The most frequently mutated gene in patients with hereditary hemochromatosis is HFE, which is located on chromosome 6 close to the HLA gene cluster. HFE encodes an HLA class I–like molecule that regulates the synthesis of hepcidin in hepatocytes. The most common HFE mutation is a cysteine-to-tyrosine substitution at amino acid 282 (C282Y). This mutation, which inactivates the HFE protein, is present in over 70% of patients diagnosed with hereditary hemochromatosis and is most common in European populations. Several other mutations can also give rise to http://ebooksmedicine.net hemochromatosis, including other mutations in HFE as well as mutations in transferrin receptor 2 and in hepcidin itself. The associated clinical condition is milder with some of these alternative mutations and more severe with others, childhood. Whatever the underlying cause, the onset of disease typically occurs after 20 gm of stored iron have accumu lated. Excessive iron appears to be directly toxic to host tissues. Mechanisms of liver injury include the following:
Stimulation of collagen formation by activation of hepatic stellate cells
DNA damage by reactive oxygen species, leading to lethal cell injury or predisposition to HCC
The deleterious effects of iron on cells that are not fatally injured are reversible, and removal of excess iron with therapy promotes recovery of tissue function.
MORPHOLOGYThemorphologicchangesinseverehemochromatosisarecharacterizedprincipallyby(1)tissue deposition of hemosiderin inthefollowingorgans(indecreasingorderofseverity):liver,pancreas,myocardium,pituitarygland,adrenalgland,thyroidandparathyroidglands,joints,andskin;(2)cirrhosis;and(3)pancreatic fibrosis.Intheliver,ironbecomesevidentfirstasgolden-yellowhemosideringranulesinthecytoplasmofperiportalhepatocytes,whichcanbehistochemicallystainedwithPrussianblue(
Fig.16.20 ).Withincreasingironload,thereisprogressivedepositionintherestofthelobule,thebileductepithelium,andKupffercells.Atthisstage,thelivertypicallyisslightlyenlargedandchocolatebrown.Fibrousseptadevelopslowly,linkingportaltractstoeachotherandleadingultimatelytocirrhosis inanintenselypigmented(verydarkbrowntoblack)liver.
Thepancreas alsobecomespigmented,acquiresdiffuseinterstitialfibrosis,andmayshowparenchymalatrophy.Hemosiderinisfoundintheacinarandtheisletcellsandsometimesintheinterstitialfibrousstroma.Theheart oftenisenlarged,withhemosideringranuleswithinthemyocardialfibers.Thepigmentationmayinduceastrikingbrowncolorationofthemyocardium.Adelicateinterstitialfibrosismayappear.Althoughskin pigmentation ispartiallyattributabletohemosiderindepositionindermalmacrophagesandfibroblasts,mostofthecolorationresultsfromincreasedepidermalmelaninproduction.Thecombinationofthesepigmentsrenderstheskinslate-gray.Withhemosiderindepositioninthejointsynoviallinings,anacutesynovitismaydevelop.Thereisalsoexcessivedepositionofcalciumpyrophosphate,whichdamagesthearticularcartilageandsometimesproducesdisablingpolyarthritis,referredtoaspseudogout. Withtheonsetofcirrhosis,thetestesmaybecomeatrophic.