Hemochromatosis

The most common mutation in hereditary hemochromatos is a homozygous G to A mutation resulting in a cysteine to tyrosine substitution at position 282 (C282Y). Another relatively common  mutation (H63D) results in a substitution of histidine to aspartic acid at codon 63.

Mutations like  transferrin receptor 2 TFR2 mutation and  ferroportin 1 gene, SLC11A3 mutation are rare.

Ref: Harrisons principles of internal medicine, 18th edition, Page: 3162

Phlebotomy is the treatment of choice of hemochromatosis. Chelating agent desferrioxamine is indicated when anemia or hypoproteinemia is severe enough to preclude phlebotomy.

Hemochromatosis is a common inherited disorder of iron metabolism in which dysregulation of intestinal iron absorption results in deposition of excessive amounts of iron in parenchymal cells resulting in tissue damage and organ dysfunction.

Liver is the first organ to be affected and hepatomegaly is seen in more than 95% of patients. Diabetes mellitus occur in 65% of patients with advanced disease. Arthropathy is seen in 20-25% of symptomatic patients. Second and third metacarpophalangeal joints are the first joints to be involved.

Manifestations of hypogonadism includes loss of libido, impotence, amenorrhea, testicular atrophy and gynecomastia. Most common cardiac manifestation is congestive heart failure.

Ans. is `a’ i.e., Iron

o Hemochromatosis is characterized by the excessive accumulation of body iron, most of which is deposited in parenchymal organs such as the liver and pancreas.

Answer is C (Increased Transferrin Saturation):

Transferrin Saturation is the first blood test to become elevated in Hemochromatosis.

The first biochemical manifestation of hemochromatosis is an increase of transferring saturation, which reflects an uncontrolled influx of iron into the blood stream _.from enterocytes and macrophages.

The serum transferrin saturation and serum ferritin levels are the two most important indicators of hemochromatosis and body iron stores.

Elevation of transferrin levels precedes elevation offerritin levels.

The first biochemical manifestation of hetnochromatosis is an increase in serum transferrin saturation.

Serum iron concentration per se is not a good indicator for iron overload states like Hemochromatosis.

Liver Enzymes may be normal or elevated depending on the extent of hepatocyte damage.

They are usually normal or only mildly elevated in the early stages of hemochromatosis.

Laboratory findings in Hemochromatosis

Transferrin saturation is the first blood test to become elevated in hemochromatosis homozygotes

The sensitivity of elevated transferring saturation to identify a patient with hemochromatosis is 94 to 98% and its specificity is 70 to 98%.

Transferrin saturation is usually > 60% in symptomatic men and >50% in symptomatic women

• Unbound
• Serum
• Liver

DNA testing by polymerase chain reaction may he used to detect mutations of the HFE gene.

Answer is C (Desferroxamine is the treatment of choice):

The therapy of hematochromatosis involves removal of excess body iron Iron removal is best acieved by periodic phlebotomies which is the treatment of choice for Hematochromosis.

Chelating agents like desferoxamine are less effective and indicated when anemia or hypoproteinemia is severe enough to preclude phlebotomy (Harrison.

Chelatingagents are not the treatment of choice for Hematochromatosis.

Answer is D (Desferrioxamine is the treatment of choice):

The treatment of choice for Hematochromatosis is removed of excess body iron by Phlebotomy and not with the use of chelating agents like desfernoxamine.

Removal of Excessive Body iron

• Phlebotomy is the treatment of choice  Iron removal is best accomplished by once or twice weekly phlebotomy of 500m1,

– These should be continued until the serum ferritin level is < 50pg/L (May be required for 1-2 years)

– Thereafter phlebotomies are performed at appropriate intervals to maintain ferritin levels between 50-100 tg/L (usually one phlebotomy every 3 months)

• Chelating agents (such as Desferoxamine) are alternative agents and indicated when anemia and hypoproteinemia are severe enough to preclude phlebotomy

Treatment of Haematochromatosis

Alcohol consumption should he eleminated^Q as increases ruck hematochronhth,sLs ten /oh/ Arthropathv,

Hypogonadism, Diabetes and Bronzing (pigmentation) of skin are all characteristic manifestation of hematochromatosis

Note: The combination of skin hyperpigmentation and insulin deficiency (diabetes) is called Bronze diabetes.

The characterstic  clinical features of Haemoehromatosis in order frequency are^Q :

• Hepatomegaly (95%1
• Skin pigmentation (90%)
• Diabetes mellitus (65%)
• Arthropathy (25-50%)
• Cardiac disease (15%)
• Hypogonadism

Answer is B Inherited as an autosomal recessive disorder

Hereditary Hemochromatosis is essentially inherited us an autosomal recessive condition.

Hereditar^y Hemochromatosis is essentiall^y an Autosomal Recessive condition

The most common form of hereditary hemochromatosis is related to mutations in HFE gene, which is a gene located on the short arm of chromosome 6 and is FILA linked

HFE related hereditary hemochromatosis (most common type) is inherited as an autosomal recessive condition

Hereditary Hemochromatosis shows incomplete penetrance

Incomplete penetrance refers to the lack of disease symptoms in an individual despite the presence of pathological gene mutation

Expression of Hemochromatosis is variable and many HFE positive people neither have nor develop disease, thus displaying the phenomenon of incomplete penetrance

This suggests that other genetic and / or environmental factors modify the pathogenesis of disease Hereditar^y Hemochromatosis is more common in Men

The clinical expression of disease is 5 –10 times more common in men than women – Harrison Phlebotom^y is an effective management option but it does not lead to cure

The therapy of hemochromatosis involves removal of excess body iron which is best accomplished by phlebotomy Phlebotomy is not curative and will be required at appropriate intervals to maintain_.ferritin levels (usually one phlebotomy every 3 months)’ – Harrison

Ans. is ‘a’ i.e., Iron

• Hemochromatosis is characterized by the excessive accumulation of body iron, most of which is deposited in parenchymal organs such as liver and pancreas.
• Hemochromatosis is a disorder of iron metabolism.
• Characterized by a triad of :-
• Micronodular cirrhosis

1. Diabetes mellitus
2. Skin pigmentation

• Organ not showing iron deposition in hemochromatosis

1. Testis

Ans. is ‘c’ i.e., Testis

In hemochromatosis, hypogonadism is caused by impairment of hypothalamic pituitary function and not due to deposition of Iron in the Testis.

Hemochromatosis

• Hemochromatosis is characterized by the excessive accumulation of body iron, most of which is deposited in parenchymal organs such as liver and pancreas.
• The total body content of the iron is tightly regulated, as the daily losses are matched by gastrointestinal absorption. In hereditary hemochromatosis, regulation of intestinal absorption of dietary iron is lost, leading to net iron accumulation of 0.5 to 1.0 gm/year.
• It may be recalled that the total body iron pool ranges from 2-6 gm in normal adults; about 0.5 gm is stored in the liver 98% of which is hepatocytes. In hemochromatosis the iron accumulation may exceed 50 gm, over one third of which accumulates in the liver.
• The iron accumulation is life long, the rate of net iron accumulation is 0.5 to 1.0 gm/year. The disease manifests itself typically after 20 gm of storage iron have accumulated. The disease first mainfests itself in the fifth to sixth decades of life.
• Excessive iron is directly toxic to host tissues
• The clinical features of hemochromatosis are characterized principally by deposition of excess iron in the following organs in decreasing order of severity.