1 Fatty Liver: AFLD & NAFLD1 Fatty Liver: AFLD & NAFLD1 Fatty Liver: AFLD & NAFLD1 Fatty Liver: AFLD & NAFLD1. Fatty Liver: AFLD & NAFLD1. Fatty Liver: AFLD & NAFLD2. Drug hepatitis2. Drug hepatitis1. Fatty Liver: AFLD & NAFLD1. Fatty Liver: AFLD & NAFLD2. Drug hepatitis2. Drug hepatitisg pg p3. Iron overload disorders3. Iron overload disorders

hemosiderosishemosiderosis

g pg p3. Iron overload disorders3. Iron overload disorders

hemosiderosishemosiderosis--hemosiderosishemosiderosis--hereditary hemochromatosishereditary hemochromatosis--hemosiderosishemosiderosis--hereditary hemochromatosishereditary hemochromatosisyy

4. Copper overload4. Copper overload——Wilson diseaseWilson disease5 Al h5 Al h 11 tit i d fi itit i d fi i

yy4. Copper overload4. Copper overload——Wilson diseaseWilson disease5 Al h5 Al h 11 tit i d fi itit i d fi i5. Alpha5. Alpha--11--antitrypsin deficiencyantitrypsin deficiency5. Alpha5. Alpha--11--antitrypsin deficiencyantitrypsin deficiency

Fatty liver and possible sequelae

AFLD ASH Cirrhosis(alcoholic fatty liver dis.) alcoholic steatohepatitis

NAFLD NASH Cirrhosis( l h li f li l h li h i i(non-alcoholic fatty liver non-alcoholic steatohepatitisdisease)

oxidative stress-steatosis-copper overload

Mallory bodyhepatocyte

Mallory body

p62cytokeratins 8 + 18 p62

ubiquitin

PATHOGENESIS OF MALLORY BODIES

ubiquitin

t ll t ll ti ti tstellate cell activation tomyofibroblasts fibrosis

Alcoholic Non-alcoholic

Hit 1obesitydiabetes

AFLD NAFLD

Hit 1:causes fat

acetaldehyde diabetesmetabolic syndrome

(alcoholic fatty liver disease) (non-alcoholic fatty liver disease)

Hit 2:causes steatohepatitis

ASH NASH(alcoholic steatohepatitis) (non-alcoholic steatohepatitis)

•cytokines•endotoxin

TWO-HIT HYPOTHESIS of STEATOHEPATITIS

Drug/ChemicalHepatotoxicity

Veno-occlusive disease (VOD): pyrrolizidine alkaloids (“bush tea”)

O l C t tiOral Contraceptives•cholestasis• liver-cell adenoma•peliosis hepatispeliosis hepatis

Metal storage diseases:Metal storage diseases:Fe and CuFe and Cu

Iron Overload DisordersIron Overload Disorders

P i I O l d• Primary Iron Overload-hereditary hemochromatosis-hereditary hemochromatosis

• Secondary Iron Overload• Secondary Iron Overload-transfusion/hemolysis/t a s us o / e o ys s/-hemodialysis

Kupffer cell hemosiderosis: hemolysis—transfus.--hemodialysis

1889: von Recklinghausen: “hemochromatosis”(“bronzed diabetes”)( bronzed diabetes )

-85-100% due to HFE mutation (C282Y/C282Y)

-<5% due to other non-HFE mutations

Hereditary HemochromatosisHereditary Hemochromatosis

• Type 1: HFE (C282Y)• Type 2: Juvenile hemochromatosis• Type 2: Juvenile hemochromatosis

-hemojuvelin: 2A-HAMP: 2B

• Type 3: TfR2• Type 3: TfR2• Type 4: Ferroportin