Alcoholism is more common in monozygotic than dizygotic twins. However,monozygotic than dizygotic twins. However, polymorphisms in the genes involved in alcoholpolymorphisms in the genes involved in alcohol metabolism, such as aldehyde dehydrogenase (ALD),metabolism, such as aldehyde dehydrogenase (ALD), have yet to be linked to alcoholic liver disease.have yet to be linked to alcoholic liver disease.  Malnutrition: Alcohol injury does not requireMalnutrition: Alcohol injury does not require malnutrition, but obesity and fatty liver from themalnutrition, but obesity and fatty liver from the effect of carbohydrate on the transcriptional controleffect of carbohydrate on the transcriptional control of lipid synthesis and transport may be factors.of lipid synthesis and transport may be factors. Patients should receive vigorous attention.Patients should receive vigorous attention.
  • Metabolism of AlcoholMetabolism of Alcohol  Alcohol is metabolised almost exclusively by theAlcohol 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 toEighty per cent of alcohol is metabolised to acetaldehyde by the mitochondrial enzyme,acetaldehyde by the mitochondrial enzyme, alcohol dehydrogenase (ADH). Acetaldehydealcohol dehydrogenase (ADH). Acetaldehyde forms adducts with cellular proteins informs adducts with cellular proteins in hepatocytes which activate the immune system,hepatocytes which activate the immune system, leading to cell injury. Acetaldehyde is thenleading to cell injury. Acetaldehyde is then metabolised to acetyl-CoA and acetate by ALD.metabolised to acetyl-CoA and acetate by ALD. This generates NADH from NAD (nicotinamideThis generates NADH from NAD (nicotinamide adenine dinucleotide), which changes the redoxadenine dinucleotide), which changes the redox potential of the cell.potential of the cell.
  • Metabolism of AlcohalMetabolism of Alcohal  The remaining 20% is metabolised by the mixed functionThe remaining 20% is metabolised by the mixed function oxidase enzymes of the smooth endoplasmic reticulum.oxidase enzymes of the smooth endoplasmic reticulum. Cytochrome CYP2E1 is an enzyme which oxidises ethanol toCytochrome CYP2E1 is an enzyme which oxidises ethanol to acetate. It is induced by alcohol, and during metabolism ofacetate. It is induced by alcohol, and during metabolism of ethanol it releases oxygen free radicals, leading to lipidethanol it releases oxygen free radicals, leading to lipid peroxidation which can induce mitochondrial damage. Theperoxidation which can induce mitochondrial damage. The CYP2E1 enzyme also metabolises acetaminophen and henceCYP2E1 enzyme also metabolises acetaminophen and hence chronic alcoholics are more susceptible to hepatotoxicity fromchronic alcoholics are more susceptible to hepatotoxicity from low doses of paracetamol.low doses of paracetamol.  It is thought that pro-inflammatory cytokines may also beIt is thought that pro-inflammatory cytokines may also be involved in inducing hepatic damage in alcoholic hepatitis,involved in inducing hepatic damage in alcoholic hepatitis, since endotoxin is released into the blood because of increasedsince endotoxin is released into the blood because of increased gut permeability, leading to release of TNF-α, IL-1, IL-2 andgut permeability, leading to release of TNF-α, IL-1, IL-2 and IL-8 from immune cells. All of these cytokines have beenIL-8 from immune cells. All of these cytokines have been implicated in the pathogenesis of liver fibrosis.implicated in the pathogenesis of liver fibrosis.
  • PathologyPathology  Alcohol can produce a wide spectrum of liverAlcohol can produce a wide spectrum of liver disease from fatty change to hepatitis anddisease from fatty change to hepatitis and cirrhosis.cirrhosis.
