Hemochromatosis is a genetic disorder characterized by excessive iron absorption and storage. It was first described in 1865 and the gene (HFE) was identified in 1996. Iron is absorbed in the duodenum and stored in the liver, heart and pancreas. Hepcidin regulates iron absorption and storage by binding to ferroportin. The HFE protein assists with iron sensing and regulation of hepcidin. Untreated iron overload can lead to cirrhosis, liver cancer, diabetes and heart disease. Evaluation involves iron studies and genetic testing. Treatment is regular phlebotomy to reduce iron levels. Prognosis is good if identified early and treated with phlebotomy. Family screening is important to identify other

1. Hemochromatosis,
evaluation and
management
Shankar Zanwar

2. 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.

3. 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

5. 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

6. Hepcidin – regulator of Fe
metabolism

7. 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

8. 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)

9. ...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

10. Patho-physio
Iron overload in
hepatocytes
Iron dependent lipid
peroxidation
Membrane
dysfunction of
miltochondria and
lysosomes
Hepatocyte death
Activation of Kupffer
cells
Release of
cytokines
activation of stellate
cells
Collagen
synthesisfibrosis
Cirrhosis

11. 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

12. 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

13. Iron indices in health and HH

14. 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.

15. 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

16. 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.

18. 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

19. Biopsy and genetics

20. 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.

21. 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

22. 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

23. 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

24. 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)

25. 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

26. 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 %

27. 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

28. 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