• Hemochromatosis• Wilson disease• α1-ANTITRYPSIN DEFICIENCY
• Hemochromatosis was first described by vonRecklinghausen in 1889. It is characterized bythe excessive accumulation of body iron,most of which is deposited in parenchymalorgans such as the liver and pancreas.
Primary or HeriditaryHemochromatosisHemochromatosis is ahomozygous-recessiveinherited disorder that iscaused by excessive ironabsorption.
Secondary Hemochromatosis• Accumulation of iron in tissues, which mayoccur as a consequence of parenteraladministration of iron, usually in the form oftransfusions, or other causes, is variablyknown as secondary hemochromatosis,acquired hemochromatosis, orhemosiderosis.
• We will use the termshemochromatosis for the hereditarydisease and• hemosiderosis for the acquireddeposition of iron in some tissues.
The total body iron pool ranges from 2 to 6gm in normal adults; about 0.5 gm is stored inthe liver, 98% of which is in hepatocytes.In hemochromatosis, total iron accumulationmay exceed 50 gm, over one third of whichaccumulates in the liver.
Characteristic features of Hemochromatosis• Fully developed cases exhibit• (1) micronodular cirrhosis in all patients;• (2) diabetes mellitus in 75% to 80% ofpatients; and• (3) skin pigmentation in 75% to 80% ofpatients.
• Males predominate (5 to 7 : 1) with slightlyearlier clinical presentation, partly becausephysiologic iron loss (menstruation,pregnancy) delays iron accumulation inwomen.
• There are at least four genetic variants ofhereditary hemochromatosis. The mostcommon form is an autosomal recessivedisease of adult onset caused by mutations inthe HFE gene.
Pathogenesis• In hereditary hemochromatosis there is adefect in the regulation ofintestinal absorption of dietaryiron, leading to net iron accumulation of 0.5to 1.0 gm/year. HFEgene isresposible for this disorder.
• HFE regulates the levels of hepcidin,the iron hormone produced by theliver. Hepcidin normally down-regulates theefflux of iron from the intestines andmacrophages into the plasma andinhibits iron absorption.• When hepcidin levels are reduced there isincreased iron absorption.
• Hereditary hemochromatosis manifeststypically after 20gmofstorage iron has accumulated.
Regardless of source, excessive ironseems to be directly toxic to tissues bythe following mechanism:(1) Lipid peroxidation by iron-catalyzed free radicalreaction,(2) Stimulation of Collagen formation(3) Direct interaction of iron with DNA.Whatever the actions of iron, they may be reversible,with the exception of nonlethal DNA damage.
Morphology• 1. The deposition of hemosiderin• 2. Cirrhosis• 3. Pancreatic fibrosisThe pancreas, heart, skin, joints and testes mayalso be affected.
Prognosis• A third of those untreated develophepatocellular carcinoma• The risk of HCC development in patients withhemochromatosis is 200-fold higherthan in normal populations.
Definition• Wilson disease is an autosomal recessive disordercaused by mutation of the ATP7B gene, resultingin impaired copper excretion into bile and a failureto incorporate copper into ceruloplasmin.
• Deficiency in the ATP7B protein causes adecrease in copper transport into bile,impairs its incorporation into ceruloplasmin,and inhibits ceruloplasmin secretion into theblood.• These changes cause copper accumulation inthe liver and a decrease in circulatingceruloplasmin.• The copper causes toxic liver injury, throughthe production of ROS.
Clinical Features.Age between 6 and 40.The most common presentation is acute orchronic liver disease.
• Neuropsychiatric manifestations,including mild behavioral changes,• frank psychosis, or a Parkinson disease–likesyndrome (such as tremor
Biochemical Diagnosis• a decrease in serum ceruloplasmin,• an increase in hepatic copper content (the mostsensitive and accurate test), and• increased urinary excretion of copper (the mostspecific screening test).
• Demonstration of Kayser-Fleischer rings(green to brown deposits of copper inDesçemets membrane in the limbus of thecornea) further favors the diagnosis.
Treatment• Early recognition and• long-term copper chelation therapy (as withD-penicillamine, or Trientine) or• zinc-based therapy.• Liver Transplantation
α1-ANTITRYPSINDEFICIENCYα1-Antitrypsin deficiency is anautosomal recessive disordermarked by very low levels of α1-antitrypsin.
α1-Antitrypsin• α1-Antitrypsin is a small 394–amino acidplasma glycoprotein synthesizedpredominantly by hepatocytes.
• The major function of this protein is theinhibition of proteases,particularly neutrophil elastase, cathepsin G,and proteinase 3, which are normallyreleased from neutrophils atsites of inflammation.
Morphology• α1-Antitrypsin deficiency is characterized bythe presence of round-to-oval cytoplasmicglobular inclusions in hepatocytes,which in routine H&E stains areacidophilic and indistinctly demarcatedfrom the surrounding cytoplasm.
Treatment• The treatment, and the cure, for severehepatic disease is liver transplantation.
Cholestasis is a condition where bilecannot flow from the liver to theduodenum.
Neonatal Hepatitis• Neonatal hepatitis is aninflammation of the liverthat occurs in earlyinfancy, usually one to twomonths after birth.
Causes of Neonatal Hepatitis• Neonatal hepatitis mainly caused by avirus, such as hepatitis B virus,cytomegalovirus, rubella virus, herpes simplexvirus and gastro-intestinal virus. Toxoplasmagondii parasite, Li Division Thac bacteria,syphilis, etc., is also one of the causes ofneonatal hepatitis.
NEONATAL CHOLESTASIS• Prolonged conjugated hyperbilirubinemia in theneonate, termed neonatal cholestasis, affectsapproximately 1 in 2500 live births.Cholestasis is a conditionwhere bile cannot flowfrom the liver to theduodenum.