Fig. 16.19 Naturalhistoryofnonalcoholicfattyliverdisease.Isolatedfattyliverdiseaseshowsminimalriskforprogressiontocirrhosisorincreasedmortal-ity,whilenonalcoholicsteatohepatitisshowsincreasedoverallmortalityaswellasincreasedriskforcirrhosisandhepatocellularcarcinoma.DM, Diabetesmellitus.Nonalcoholic fatty liver disease (NAFLD) Isolated fatty liver NASH cirrhosis Decompensation HCC Nonalcoholic steatohepatitis (NASH) >80% ~11% over 15 years, but significant variability ~31% over 8 years ~7% over 6.5 years 1. None to very minimal progression to cirrhosis 2. No increased risk of death compared with the general population
Nonalcoholicfattyliverdisease(NAFLD)isassociatedwiththemetabolicsyndrome,obesity,type2diabetes,anddyslipidemiaand/orhypertension.
NAFLDmayshowallthechangesassociatedwithalcoholicliverdisease:steatosis,nonalcoholicsteatohepatitis(NASH),andcirrhosis,althoughthefeaturesofsteatohepatitis(suchashepatocyteballooning,Mallory-Denkbodies,andneutrophilicinfiltration)oftenarelessprominentthantheyareinalcohol-relatedinjury.
PediatricNAFLDisincreasinglybeingrecognizedastheobesityepidemicspreadstopediatricagegroups,althoughitshistologicpatterndifferssomewhatfromthatseeninadults.
Although there are many inherited metabolic liver diseases, only some relatively common, pathogenically interesting entities are discussed here: hereditary hemochromatosis, Wilson disease, and alpha-1-anti-trypsin (α1AT) deficiency.
Hemochromatosis is caused by excessive absoprtion of iron, which is primarily deposited in parenchymal organs such as the liver and pancreas, as well as in the heart, joints, and endocrine organs. It results most commonly from an inherited disorder, hereditary hemochromatosis. When iron accumulation occurs as a consequence of parenteral administration of iron, usually in the form of transfusions, it is called acquired hemochromatosis. Secondary iron overload also can complicate diseases that are associated with persistent ineffective erythropoiesis, particularly thalassemia and myelodysplastic syndromes (Chapter 12).
As discussed in Chapter 12, the total body iron pool ranges from 2 to 6 gm in normal adults; about 0.5 gm is stored in hepatocytes. In severe hemochromatosis, total iron may exceed 50 gm, one-third of which accumulates in the liver. Fully developed cases exhibit (1) micronodular cirrhosis; (2) diabetes mellitus (up to 80% of patients); and (3) abnormal skin pigmentation (up to 80% of patients).
Because there is no regulated iron excretion from the body, the total body content of iron is tightly regulated by intestinal absorption. As discussed in Chapter 12, hepcidin is a circulating peptide hormone that acts as a key negative regulator of intestinal iron uptake. Diverse mutations in several genes have been described in hereditary hemochromatosis, all of which lower hepcidin levels or diminish hepcidin function. Whatever the underlying defect, the net result is an increase in intestinal absorption of dietary iron, leading to an accumulation of 0.5 to 1 gm of iron per year.