Does HFE hemochromatosis exist in India Rakesh Aggarwal

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

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

Hemochromatosis A progressive increase in body iron content, leading to systemic iron loading of

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

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

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

Hemochromatosis: Types • Primary • Secondary – Parenteral iron overload • RBCs • Iron

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

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

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

HFE gene frequency in Caucasians Population sample Country Sample size Prevalence of C 282

HFE gene frequency in Caucasians Population sample Country Sample size Prevalence of C 282 homozygotes Allele frequency 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: S 14 -S 23.

C 282 Y HFE mutation: Indian population Study City Number of subjects Y alleles

C 282 Y HFE mutation: Indian population Study City Number of subjects Y alleles 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 1 2974 0. 034 Total * PCR using sequence-specific primers Number of % of total alleles Y allelles

HFE C 282 Y: Indian Thallassemics Study City Kaur, 2003 Delhi Garewal, 2005 Number

HFE C 282 Y: Indian Thallassemics Study City Kaur, 2003 Delhi Garewal, 2005 Number of subjects Y alleles Number of % of total alleles Y allelles 75 *6 150 4. 0 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 6 1616 0. 371 Total * PCR using sequence-specific primers

HFE C 282 Y: Indian liver disease patients Study City Thakur, 2004 Delhi Duseja,

HFE C 282 Y: Indian liver disease patients Study City Thakur, 2004 Delhi Duseja, 2005** Agarwal, 2006 Number of subjects Y alleles Number of % of total alleles Y allelles 249 0 498 0. 0 Chandigarh 16 0 32 0. 0 Lucknow 65 0 130 0. 0 31 0 62 0. 0 Panigrahi, 2006*** Delhi Dhillon, 2007 Chandigarh 236 0 472 0. 0 Jain, 2011 Lucknow 496 *1 992 0. 1 1 2186 0. 046 Total * PCR-RFLP ** Non-alcoholic steatohepatitis *** With transferrin saturation >45%

H 63 D HFE mutation in Indian population Study City Kaur, 2003 Delhi 116

H 63 D HFE mutation in Indian population Study City 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. 6 138 2586 5. 3 Total Number of subjects Y alleles Number of % of total alleles Y allelles

HFE H 63 D: Thallassemia / Liver disease Study City Number of subjects Y

HFE H 63 D: Thallassemia / Liver disease Study City Number of subjects Y alleles Number of % of total alleles Y allelles Thallassemia Kaur, 2003 Delhi Agarwal, 2007 Lucknow Sharma, 2007 Delhi 75 19 150 12. 7 308 49 616 8. 0 63 8 126 6. 3 76 892 8. 5 Total 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. 0 108 1558 6. 9 Total

Indian liver disease patients: Fe overload Author N Findings Thakur 249 24 (9. 6%)

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

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

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

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

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

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

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

Indian patients with iron overload PCR-RFLP for C 282 Y Shukla et al. Natl

Indian patients with iron overload PCR-RFLP for C 282 Y Shukla et al. Natl Med J India 2006; 19: 20 -3.

Indian patients with iron overload • HFE gene – None of the 5 patients

Indian patients with iron overload • HFE gene – None of the 5 patients had C 282 Y mutation – One had homozygous H 63 D mutation – None had previously known splice site mutations – Four had a IVS 2+4 T/C change • HAMP gene (Hepcidin) – None had G 71 A or IVS 2+1(-G) mutation • SLC 11 A 3 gene (Ferroportin) – None had G 71 A or IVS 2+1(-G) mutation Shukla et al. Natl Med J India 2006; 19: 20 -3.

Indian patients with iron overload 1 1 2 2 3 3 4 4 5

Indian patients with iron overload 1 1 2 2 3 3 4 4 5 5 6 6 Intron Z 92910. 1 Splice site AAGG GTATGTGGAGAGGGGGC Patient #1 AAGG GTATGTGGAGAGGGGGC Patient #2 AAGG GTACGTCGAGAGGGGGC Patient #3 AAGG GTAYGTGGAGAGGGGGC Patient #4 AAGG GTACGTCGAGAGGGGGC Patient #5 AAGG GTAYGTGGAGAGGGGGC Shukla et al. Natl Med J India 2006; 19: 20 -3. Exon Y = T or C

Other data from the Indian subcontinent Family Origin Onset age Protein Exon AA change

Other data from the Indian subcontinent Family Origin Onset age Protein Exon AA change A Bangladesh 19 Hemojuvelin 3 C 80 Y B Pakistan 26 Hemojuvelin 3 G 99 R C Pakistan 11 Hemojuvelin 3 G 99 R D Pakistan 23 Hemojuvelin 3 P 192 L E Pakistan 32 Hemojuvelin 3 L 194 P F Sri Lanka 17 Hemojuvelin 4 A 343 fs. X 23 G Pakistan 21 Hepcidin 2 R 42 Sfs H Thailand 38 Ferroportin 7 C 326 Y Lok et al. Blood 2009; 114: 20 -5.

Hemochromatosis in India: Summary • Iron overload Occasional • C 282 Y mutation Very

Hemochromatosis in India: Summary • Iron overload Occasional • C 282 Y mutation Very infrequent • C 282 Y HFE disease Extremely rare