  • Pathology- Fatty liverPathology- 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 largerThis is minimal with small amounts of alcohol, but with larger amounts, the cells become swollen with fatamounts, the cells become swollen with fat (steatosis(steatosis) giving) giving eventually, a Swiss-cheese effect on haematoxylin and eosineventually, a Swiss-cheese effect on haematoxylin and eosin stain. Steatosis can also be seen in obesity, diabetes, starvationstain. Steatosis can also be seen in obesity, diabetes, starvation and occasionally in chronic illness . There isand occasionally in chronic illness . There is no liver cellno liver cell damagedamage. The fat disappears on stopping alcohol.. The fat disappears on stopping alcohol.  In some cases collagen is laid down around the central hepaticIn some cases collagen is laid down around the central hepatic veins (perivenular fibrosis) and this can sometimes progress toveins (perivenular fibrosis) and this can sometimes progress to cirrhosis without a preceding hepatitis. Alcohol directly affectscirrhosis without a preceding hepatitis. Alcohol directly affects stellate cells, transforming them into collagen-producingstellate cells, transforming them into collagen-producing myofibroblast cells. Cirrhosis might then develop if there is anmyofibroblast cells. Cirrhosis might then develop if there is an imbalance between degradation and production of collagen.imbalance between degradation and production of collagen.
  • Pathology- Alcoholic HepatitisPathology- Alcoholic Hepatitis  In addition to fatty change there is infiltration byIn addition to fatty change there is infiltration by polymorphonuclear leucocytes and hepatocytepolymorphonuclear leucocytes and hepatocyte necrosis. Dense cytoplasmic inclusions callednecrosis. Dense cytoplasmic inclusions called Mallory bodiesMallory bodies are sometimes seen in hepatocytesare sometimes seen in hepatocytes andand giant mitochondriagiant mitochondria 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 liveralcoholic damage as they can be found in other liver disease, such as Wilson's disease and Primary Biliarydisease, such as Wilson's disease and Primary Biliary Cirrhosis. If alcohol consumption continues,alcoholicCirrhosis. If alcohol consumption continues,alcoholic hepatitis may progress to cirrhosis.hepatitis may progress to cirrhosis.
  • Pathology- Alcoholic CirrhosisPathology- Alcoholic Cirrhosis  This is classically of the micronodular type,This is classically of the micronodular type, but a mixed pattern may also be seenbut a mixed pattern may also be seen accompanying fatty change, and evidence ofaccompanying fatty change, and evidence of pre-existing alcoholic hepatitis may be present.pre-existing alcoholic hepatitis may be present.
  • Clinical Features- Fatty liverClinical Features- Fatty liver  There are often no symptoms or signs. VagueThere are often no symptoms or signs. Vague abdominal symptoms of nausea, vomiting andabdominal symptoms of nausea, vomiting and diarrhoea are due to the more general effectsdiarrhoea are due to the more general effects of alcohol on the gastrointestinal tract.of alcohol on the gastrointestinal tract.  Hepatomegaly, sometimes huge, can occurHepatomegaly, sometimes huge, can occur together with other features of chronic livertogether with other features of chronic liver disease.disease.
  • 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 onlyThe 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 withMild to moderate symptoms of ill-health, occasionally with mild jaundice, may occur. Signs include all the features ofmild jaundice, may occur. Signs include all the features of chronic liver disease. Liver biochemistry is deranged and thechronic liver disease. Liver biochemistry is deranged and the diagnosis is made on liver histology.diagnosis is made on liver histology.  In the severe case, usually superimposed on patients withIn the severe case, usually superimposed on patients with alcoholic cirrhosis, the patient is ill, with jaundice and ascites.alcoholic cirrhosis, the patient is ill, with jaundice and ascites. Abdominal pain is frequently present, with a high feverAbdominal pain is frequently present, with a high fever associated with the liver necrosis. On examination there is deepassociated with the liver necrosis. On examination there is deep jaundice, hepatomegaly, sometimes splenomegaly, and ascitesjaundice, hepatomegaly, sometimes splenomegaly, and ascites with ankle oedema.with ankle oedema.
  • Clinical Features- Alcoholic cirrhosisClinical Features- Alcoholic cirrhosis  This represents the final stage of liver diseaseThis represents the final stage of liver disease from alcohol abuse. Nevertheless, patients canfrom alcohol abuse. Nevertheless, patients can be very well with few symptoms. Onbe very well with few symptoms. On examination, there are usually signs of chronicexamination, there are usually signs of chronic liver disease. The diagnosis is confirmed byliver disease. The diagnosis is confirmed by liver biopsy.liver biopsy.  Alcohol-induced cirrhosis often presents withAlcohol-induced cirrhosis often presents with a serious complication such as variceala serious complication such as variceal haemorrhage or ascites.haemorrhage or ascites.
