education

1. © 2015 International Journal of Health & Allied Sciences | Published by Wolters Kluwer - Medknow174
ABSTRACT
Hereditary hemochromatosis (HH) is manifested as an
iron overload in different organs due to homozygosity
of a single autosomal mutation. If untreated it leads to
conditions such as liver cirrhosis, type 1 diabetes mellitus,
hypogonadotropic hypogonadism, cardiomyopathy,
arthritis, and bronze coloring of the skin. Hemochromatosis
affects as many as 1 in every 200 people in the United
States, but in India the reports of genetic study are rare
and virtually unexplored. It is also possible that in India
clinical hemochromatosis could be masked by iron
deficiency. Patients with HH may be either asymptomatic
or symptomatic. When symptomatic, there is a wide range
of symptoms and a high index of suspicion based on the
symptoms is necessary to diagnose the entity. We report
an interesting and rare case of HH in a 35‑year‑old male
of Indian origin, who presented with icterus and fever of
acute onset with negative HFE genetic mutations.
Key words: Autosomal recessive disorder,
hemochromatosis, India
triad of glycosuria, cirrhosis, and hyperpigmentation
of skin.[1]
The term hemochromatosis was first used by
Von Recklinghausen in 1889.[1]
HH is commonly due to
two histone family E1 (HFE1), gene mutations‑C282Y,
and H63D.[2]
HFE gene is located within the human
leukocyte antigen (HLA) class 1 region on chromosome
6 between the genes coding for HLA‑A and HLA‑B.[3]
Two mutations in the HFE gene have been described.
The first, C282Y, comprises the substitution of tyrosine
for cystine at amino acid position 282. In the second,
H63D, aspartic acid is substituted for histidine in position
63. C282Y/H63D is found in most patients with HH.[3]
Secondary hemochromatosis is caused by disorders of
erythropoiesis and treatment of the diseases with blood
transfusions.[4]
Hereditary hemochromatosis is characterized by
abnormal iron absorption from the diet resulting in
progressive iron overload, causing tissue damage in
several organs, particularly the liver.[5]
Historically, HH
has been regarded as an extremely rare inborn error of
metabolism resulting in the causation of bronze diabetes,
liver cirrhosis, and hepatocellular carcinoma due to heavy
iron overload in the liver and pancreas.[6]
HFE gene
mutations are strongly associated with predisposition to
HH and are also implicated in other disorders such as
rheumatoid arthritis, type 2 diabetes mellitus, porphyria
cutanea tarda, and coronary heart disease.[7]
Considerable
ethnic variation is observed in the frequency distribution
of HFE mutations. HH is rare in India, whereas in
northwestern Europe one in every Caucasian is a carrier
of HFE gene.[7]
Hereditary hemochromatosis in an Indian origin:
A rare case report
RL Geetha, BR Vani, V Srinivasa Murthy, Deepak Kumar, K Geethamala
Department of Pathology, ESIC Medical College and PGIMSR, Bengaluru, Karnataka, India
Access this article online
Quick Response Code:
Website:
www.ijhas.in
DOI:
10.4103/2278-344X.160894
Address for correspondence: Dr. RL Geetha,
Department of Pathology, ESIC Medical College and PGIMSR, Rajajinagar,
Bengaluru, Karnataka, India.
E‑mail: gitaumi@gmail.com
INTRODUCTION
Hereditary hemochromatosis (HH), is an autosomal
recessive disorder with Iron overload in different
organs, especially in the liver.[1]
The monoallelic genetic
disease was first described by Trousseau in 1889 as a
Case Report
This is an open access article distributed under the terms of the Creative
Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows
others to remix, tweak, and build upon the work non‑commercially, as long as the
author is credited and the new creations are licensed under the identical terms.
For reprints contact: reprints@medknow.com
How to cite this article: Geetha RL, Vani BR, Murthy VS, Kumar D,
Geethamala K. Hereditary hemochromatosis in an Indian origin: A rare
case report. Int J Health Allied Sci 2015;4:174-7.
[Downloaded free from http://www.ijhas.in on Friday, October 5, 2018, IP: 120.59.221.43]

2. Geetha, et al.: Hereditary hemochromatosis in an Indian origin
International Journal of Health & Allied Sciences • Vol. 4 • Issue 3 • Jul-Sep 2015 175
CASE REPORT
A 35‑year‑old male patient, an agriculturist by occupation
presented to our medical outpatient department with
yellowish discoloration of the conjunctiva, fever of acute
onset with reduced appetite and tiredness. Patient had an
earlier episode of jaundice ten years back for which he
took herbal medicine and was cured. He was diagnosed
with diabetes mellitus five years back and was stated on
oral medication. A year back patient presented with severe
anemia and was transfused with one pint of whole blood.
