1

1. Fatty Liver: AFLD & NAFLD2. Drug hepatitis3. Iron overload disorders

-hemosiderosis-hereditary hemochromatosis

4. Copper overload—Wilson disease5. Alpha-1-antitrypsin deficiency

1. Fatty Liver: AFLD & NAFLD1. Fatty Liver: AFLD & NAFLD2. Drug hepatitis2. Drug hepatitis3. Iron overload disorders3. Iron overload disorders

--hemosiderosishemosiderosis--hereditary hereditary hemochromatosishemochromatosis

4. Copper overload4. Copper overload——Wilson diseaseWilson disease5. Alpha5. Alpha--11--antitrypsin deficiencyantitrypsin deficiency

Fatty liver and possible sequelae

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

NAFLD NASH Cirrhosis(non-alcoholic fatty liver non-alcoholic steatohepatitisdisease)

2

3

hepatocyte

oxidative stress-steatosis-copper overload

cytokeratins 8 + 18

Mallory body

PATHOGENESIS OF MALLORY BODIES

p62

ubiquitin

4

stellate cell activation tomyofibroblasts fibrosis

5

6

7

8

Alcoholic Non-alcoholic

AFLD(alcoholic fatty liver disease)

NAFLD(non-alcoholic fatty liver disease)

Hit 1:causes fat

Hit 2:causes steatohepatitis

acetaldehydeobesitydiabetesmetabolic syndrome

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

TWO-HIT HYPOTHESIS of STEATOHEPATITIS

•cytokines•endotoxin

9

Drug/ChemicalHepatotoxicity

10

11

12

13

14

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

Oral Contraceptives•cholestasis• liver-cell adenoma•peliosis hepatis

15

Metal storage diseases:Fe and Cu

16

Iron Overload Disorders

• Primary Iron Overload-hereditary hemochromatosis

• Secondary Iron Overload-transfusion/hemolysis/-hemodialysis

Kupffer cell hemosiderosis: hemolysis—transfus.--hemodialysis

17

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

-<5% due to other non-HFE mutations

Hepatocellular iron overload

18

19

From Robbins’Path. Basis of Disease7/e

hepcidin

Iron Homeostasis

Hereditary Hemochromatosis

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

-hemojuvelin: 2A-HAMP: 2B

• Type 3: TfR2• Type 4: Ferroportin

20

21

22

23