Hemochromatosis, evaluation and managementShankar Zanwar

Time line First description – Trousseau - 1865 Termed “hemochromatosis” – von Recklinghausen - 1889

Genetic association – Simon et al - 1976 Gene identified – Gnirke et al -1996

Word hemochromatosis – blood disorder, that caused increased skin pigmentation.

Iron metabolism Iron absorption primarily occurs from duodenum No excretion actual excretion of absorbed iron Absorption 2 forms – Ionic as ferrous from ferric via DMT-1 Heme – unidentified protein transporter Once absorbed stored in enterocyte as ferritin (till they die) or transported to blood via ferroportin

Hepcidin Co-ordinates absorption, mobilization and storage Predominantly expressed in hepatocytes Binds to Ferroportin internalization and degradation of FPN inhibition of iron export in the circulation

Inducers – excess iron, inflammation Inhibitors – low iron, erythropoiesis & hypoxia

Hepcidin – regulator of Fe metabolism

HFE protein Similar to MHC – 1 Exact mechanism relating to iron dependent regulation of Hepcidin unclear

Binds to TFR-1 intraction may help iron sensing and Hepcidin regulation

Iron overload Hereditary hemochromatosis HFE related – Type 1 C282Y homozygosity (1 in 250 individuals in European decent) C282Y/H63D compound heterozygosity Other HFE mutations Non – HFE related Hemojuvelin(HJV) mutation – type 2A Hepcidin (HAMP) mutation – type 2B Transferrin receptor(TFR2) mutation – type 3 Ferroportin receptor (SLC40A1) mutations type 4 African iron load (reverse iron storage pattern)

...Iron overload Secondary Iron loading anemias Sideroblastic anemia Chronic hemolytic anemia Thalassemia Parentral overload – Long term HD pts., multiple PRCs. Chronic liver disease ALD NAFLD Hepatitis B/C, porphyria cutanea tarda, Portocaval shunts

Patho-physioIron overload

in hepatocytesIron dependent

lipid peroxidation

Membrane dysfunction of

miltochondria and lysosomes

Hepatocyte death

Activation of Kupffer cells

Release of cytokines activation

of stellate cells

Clinical features Male : Female 2:1 Weakness – 25% Abdo. pain(RUQ) - 3% Loss of libido – 12% Hepatomegaly – 13% Skin pigmentation – 5% DM – 5% High enzymes – 33% Cirrhosis – 13%

Joint involvemen 2-24% 2-3rd MCP joint s/chondral cyst Osteopenia Swelling and pain No relief with phlebotpomy Cardiac involvement – Cardiomyopathy AF/Ventricular dysrhythmia

and HF

Evaluation Diagnosis suspected if typical symptom, abnormal iron screening tests or family history.

Iron indices to be studied – serum iron, ferritin, TIBC and transferrin saturation

Transferrin saturation = serum iron/TIBC X 100 Fasting state blood samples are not needed as previously thought

Iron indices in health and HH

Ferritin as evident is not a good measure for screening of HH

Since it may be normal in young persons with HFE related HH, or elevated in unaffected person with other inflammatory liver diseases like ASH, viral hepatitis, NASH etc.

Thus elevated TS with normal ferritin does not r/o HH.

Genetic testing In west the next level of investigation is gene analysis.

HFE mutation analysis is performed. If patient is C282Y homozygote or compound heterozygote C282Y/H63D with ferritin <1000, normal liver enzymes, biopsy is not needed

If ferritin >1000, elevated enzymes biopsy is done to exclude other causes.

Annal Int Med 2003

Liver biopsy Sample has to be obtained for HPE, biochemistry for HIC – hepatic iron concentration

Perl’s Prussian blue stain for presence and localisation of hepatic iron

In HFE related HH iron typically in periportal areas with little of none in kupffer cells, when HIC is very high it becomes pan lobular.

Grade 1-2 may be seen in normal livers or very early HFE related HH

Grade 3 may be seen in other cases of iron over load (ASH)

Biochemistry HIC – normal liver iron concentration is <1500mcg/g dry weight

Hepatic iron index = HIC/patients age in years higher values suggest HH versus secondary hemochromatosis

Biopsy and genetics

Imaging MRI – magnetic susceptibility testing method for iron in liver – available in US and Europe

Sensitivity and specificity values when compared in studies does not eliminate need of biopsy.

Management Straight forward – phlebotomy Ideally should begin before hepatic fibrosis sets in will lead to a normal life

Each unit of blood(500ml) 200-250 mg iron Usually HH pts. have 10-20 gram of excess iron needing 40-80 units removal

Most will tolerated 1 unit phlebotomy per week Treatment with PPI reduces absorption of non heme iron decrease number of phlebotomies

Older patients with underlying anemia 1 U/2 weeks Iron chelators Deferoxamine 20-50mg/kg/day – continuous infusion

via pump 12 hours per day Deferasirox – oral chelator for HH – in trial phase 1-2 Deferipirone – Used in thalassemics, not yet approved

for HH – 1.7% risk of agranulocytosis. Side effects hepatic failure, GI bleed, renal injury,

cost(vs phlebotomy). Avoid vitamin C

Target Weekly phlebotomies till hematocrit <37% Transferrin saturation <50% Ferritin 50-100mg/dl Once target achieved phlebotomies – 1 U every

2-3 months Check TS every 2-3 months

Response to phleobotomies Reduction of tissue iron stores to normal Improved sense of well-being, energy level Improved cardiac function Improved control of diabetes Reduction in abdominal pain Reduction in skin pigmentation Normalization of elevated liver enzymes Reversal of hepatic fibrosis (in approximately 30% of cases)

Prognosis Life expectancy – normal phlebotomies started

even before fibrosis HCC risk increases in patients with cirrhosis, RR

20, annual incidence 3-4% in established cirrhotics

Arthritis and hypogonadism does not reverse with phlebotomies

HCC screening USG and AFP every 6 months SOS CT scan

Liver transplant for established cirrhosis Five years survival rates post transplant 34-55%

compared to overall 72-75% Similarly in non HFE iron overload survival 63%

vs HFE related 34 %

Family screening Proband identified screen family HFE genotyping and phenotyping(iron studies) is needed

When C282Y homozygous or heterozygous with H63D with high ferritin is seen initiate phlebotomies

Heterozygotes with C282Y are not at risks For children of HFE Proband screen other parent if negative no risk to child

Indian scenario Primary iron overload in Indians is non-HFE type, which is different from that in Europeans

Studied 236 patient with CLD None had C282Y mutation, H63D heterozygosity

was seen in only 2 of 17 primary iron overload patients

WJG 2007 RK Dhiman et al Our patients with HH lack mutations in, Hepcidin and Ferroportin genes

Nat Med Jour Of India 2006 Rakesh Aggrawal et al