On examination, he was obese, febrile, pale, and had bilateral
pedal edema. Cardiac examination was unremarkable.
Abdomen was soft and pendulous. Hepatosplenomegaly was
present. Patient had gynecomastia and history of infertility.
In view of obesity with diabetes mellitus, gynecomastia and
infertility, a probable clinical diagnosis of hemochromatosis
was made and the patient was evaluated for the same.
On investigating, the patient’s hemoglobin was 5.5 g/dL,
peripheral smear showed severe macrocytic anemia with
pancytopenia. Serum iron (248 mg/dL) and serum
ferritin (1179 mg/dL) were increased with marked
increase in transferrin saturation of 68.9%. Serum Folate
(1.31 ng/mL) and serum Vitamin B12
(55 pg/mL) were
decreased. Liver function test revealed raise in serum
bilirubin (2.6 mg/dL) and the rest of the parameters
were normal. Renal function tests, thyroid function tests,
and hormone levels were within normal limits. Serology
for HIV, Venereal Disease Research Laboratory, and
hepatitis were negative. Ultrasonogram abdomen revealed
hepatosplenomegaly. Magnetic resonance imaging revealed
moderate hepatomegaly with diffusely hypo‑intense
signal changes in all the sequences – and was diagnosed
as features suggestive of hemochromatosis. A liver biopsy
was done. Hematoxylin and eosin stained sections of the
liver showed extensive golden brown pigment deposition
in the cytoplasm of hepatocytes, predominantly periportal
and in hepatic sinusoids [Figures 1 and 2]. A Perl’s stain
was performed on the liver tissue, which showed marked
increase in iron stores with extensive blue staining
hemosiderin deposits [Figure 3], predominantly in
periportal hepatocytes and also in perisinusoidal lining
cells (Kupffer cells).Reticulin stain revealed an altered liver
architecture with extensive fibrosis [Figure 4]. Based on the
clinical features, laboratory investigations, and liver biopsy
findings, a diagnosis of hemochromatosis was made. As
the various causes of secondary hemochromatosis were
ruled out, the above features pointed toward a diagnosis
of HH. Genetic studies for HFE gene, C282Y and H63D
mutations were done by polymerase chain reaction using
Qiagen mini kits for DNA extraction and was negative.
Since our patient was severely anemic of megaloblastic
type, Vitamin B12
injections, and folic acid supplementation
was given for 6 months till hemoglobin was brought to
normal. Later effective phlebotomy was started: One 500
cc unit every 2–3 months with an intention to bring serum
ferritin levels to 50–150 ng/mL and transferrin saturation
to <45%. The patients present serum ferritin level is
400 ng/mL, transferrin saturation is 52%, and is on the
continuation of phlebotomy.
DISCUSSION
Hereditary hemochromatosis is characterized by abnormal
iron absorption from the diet resulting in progressive
iron overload, causing tissue damage of several organs,
particularly the liver. Two different mutations C282Y and
H63D in the HFE gene have been shown to be associated
with over 93% of HH cases. The disease is seen in Northern
European population but in India the reports of genetic
study are rare.[7]
Figure 1: Photomicrograph of liver showing golden brown
pigment deposition in the cytoplasm of hepatocytes.
(H&E 10X).
Figure 2: Photomicrograph of liver showing golden brown
pigment deposition in the cytoplasm of hepatocytes. (H& E 40X)
[Downloaded free from http://www.ijhas.in on Friday, October 5, 2018, IP: 120.59.221.43]

3. Geetha, et al.: Hereditary hemochromatosis in an Indian origin
International Journal of Health & Allied Sciences • Vol. 4 • Issue 3 • Jul-Sep 2015176
HH can be either asymptomatic or symptomatic.
Some individuals who test positive for HH remain
asymptomatic throughout their life. In the present case,
the patient presented with icterus, fever of acute onset
with reduced appetite and tiredness. Diagnosis of HH is
based on measurement of transferrin saturation, serum
ferritin levels, and mutation analysis of HFE. In the
present case, serum iron (248 mg/dL) and serum ferritin
(1179 mg/dL) were increased with marked increase
in transferrin saturation– (68.9%), which is diagnostic
of hemochromatosis. Patient had hepatomegaly with
a raised serum bilirubin, a common clinical finding in
hemochromatosis. Liver biopsy confirmed the deposition
of iron and fibrosis. Liver biopsy is used to evaluate the
underlying disease, determine the fibrosis and degree of
iron load.[8]
Importance of liver biopsy also lies in the
fact that documentation of extensive bridging fibrosis or
cirrhosis has a profound impact on the prognosis in HH
patients.[9]
Given the prevalence of the condition, some specialists
suggest screening to detect HH before it causes problems.
