FattyliverdiseaseLargeandsmalldropletfatEthanol,corticosteroids,methotrexate,totalparenteralnutrition “Microvesicularsteatosis”(diffusesmalldropletfat)Valproate,tetracycline,aspirin(Reyesyndrome),HAART
SteatohepatitiswithMallory-DenkbodiesEthanol,amiodarone
FibrosisandcirrhosisPeriportalandpericellularfibrosisAlcohol,methotrexate,enalapril,vitaminAandotherretinoids
GranulomasNoncaseatingepithelioidgranulomasSulfonamides,amiodarone,isoniazid
VascularlesionsSinusoidalobstructionsyndrome(veno-occlusiveHigh-dosechemotherapy,bushteasdisease):obliterationofcentralveins
Peliosishepatis:blood-filledcavities,notlinedbyAnabolicsteroids,tamoxifenendothelialcells
HAART, Highlyactiveanti-retroviraltherapyAdaptedfromWashingtonK:Metabolicandtoxicconditionsoftheliver.InIacobuzio-DonahueCA,MontgomeryEA,editors:Gastrointestinal and liver pathology, Philadelphia,2005,ChurchillLivingstone.
Predictable drug or toxin reactions affect all individuals in a dose-dependent fashion. Unpredictable reactions depend on idiosyncrasies of the host, particularly the propensity to mount an immune response to the antigenic stimulus or the rate at which the agent can be metabolized. Both classes of injury may be immediate or take weeks to months to develop (
Table 16.3
A classic, predictable hepatotoxin is acetaminophen, now the most common cause of acute liver failure necessitating transplantation in the United States. The toxic agent is not acetaminophen itself but rather toxic metabolites produced by the cytochrome P-450 system. The damage begins in centrilobular hepatocytes but extends to encompass entire lobules in the most severe cases.
Examples of drugs that can cause idiosyncratic reactions include chlorpromazine, an agent that causes cholestasis in patients who are slow to metabolize it, and halothane and its derivatives, which can cause a fatal immune-mediated hepatitis after repeated exposure.
Alcohol is a well-known cause of fatty liver disease in adults and can manifest histologically as steatosis, steatohepatitis, and cirrhosis. In recent years, it has become evident that another entity, so-called “nonalcoholic fatty liver disease (NAFLD),” can mimic the entire spectrum of hepatic changes associated with alcohol abuse. Since the morphologic changes of alcoholic and NAFLD are indistinguishable, they are discussed together, followed by the pathogenesis and distinctive clinical features of each entity.
Threetypesofliveralterationsareobservedinfattyliverdisease:steatosis(fattychange),hepatitis(alcoholicorsteatohepatitis),andfibrosis.
Hepatocellular steatosis. Hepatocellularfataccumulationtypicallybeginsincentrilobularhepatocytes.Thelipiddropletsrangefromsmall(microvesicular)tolarge(macrovesicular),thelargestfillingandexpandingthecellanddisplacingthenucleus.Assteatosisbecomesmoreextensive,thelipidaccumulationspreadsoutwardfromthecentralveintohepatocytesinthemidlobuleandthentheperiportalregions(
Fig.16.16