  • Laboratory InvestigationLaboratory Investigation  The typical laboratory abnormalities seen in fattyThe typical laboratory abnormalities seen in fatty liver are nonspecific and include modest elevations ofliver are nonspecific and include modest elevations of the aspartate aminotransferase (AST), alaninethe aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamylaminotransferase (ALT), and gamma-glutamyl transpeptidase (GGTP), accompanied bytranspeptidase (GGTP), accompanied by hypertriglyceridemia, hypercholesterolemia, andhypertriglyceridemia, hypercholesterolemia, and occasionally hyperbilirubinemia.occasionally hyperbilirubinemia.  In alcoholic hepatitis and in contrast to other causesIn alcoholic hepatitis and in contrast to other causes of fatty liver, the AST and ALT are usually elevatedof fatty liver, the AST and ALT are usually elevated two- to sevenfold. They are rarely >400 IU, and thetwo- to sevenfold. They are rarely >400 IU, and the AST/ALT ratio >1AST/ALT ratio >1
  • Laboratory InvestigationLaboratory Investigation  Hyperbilirubinemia is common and is accompaniedHyperbilirubinemia is common and is accompanied by modest increases in the alkaline phosphatase level.by modest increases in the alkaline phosphatase level. Derangement in hepatocyte synthetic functionDerangement in hepatocyte synthetic function indicates more serious disease. Hypoalbuminemiaindicates more serious disease. Hypoalbuminemia and coagulopathy are common in advanced liverand coagulopathy are common in advanced liver injury.injury.  Ultrasonography is useful in detecting fattyUltrasonography is useful in detecting fatty infiltration of the liver and determining liver size. Theinfiltration of the liver and determining liver size. The demonstration by ultrasound of portal vein flowdemonstration by ultrasound of portal vein flow reversal, ascites, and intraabdominal collateralsreversal, ascites, and intraabdominal collaterals indicates serious liver injury with less potential forindicates serious liver injury with less potential for complete reversal of liver disease.complete reversal of liver disease.
  • ManagementManagement  Complete abstinence from alcohol is the cornerstoneComplete abstinence from alcohol is the cornerstone in the treatment of alcoholic liver disease. Improvedin the treatment of alcoholic liver disease. Improved survival and the potential for reversal of histologicsurvival and the potential for reversal of histologic injury regardless of the initial clinical presentation areinjury regardless of the initial clinical presentation are associated with total avoidance of alcohol ingestion.associated with total avoidance of alcohol ingestion.  Referral of patients to experienced alcohol counselorsReferral of patients to experienced alcohol counselors and/or alcohol treatment programs should be routineand/or alcohol treatment programs should be routine in the management of patients with alcoholic liverin the management of patients with alcoholic liver disease.disease.
  • ManagementManagement  Attention should be directed to the nutritional andAttention should be directed to the nutritional and psychosocial states during the evaluation andpsychosocial states during the evaluation and treatment periods. Because of data suggesting that thetreatment periods. Because of data suggesting that the pathogenic mechanisms in alcoholic hepatitis involvepathogenic mechanisms in alcoholic hepatitis involve cytokine release and the perpetuation of injury bycytokine release and the perpetuation of injury by immunologic processes, glucocorticoids have beenimmunologic processes, glucocorticoids have been extensively evaluated in the treatment of alcoholicextensively evaluated in the treatment of alcoholic hepatitis.hepatitis.  Patients with severe alcoholic hepatitis, defined as aPatients with severe alcoholic hepatitis, defined as a discriminant function > 32, were given prednisolone,discriminant function > 32, were given prednisolone, 32 mg/d, for 4 weeks followed by a steroid taper .32 mg/d, for 4 weeks followed by a steroid taper .
  • ManagementManagement  Pentoxifylline, which has a weak anti-TNF action,Pentoxifylline, which has a weak anti-TNF action, may also be beneficial and is alternative to themay also be beneficial and is alternative to the corticosteroid in severe alcoholic hepatitis. It appearscorticosteroid in severe alcoholic hepatitis. It appears to reduce the incidence of hepatorenal failure and itsto reduce the incidence of hepatorenal failure and its use is not complicated by sepsis.use is not complicated by sepsis.  In the acute presentation of alcoholic liver disease itIn the acute presentation of alcoholic liver disease it is also important to identify and anticipate alcoholis also important to identify and anticipate alcohol withdrawal and Wernicke's encephalopathy, whichwithdrawal and Wernicke's encephalopathy, which need treating in parallel with the liver diseaseneed treating in parallel with the liver disease
  • ManagementManagement  Treatment for complications of cirrhosis, suchTreatment for complications of cirrhosis, such as variceal bleeding, encephalopathy andas variceal bleeding, encephalopathy and ascites, may also be needed.ascites, may also be needed.  A trial of abstention to establish if liver diseaseA trial of abstention to establish if liver disease can improve is mandatory, but transplantationcan improve is mandatory, but transplantation should not be denied if the patient continues toshould not be denied if the patient continues to deteriorate.deteriorate.
