Hemochromatosis - DOES IT EXIST IN iNDIAx

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Dec 13, 2013 (3 years and 10 months ago)

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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 parenchymal
cells (
particularly hepatocytes
) and, eventually,

to
organ disease
.

Iron homeostasis in humans

Pietrangelo
. New
Engl

J Med 2004; 350: 2383
-
97.

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.

HFE gene frequency in Caucasians

Population
sample


Country



Sample
size


Prevalence of
C282
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: S14
-
S23.

C282Y HFE mutation: Indian population

Study

City

Number of

subjects

Number

of


Y alleles

Number of
total alleles

% of

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

HFE C282Y: Indian
Thallassemics

Study

City

Number of

subjects

Number

of


Y alleles

Number of
total alleles

% of

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

HFE C282Y: Indian liver disease patients

Study

City

Number of

subjects

Number

of


Y alleles

Number of
total alleles

% of

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%

H63D HFE mutation in Indian population

Study

City

Number of

subjects

Number

of


Y alleles

Number of
total alleles

% of

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

HFE H63D:
Thallassemia

/ Liver disease

Study

City

Number of

subjects

Number

of


Y alleles

Number of
total alleles

% of

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

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: 20
-
3.

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: 20
-
3.

Shukla et al.
Natl

Med J India 2006; 19: 20
-
3.

Indian patients with iron overload

PCR
-
RFLP for C282Y


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

Indian patients with iron overload

Shukla et al.
Natl

Med J India 2006; 19: 20
-
3.

1

2

3

4

5

6

3

4

5

2

6

1

GTA
T
GTGGAGAGGGGGC

AAGG

GTA
T
GTGGAGAGGGGGC

AAGG

GTA
C
GTCGAGAGGGGGC

AAGG

GTA
Y
GTGGAGAGGGGGC

AAGG

GTA
C
GTCGAGAGGGGGC

AAGG

GTA
Y
GTGGAGAGGGGGC

AAGG

Z92910.1

Patient #1

Patient #2

Patient #3

Patient #4

Patient #5

Y = T or C

Splice
site

Intron

Exon

Indian patients with iron overload

Shukla et al.
Natl

Med J India 2006; 19: 20
-
3.

Other data from the Indian subcontinent

Family

Origin

Onset

age

Protein

Exon

AA
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.

Hemochromatosis in India: Summary



Iron overload



Occasional



C282Y mutation


Very infrequent



C282Y HFE disease


Extremely rare