1. Does (HFE) hemochromatosis exist
in India?
Rakesh Aggarwal
Department of Gastroenterology
SGPGI, Lucknow

2. Hemochromatosis
A progressive increase in body iron content,
leading to systemic iron loading of parenchymal
cells (particularly hepatocytes) and, eventually,
to organ disease.

3. Iron homeostasis in humans
Pietrangelo. New Engl J Med 2004; 350: 2383-97.

4. Hemochromatosis: Types
• Primary
• Secondary
– Parenteral iron overload
• RBCs
• Iron
– Anemias
– Chronic liver disease (esp alcohol)

5. Hemochromatosis
Pietrangelo. New Engl J Med 2004; 350: 2383-97.

6. HFE gene frequency in Caucasians
Population Country Sample Prevalence of Allele
sample size C282 frequency
homozygotes
Electoral roll New Zealand 1,064 1 in 213 6.9%
Field survey Australia 3,011 1 in 188 7.3%
Primary care USA 4,865 1 in 405 5.0%
Health clinic USA 41,038 1 in 270 6.1%
Primary care USA/Canada 20,130 1 in 322 5.6%
Harrison SA, Bacon BR. J Hepatol 2003; 38: S14-S23.

7. C282Y HFE mutation: Indian population
Study City Number of Number of Number of % of
subjects Y alleles total alleles Y allelles
Kaur, 2003 Delhi 116 *1 232 0.4
Thakur, 2004 Delhi 134 0 268 0.0
Garewal, 2005 Chandigarh 60 0 120 0.0
Panigrahi, 2006 Delhi 74 0 148 0.0
Dhillon, 2007 Chandigarh 100 0 200 0.0
Dhillon, 2007 Chandigarh 80 0 160 0.0
Agarwal, 2007 Lucknow 421 0 842 0.0
Jain, 2011 Lucknow 502 0 1004 0.0
Total 1 2974 0.034
* PCR using sequence-specific primers

8. HFE C282Y: Indian Thallassemics
Study City Number of Number of Number of % of
subjects Y alleles total alleles Y allelles
Kaur, 2003 Delhi 75 *6 150 4.0
Garewal, 2005 Chandigarh 215 0 430 0.0
Agarwal, 2006 Lucknow 147 0 294 0.0
Agarwal, 2007 Lucknow 308 0 616 0.0
Sharma, 2007 Delhi 63 0 126 0.0
Total 6 1616 0.371
* PCR using sequence-specific primers

9. HFE C282Y: Indian liver disease patients
Study City Number of Number of Number of % of
subjects Y alleles total alleles Y allelles
Thakur, 2004 Delhi 249 0 498 0.0
Duseja, 2005** Chandigarh 16 0 32 0.0
Agarwal, 2006 Lucknow 65 0 130 0.0
Panigrahi, 2006*** Delhi 31 0 62 0.0
Dhillon, 2007 Chandigarh 236 0 472 0.0
Jain, 2011 Lucknow 496 *1 992 0.1
Total 1 2186 0.046
* PCR-RFLP
** Non-alcoholic steatohepatitis
*** With transferrin saturation >45%

10. H63D HFE mutation in Indian population
Study City Number of Number of Number of % of
subjects Y alleles total alleles Y allelles
Kaur, 2003 Delhi 116 20 232 8.6
Panigrahi, 2006 Delhi 74 6 148 4.1
Dhillon, 2007 Chandigarh 100 13 200 6.5
Dhillon, 2007 Chandigarh 80 6 160 3.8
Agarwal, 2007 Lucknow 421 47 842 5.6
Jain, 2011 Lucknow 502 46 1004 4.6
Total 138 2586 5.3

11. HFE H63D: Thallassemia / Liver disease
Study City Number of Number of Number of % of
subjects Y alleles total alleles Y allelles
Thallassemia
Kaur, 2003 Delhi 75 19 150 12.7
Agarwal, 2007 Lucknow 308 49 616 8.0
Sharma, 2007 Delhi 63 8 126 6.3
Total 76 892 8.5
Chronic liver disease
Duseja, 2005 Chandigarh 16 4 32 12.5
Panigrahi, 2006 Delhi 31 8 62 12.9
Dhillon, 2007 Chandigarh 236 36 472 7.6
Jain, 2011 Lucknow 496 60 992 6.0
Total 108 1558 6.9

12. Indian liver disease patients: Fe overload
Author N Findings
Thakur 249 24 (9.6%) had transferrin saturation >60%
Duseja 31 Only 1/23 (5%) had transferrin saturation >45%;
Liver biopsy in 16: none had 3+/4+ Perl stain
Dhillon 236 Only 17 (7.2%) had iron overload
Jain 496 Only 13 (2.6%) had iron overload

13. Indian patients with iron overload
Shukla et al. Natl Med J India 2006; 19: 20-3.

14. Indian patients with iron overload
Shukla et al. Natl Med J India 2006; 19: 20-3.

15. Indian patients with iron overload
Shukla et al. Natl Med J India 2006; 19: 20-3.

16. Indian patients with iron overload
PCR-RFLP for C282Y
Shukla et al. Natl Med J India 2006; 19: 20-3.

17. Indian patients with iron overload
• HFE gene
– None of the 5 patients had C282Y mutation
– One had homozygous H63D mutation
– None had previously known splice site mutations
– Four had a IVS2+4 T/C change
• HAMP gene (Hepcidin)
– None had G71A or IVS2+1(-G) mutation
• SLC11A3 gene (Ferroportin)
– None had G71A or IVS2+1(-G) mutation
Shukla et al. Natl Med J India 2006; 19: 20-3.

18. Indian patients with iron overload
1 2 3 4 5 6
1 2 3 4 5 6
Intron
Splice Exon
site
Z92910.1 AAGG GTATGTGGAGAGGGGGC
Patient #1 AAGG GTATGTGGAGAGGGGGC
Patient #2 AAGG GTACGTCGAGAGGGGGC
Patient #3 AAGG GTAYGTGGAGAGGGGGC
Patient #4 AAGG GTACGTCGAGAGGGGGC
Patient #5 AAGG GTAYGTGGAGAGGGGGC Y = T or C
Shukla et al. Natl Med J India 2006; 19: 20-3.

19. Other data from the Indian subcontinent
Family Origin Onset Protein Exon AA
age change
A Bangladesh 19 Hemojuvelin 3 C80Y
B Pakistan 26 Hemojuvelin 3 G99R
C Pakistan 11 Hemojuvelin 3 G99R
D Pakistan 23 Hemojuvelin 3 P192L
E Pakistan 32 Hemojuvelin 3 L194P
F Sri Lanka 17 Hemojuvelin 4 A343fsX23
G Pakistan 21 Hepcidin 2 R42Sfs
H Thailand 38 Ferroportin 7 C326Y
Lok et al. Blood 2009; 114: 20-5.

20. Hemochromatosis in India: Summary
• Iron overload Occasional
• C282Y mutation Very infrequent
• C282Y HFE disease Extremely rare