nonalcoholic fatty liver diseases alcoholic liver diseases acute liver failure

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nonalcoholic fatty liver diseases Alcoholic liver diseases Acute liver failure. Yasar Kucukardali MD Professor / I nternal Medicine. Non-Alcoholic Steatohepatitis. Represents only a part of wide spectrum of non alcoholic fatty liver Prevalence – 2 to 3 % - PowerPoint PPT Presentation


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nonalcoholic fatty liver diseases Alcoholic liver diseases Acute liver failure Yasar Kucukardali MD Professor / Internal Medicine

Non-Alcoholic SteatohepatitisRepresents only a part of wide spectrum of non alcoholic fatty liverPrevalence 2 to 3 % NASH 3rd most common cause of CLD in North America after alcoholic liver disease & Hepatitis CThe most common cause of raised transaminases more than 6 months.NASH was coined by Ludwig et al while describing a series of patients of non-alcoholic, diabetic patients, mostly females, in whom liver histology was consistent with alcoholic liver disease but did not have a history of alcohol consumption.PrevalenceSteatosis is the most common cause of raised transaminases & affects 10-24 % of gen.population while only 2-3 % of gen.population have steatohepatitis.In pts undergoing liver biopsy, the prevalence of NAFLD & steatohepatitis ranges from 15-39% &1.2-4.8% respectively.Risk Factors for NAFLDObesityDiabetes HyperlipidemiaFemale sex

etiologyDrugs / ToxinsMetals Antimony Barium salts Carbon disulfide Thallium compoundsCytotoxic/cytostatic drugsAntibiotics Bleomycin TetracyclineOthers Amiodarone Estrogen Glucocorticoids

etiologyInborn errors of metabolism AbetalipoproteinemiaGalactosemiaGlycogen storage diseaseWeber-Christian syndromeWilsons DiseaseNutritional ObesityRapid weight lossKwashiorkor

etiologySurgical Jejuno colic bypassJejuno ileal bypassGastroplastyExtensive bowel resectionPathogenesisIncreased delivery of fatty acids to liver Obesity StarvationIncreased synthesis of fatty acids in liver excess carbohydrate ( TPN )Decreased mitochondrial beta oxidation of fatty acids Carnitine deficiency Mitochondrial dysfunctionDecreased incorporation of triglycerides into functional VLDL Impaired apolipoprotein synthesisPathogenesisImpaired cholesterol esterification Choline deficiency Protein malnutritionImpaired export of VLDL from hepatocyteInsulin resistance increased lipolysis hyperinsulinemia PathologyDiagnosis of NASH depends on histopathological features & exclusion of alcohol as the cause of disease.Liver biopsy features : steatosis polymorphonuclear and / mononuclear hepatocyte ballooning and necrosi, mallory hyaline,glycogenated nuclei,metamitochondria and fibrosis indistinguishable from alcoholic liver disease

PathologySteatosis in NASH macrovesicularInflammation of steatohepatitis is predominantly lobular, whereas intense portal inflammation with interface activity is seen in chronic viral, autoimmune & drug indued hepatitisBut in children , NASH may have portal infiltrate.Neutrophilic cells in lobular inflammatory infiltrate Balloon degeneration recognized form & characteristic finding in NASH.Mallory hyaline may be +/- . It is characteristic of alcoholic hepatitisPathologyPattern of fibrosis is initial collagen deposition in perivenular & peri sinusoidal spaces of Zone 3 .Chicken wire fibrosisFibrosis in 66% ptsWhile 25% have severe fibrosisAnd 14% have well established cirrhosis

Histological Differential DiagnosisHepatitis CPrimary Biliary CirrhosisAutoimmune hepatitisAlpha 1 anti trypsin deficiencyHemochromatosis

Clinical features Symptoms & SignsMost of the patients are asymptomatic 1/3rd present with nonspecific constitutional symptoms like weakness, fatigue & malaise.Rapid onset of Fulminant hepatic failure NASH d//t drugs like nucleoside analogues, tetracyclinesHepatomegaly , splenomegalyPresence of ascites, spider angiomata indicate development of cirrhosis

20Alcoholic hepatitis - symptomaticClinical featuresLaboratory findingsMild moderate elevations of S.Transaminases, typically less than 4 times the upper normal limit.ALT level greater than AST in absence of cirrhosis.Liver biopsyDiagnosisClinical historyExclusion of significant alcohol intakePursue dietary history, medication, occupational exposure to organic solventsFamily history of liver diseaseOther causes of CLD infections, metabolic heriditary & autoimmune causes to be ruled outLiver biopsy confirm diagnosis & for prognostic information

Natural course SteatosisSteatohepatitisCirrhosisSteatosis good prognosisSteatohepatitis , cirrhosis bad prognosis

TreatmentTreatment options are limitedWeight Reduction: wt loss normalization of s.aminotransferases.Means of wt loss is important not the amount of wt lossRecommended wt loss 230 g/day or 1.6 kg/weekDiet : 45 -100 g high quality animal protein less than 100g carbohydrates less than 10 g fat per day providing 600 -800 kcal