  • Liver TransplantationLiver Transplantation  The role of liver transplantation in the management ofThe role of liver transplantation in the management of alcoholic liver disease remains controversial. In manyalcoholic liver disease remains controversial. In many centres, however, alcoholic liver disease is a commoncentres, however, alcoholic liver disease is a common indication for liver transplantation. The challenge isindication for liver transplantation. The challenge is to identify patients with an unacceptable risk ofto identify patients with an unacceptable risk of returning to harmful alcohol consumption.returning to harmful alcohol consumption.  Many programmes require a 6-month period ofMany programmes require a 6-month period of abstinence from alcohol before a patient is consideredabstinence from alcohol before a patient is considered for transplantationfor transplantation
  • Liver TransplantationLiver Transplantation  Although this relates poorly to the incidence ofAlthough this relates poorly to the incidence of alcohol relapse after transplantation, liver functionalcohol relapse after transplantation, liver function may improve to the extent that transplantation is nomay improve to the extent that transplantation is no longer necessary.longer necessary.  The outcome of transplantation for alcoholic liverThe outcome of transplantation for alcoholic liver disease is good (if the patient remains abstinent)disease is good (if the patient remains abstinent) because minimal immunosuppression is oftenbecause minimal immunosuppression is often required and there is no risk of disease recurrence.required and there is no risk of disease recurrence.  Transplantation for alcoholic hepatitis has a poorerTransplantation for alcoholic hepatitis has a poorer outcome than for complications of alcoholic cirrhosis.outcome than for complications of alcoholic cirrhosis.
  • PrognosisPrognosis  Critically ill patients with alcoholic hepatitis haveCritically ill patients with alcoholic hepatitis have short-term (30 day) mortality rates >50%. Severeshort-term (30 day) mortality rates >50%. Severe alcoholic hepatitis is heralded by coagulopathyalcoholic hepatitis is heralded by coagulopathy (prothrombin time > 5 s), anemia, serum albumin(prothrombin time > 5 s), anemia, serum albumin concentrations <25 g/L (2.5 mg/dL), serum bilirubinconcentrations <25 g/L (2.5 mg/dL), serum bilirubin levels > 137 mol/L (8 mg/dL), renal failure, andlevels > 137 mol/L (8 mg/dL), renal failure, and ascites.ascites.  AA discriminant functiondiscriminant function calculated as 4.6 xcalculated as 4.6 x [prothrombin time control (seconds)] + serum[prothrombin time control (seconds)] + serum bilirubin (mg/dL) can identify patients with a poorbilirubin (mg/dL) can identify patients with a poor prognosis (discriminant function > 32).prognosis (discriminant function > 32).
  • PrognosisPrognosis  The presence of ascites, variceal hemorrhage,The presence of ascites, variceal hemorrhage, deep encephalopathy, or hepatorenal syndromedeep encephalopathy, or hepatorenal syndrome predicts a dismal prognosis. The pathologicpredicts a dismal prognosis. The pathologic stage of the injury can be helpful in predictingstage of the injury can be helpful in predicting prognosisprognosis  Liver biopsy should be performed wheneverLiver biopsy should be performed whenever possible to confirm the diagnosis, to establishpossible to confirm the diagnosis, to establish potential reversibility of the liver disease, andpotential reversibility of the liver disease, and to guide the therapeutic decisions.to guide the therapeutic decisions.
  • ReferencesReferences  Harrison’s Principle of Internal Medicine 17Harrison’s Principle of Internal Medicine 17thth editionedition  Davidson’s Principle and Practice of MedicineDavidson’s Principle and Practice of Medicine 2121stst editionedition  Kumar and Clark Clinical Medicine 6Kumar and Clark Clinical Medicine 6thth editionedition