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Toronto Notes 2019 Liver
Investigations
• suspectifincreasedliverenzymeswithclinicalmanifestationsatyoungage(<30);especially combination of liver disease with dystonia, psychiatric symptoms
• screeningtests
1. reduced serum ceruloplasmin (<50% of normal)
2. Kayser-Fleischer rings (usually require slit-lamp examination) 3. increased urinary copper excretion
• goldstandard
1. increased copper on liver biopsy by quantitative assay
2. genetic analysis imperfect as many mutations in ATP7B are possible
Treatment
• 4drugsavailable
1. penicillamine chelates copper, poorly tolerated
2. trientine chelates copper
3. zinc impairs copper excretion in stool and decreases copper absorption from gut 4. tetrathiomolybdate preferred if neurological involvement
• screenrelatives
• livertransplantinseverecases
Hemochromatosis
Definition
• excessiveironstoragecausingmultiorgansystemdysfunction(liver,inparticular)withtotalbodystores of iron increased to 20-40 g (normal 1 g)
Etiology
• primary(hereditary)hemochromatosis
■ hepcidin deficiency results in ongoing gut absorption of iron despite adequate iron stores
• secondaryhemochromatosis
■ parenteral iron overload (e.g. transfusions)
■ chronic hemolytic anemia: thalassemia, pyruvate kinase deficiency ■ excessive iron intake
Epidemiology
• hereditaryhemochromatosismostcommoninNorthernEuropeandescent
• primarilyduetocommonrecessivegene(HFE,5%);1/400patientsarehomozygotes
Clinical Features
• usuallypresentswithtrivialelevationinserumtransaminases
• liver:cirrhosis(30%),HCC(200xincreasedrisk)–mostcommoncauseofdeath(1/3ofpatients) • pancreas:DM,chronicpancreatitis
• skin:bronzeorgrey(duetomelanin,notiron)
• heart:dilatedcardiomyopathy
• pituitary:hypogonadotropichypogonadism(impotence,decreasedlibido,amenorrhea)
• joints:arthralgia(anyjoint,butespeciallyMCPjoints),chondrocalcinosis
Investigations
• screeningforindividualswithclinicalfeaturesand/orfamilyhistory(1/4chanceofsiblinghavingthe disease)
■ transferrin saturation (free Fe2+/TIBC) >45%
■ serumferritin>400ng/mL
■ HFE gene analysis: 90% of primary hemochromatosis involves C282Y allele, while H63D and S65C
alleles also commonly involved and screened
• liverbiopsy(generallyusedtodetectcirrhosisorifpotentialforothercausesofliverdisease)
■ markers of advanced fibrosis: if any of the following are present at the time of diagnosis → age >40, elevated liver enzymes, or ferritin >1000
■ considered if compound heterozygote and potential other cause of liver injury (e.g. fatty liver, etc.)
■ if C282Y/C282Y and no markers of advanced fibrosis, then biopsy generally not needed
• HCCscreeningifcirrhosis
Treatment
• phlebotomy:weeklyorq2wkthenlifelongmaintenancephlebotomiesq2-6mo
• deferoxamineifphlebotomycontraindicated(e.g.cardiomyopathy,anemia)
• primaryhemochromatosisrespondswelltophlebotomy
• secondaryhemochromatosisusuallyrequireschelationtherapy(administrationofagentsthatbindand
sequester iron, and then excreted)
Prognosis
• normallifeexpectancyiftreatedbeforethedevelopmentofcirrhosisorDM
Gastroenterology G33
Hemochromatosis Clinical Features ABCD
• Arthralgia
• Bronze skin
• Cardiomyopathy, cirrhosis of liver
• Diabetes (pancreatic damage)
• Hypogonadism (anterior pituitary damage)
Ferritin may never normalize if other causes of high ferritin present (e.g. fatty liver from metabolic syndrome or alcohol)
Gene mutation not 100% penetrant, so not all with homozygous gene defect have clinically significant iron overload