The following approaches to screening have been
suggested.[8-11]
• Transferrin saturation testing in all adults at age 20,
and every five years thereafter for anyone who has a
family history of the disease
• Genetic screening of newborns to potentially benefit
both the child and the rest of the family
• Routine iron testing of all kids at age 4, those who have
a genetic risk, but remain symptom‑free, continue to be
tested every five years thereafter.
Absenceof symptomsisnonethelesscommon,particularlyin
young individuals, due to the variable phenotypic expression
of the disease and variations of lifetime accumulation of
iron stores. Early detection, in conjunction with routine
screening procedures is of utmost importance because
effective therapy is available through phlebotomy.[8‑10]
Kaur et al.[7]
and Shukla et al.[12]
concluded that, in India,
the disease is uncommon and lacked the genetic defects
like mutations in the HFE and other genes such as hepcidin
and ferroportin similar to our case where in genetic studies
carried out were negative for HFE mutations. Further,
genetic analysis may help identify novel mutations
responsible for primary hemochromatosis.
In hemochromatosis, a normal life expectancy can be
achieved if early diagnosis and treatment are given before
irreversible damage can occur.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Poddar S. Hereditary hemochromatosis – Special reference to Indian
scenario. Int J Hum Genet 2006;6:73‑9.
2. Panigrahi I, Ahmad F, Kapoor R, Sharma PK, Makharia G, Saxena R.
Evidence for non‑HFE linked hemochromatosis in Asian Indians. Indian
J Med Sci 2006;60:491‑5.
3. Capell P. Case study: Hemachromatosis in type 2 diabetes. Clin
Diabetes 2004;22:101‑2.
4. Gattermann N. The treatment of secondary hemochromatosis. Dtsch
Arztebl Int 2009;106:499‑504.
5. Bothwell TH, MacPhail AP. Hereditary hemochromatosis: Etiologic,
pathologic, and clinical aspects. Semin Hematol 1998;35:55‑71.
6. Brissot P, Guyader D, Loréal O, Lainé F, Guillygomarc’h A,
Figure 3: Perl’s stain showing marked increase in iron stores
with extensive blue staining hemosiderin deposits. (10X)
Figure 4: Reticulin stain showing an altered liver architecture
with extensive fibrosis. (10X)
[Downloaded free from http://www.ijhas.in on Friday, October 5, 2018, IP: 120.59.221.43]

4. Geetha, et al.: Hereditary hemochromatosis in an Indian origin
International Journal of Health & Allied Sciences • Vol. 4 • Issue 3 • Jul-Sep 2015 177
Moirand R, et al. Clinical aspects of hemochromatosis. Transfus Sci
2000;23:193‑200.
7. Kaur G, Rapthap CC, Xavier M, Saxena R, Choudhary VP,
Reuben SK, et al. Distribution of C282Y and H63D mutations in the
HFE gene in healthy Asian Indians and patients with thalassaemia
major. Natl Med J India 2003;16:309‑10.
8. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American
Association for the Study of Liver Diseases. Diagnosis and
management of hemochromatosis: 2011 practice guideline by the
American Association for the Study of Liver Diseases. Hepatology
2011;54:328‑43.
9. Phatak PD, Bonkovsky HL, Kowdley KV. Hereditary hemochromatosis:
Time for targeted screening. Ann Intern Med 2008;149:270‑2.
10. Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening
for hereditary hemochromatosis: A systematic review for the U.S.
Preventive Services Task Force. Ann Intern Med 2006;145:209‑23.
11. Tavill AS, American Association for the Study of Liver Diseases,
American College of Gastroenterology, American Gastroenterological
Association. Diagnosis and management of hemochromatosis.
Hepatology 2001;33:1321‑8.
12. Shukla P, Julka S, Bhatia E, Shah S, Nagral A, Aggarwal R.
HFE, hepcidin and ferroportin gene mutations are not present in
Indian patients with primary haemochromatosis. Natl Med J India
2006;19:20‑3.
[Downloaded free from http://www.ijhas.in on Friday, October 5, 2018, IP: 120.59.221.43]