Primary Hemochromatosis Prevalence Studies in India

Overview

Key Studies from India

1. Thakur et al., 2004 - AIIMS, New Delhi (PMID: 14675248)

• Design: Prospective case-control, 249 biopsy-proven chronic liver disease (CLD) patients + 134 healthy controls, tertiary care center
• Key finding: Zero cases of the C282Y (Cys282Tyr) mutation in either patients or controls
• Iron overload phenotype (TSI >60%) was found in 9.64% of CLD patients, but this was independent of the C282Y mutation
• Conclusion: Large population-based studies needed; classic HFE hemochromatosis appears absent in India

2. Dhillon et al., 2007 - Chandigarh, North India (PMID: 17589946)

• Design: Case-control, 236 CLD patients + 100 controls; tested all three common HFE mutations (C282Y, H63D, S65C)
• Key findings:
  • C282Y and S65C: completely absent in all subjects
  • H63D heterozygosity: present in ~12% of normal controls and ~14.8% of CLD patients
  • Iron overload was found in 17 patients (7.2%), predominantly those with cryptogenic cirrhosis
  • Only 2 of 17 iron overload patients were heterozygous for H63D
  • One H63D homozygote had no iron overload
• Conclusion: "Primary iron overload in Indians is non-HFE type, different from Europeans"

3. Garewal et al., 2005 - North India (PMID: 15777346)

• Design: Screened 60 normal subjects + 215 beta-thalassemia trait patients for C282Y and H63D
• Key findings:
  • C282Y: absent in all
  • H63D allele frequency: 9.09% overall; 3 individuals homozygous for H63D
  • H63D did not increase body iron stores in thalassemia trait
  • H63D haplotype pattern was European-type, suggesting a common ancestral origin
• Conclusion: H63D is prevalent in north Indians but does not drive iron overload

4. Panigrahi et al., 2006 - AIIMS, New Delhi (PMID: 17130663)

• Design: Prospective study of unexplained liver cirrhosis with high transferrin saturation (>45%)
• Key findings:
  • 7 of 31 unexplained cirrhosis cases (22.6%) had HFE mutations
  • No C282Y mutation found in any patient or control
  • H63D prevalence in healthy controls: 8.1% (6/74)
  • One family showed autosomal dominant inheritance, suggesting a non-HFE gene with dominant pattern
  • Y250X mutation of TFR gene: absent in all subjects
• Conclusion: Non-HFE linked hemochromatosis exists in Indian patients; a dominant-acting gene may be involved in some families

5. Duseja et al., 2005 - Chandigarh, North India (PMID: 15637751)

• Design: NASH patients studied for iron status and HFE mutations
• Key findings:
  • No C282Y mutation detected
  • H63D heterozygosity: 25% of NASH patients
  • Iron overload (TSI >55%) in only 4.3% of NASH patients
• Conclusion: Iron overload and HFE mutations are not significant factors in NASH pathogenesis in Asian Indians

6. Danda et al., 2010 - South India, Vellore (PMID: 22842326)

• Studied HFE mutant allele prevalence in a Tamilian cohort (South India)
• Extended the finding of low/absent C282Y to South Indian populations
• Confirmed regional consistency of low HFE mutation burden across India

7. Dhillon et al., 2018 - North India (PMID: 30195625) - Most Recent & Molecularly Detailed

• Design: Screened 258 CLD patients; 19 identified with HH based on transferrin saturation, ferritin >1000 ng/L, and Perl's stain on biopsy
• Complete gene sequencing of HFE, HJV, HAMP, TFR2, and SLC40A1
• Key findings:
  • C282Y: absent
  • Novel HJV (hemojuvelin) mutation p.Gly336Ter identified in 4 unrelated patients - proposed as a recurrent mutation in North Indians
  • Compound heterozygosity for TFR2/HFE mutations in 1 patient
  • Novel polymorphisms in 5'UTR of HJV gene in 2 patients
• Significance: First molecular characterization of non-HFE HH in India; HJV mutations appear to be the dominant genetic cause in Indians; interestingly, these cases presented in adults (typically juvenile HH presents earlier), possibly due to nutritional iron deficiency and menstrual losses masking the phenotype

Summary of Prevalence Data

Why is Classic HFE Hemochromatosis Rare in India?

1. Population genetics: The C282Y mutation arose as a single founder event ~60-70 generations ago in Celtic/Viking ancestry populations and did not spread to South Asian gene pools.
2. Low baseline iron stores: Nutritional iron deficiency is common in India, masking the phenotypic expression of even partial iron-loading mutations.
3. Menstrual iron losses: May delay clinical presentation in women, contributing to underdiagnosis.
4. Different molecular substrate: When hereditary iron overload does occur, it is driven by mutations in other genes - particularly HJV - rather than HFE.

Limitations of the Existing Indian Data

• All studies are from tertiary care centers (selection bias)
• No large community-based or population-level prevalence studies exist
• Sample sizes are small (most under 300 subjects)
• Most studies pre-date next-generation sequencing, so non-HFE mutations were under-investigated in early work
• The 2018 Dhillon study is the most comprehensive molecular analysis but still covers only 258 patients
• South India is underrepresented in the literature relative to North India