TreatmentUrsodeoxycholic acid : Has membrane stabilizing / cytoprotective / immunological effect10-15 mg/kg/day for 6-12 months significant improvement in transaminases levels and degree of steatohepatitis

TreatmentLiver Transplantation :NASH A relative contraindicationMany of pts with NASH with CLD who underwent Liver Transplant redeveloped NASH in the new donor liver ( 2/3 cases ) &1/3rd cases liver transplantation is unsuccessful.Newer treatment modalitiesInhibition of macrophage activation:

Anti oxidant ( Vit E ) glutathione prodrugsAntibiotics, preprobioticsAnti cytokines ( anti TNF alpha antibodies, pentoxiphylline )

Protect hepatocyte ATP storesPARP inhibitorsMinimize CYP2F activityDietary modification ( avoid fats )Insulin sensitizers : pioglitazoneAntiobesity drugs : sibutramine, orlistatAntilipid drugs : Simvastatin, Procusol

Alcoholic liver diseases INTRODUCTIONThere is a spectrum of clinical and laboratory findings in patients with alcoholic liver disease, ranging from asymptomatic fatty liver to alcoholic hepatitis to end-stage liver failure with jaundice, coagulopathy, and encephalopathy

Unfortunately, many alcoholics first become symptomatic only when severe, life threatening liver disease is already present.

Even at this stage, abstinence can result in significant reversal in some patients. Patients with alcoholic liver disease often have coexisting dysfunction in other organs. cardiomyopathy, skeletal muscle wasting, neuropathies, pancreatic dysfunction. The presence of fever and abdominal pain should not be taken lightly in a patient with alcoholic hepatitis with cirrhosis and ascites, and can mimic the presentation of spontaneous bacterial peritonitis.

The distinction between these disorders should be made by ascitic fluid analysis. A polymorphonuclear leukocyte count that is 250/mm3 is presumptive evidence of spontaneous bacterial peritonitis since it does not occur with alcoholic hepatitis alone. Excessive alcohol consumption is the leading cause of liver disease.Alcoholic liver disease comprises of three main stagesHepatic steatosisAlcoholic hepatitisCirrhosisHepatic steatosisPathogenesis :Fatty change is an acute, reversible manifestation of ethanol ingestion.Ethanol causes Increased fatty acid synthesis by causing catabolism of fat in the peripheral tissuesAcetaldehyde which is metabolite of ethanol converts NAD+ to NADH. An excess NADH stimulates lipid biosynthesis. Oxidation of fatty acid by mitochondria is decreasedAcetaldehyde impairs the function of microtubules, resulting in decreased transport of lipoproteins from liverCollectively these metabolic consequences produce fatty liver.Pathology:Gross:The liver becomes yellow, greasy and is enlarged (up to 4 to 6 kg)The increase in weight is because of accumulation of fat, protein and waterMicroscopy:Following even moderate intake of alcohol, small (microvesicular) lipid droplets accumulates in the liverWith chronic intake of alcohol, more lipid accumulates, creating a large macrovesicular globules, compressing the nucleus the periphery.Steatosis in AlcoholismClinical features of alcoholic steatosisHepatomegaly Mild elevation of serum bilirubin, alkaline phasphatase and gamma GTAlcoholic hepatitisIs characterized byHepatocyte swelling and necrosisMallory bodiesNeutrophilic inflammatory responsePerivenular fibrosisHepatocyte swelling and necrosis:Single or scattered foci of cells undergo swelling (ballooning degeneration) and necrosis Mallory bodies:Scattered hepatocytes accumulate cytokeratin intermediate filaments and other proteinsVisible as eosinophilic cytoplasmic inclusions in degenerating hepatocytes Neutrophilic reaction:Neutrophils accumulate around the degenerating hepatocytes, particularly those having Mallory bodies.Lymphocytes and macrophages also enter portal tracts and spill into parenchymaFibrosis :Commonly seen in the form of sinusoidal and perivenular fibrosisOccasionaly periportal fibrosis may predominateFibrosis mainly occurs because of the activation of sinusoidal stellate cells and portal tract fibroblastsClinical features:Malaise, anorexia, weight loss, upper abdominal discomfort, tender hepatomegaly.Laboratory findings:HyperbilirubinemiaElevated ALP,GGT, moderate elevation of AST Neutrophilic leucocytosisAlcoholic cirrhosis:The final and irreversible form of alcoholic liver diseaseUsually evolves slowlyGross:Initially the liver is yellow-tan, fatty and enlarged.Later it is transformed into brown, shrunken, nonfatty organ with multiple nodules.Sometimes nodularity becomes very prominent with scattred lager nodules creating a hobnail appearance on the surface of liver Microscopy:Initially fibrous septae are very delicate and extend through sinusoids from central to portal regions as well as from portal tract to portal tract.As the fibrous septae dissect and surround nodules, the liver becomes more fibrotic, loses fat, and shrinks in size. (Laennec cirrhosis)Bile stasis may be seen.


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