|Year : 2015 | Volume
| Issue : 3 | Page : 174-177
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
|Date of Web Publication||16-Jul-2015|
R L Geetha
Department of Pathology, ESIC Medical College and PGIMSR, Rajajinagar, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
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.
Keywords: Autosomal recessive disorder, hemochromatosis, India
|How to cite this article:|
Geetha R L, Vani B R, Murthy V S, Kumar D, Geethamala K. Hereditary hemochromatosis in an Indian origin: A rare case report. Int J Health Allied Sci 2015;4:174-7
|How to cite this URL:|
Geetha R L, Vani B R, Murthy V S, Kumar D, Geethamala K. Hereditary hemochromatosis in an Indian origin: A rare case report. Int J Health Allied Sci [serial online] 2015 [cited 2020 Jul 7];4:174-7. Available from: http://www.ijhas.in/text.asp?2015/4/3/174/160894
| Introduction|| |
Hereditary hemochromatosis (HH), is an autosomal recessive disorder with Iron overload in different organs, especially in the liver.  The monoallelic genetic disease was first described by Trousseau in 1889 as a triad of glycosuria, cirrhosis, and hyperpigmentation of skin.  The term hemochromatosis was first used by Von Recklinghausen in 1889.  HH is commonly due to two histone family E1 (HFE1), gene mutations-C282Y, and H63D.  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.  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.  Secondary hemochromatosis is caused by disorders of erythropoiesis and treatment of the diseases with blood transfusions. 
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.  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.  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.  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. 
| 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 B 12 (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 [Figure 1] and [Figure 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 B 12 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.
|Figure 1: Photomicrograph of liver showing golden brown pigment deposition in the cytoplasm of hepatocytes. (H&E 10X).|
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|Figure 3: Perl's stain showing marked increase in iron stores with extensive blue staining hemosiderin deposits. (10X)|
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|Figure 4: Reticulin stain showing an altered liver architecture with extensive fibrosis. (10X)|
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| 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. 
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.  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. 
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. ,,,
- 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.
Absence of symptoms is nonetheless common, particularly in 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. ,,
Kaur et al.  and Shukla et al.  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.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]