Hereditary Hemochromatosis Genetics and Development Fall 2016

Hereditary Hemochromatosis Hereditary hemochromatosis is an autosomal recessive disorder that causes the body to absorb too much iron from the diet. The excess iron is stored in the body's tissues and organs, particularly the skin, heart, liver, pancreas, and joints hereditary hemochromatosis is also called an iron overload disorder.

Signs and Symptoms

Symptoms Some people with hereditary hemochromatosis never have symptoms. Early signs and symptoms often overlap with those of other common conditions. Common symptoms include: Joint pain Abdominal pain Fatigue Weakness Bronze Colored Skin

Later / Chronic signs and symptoms Later signs and symptoms of the disease may include: Diabetes Loss of sex drive Impotence Heart failure Liver failure

Liver Damage Liver absorpted bounded (transferrin) & unbound form (Fe3+).

Risk factors Factors that increase your risk of hereditary hemochromatosis include: Having 2 copies of a mutated HFE gene. This is the greatest risk factor for hereditary hemochromatosis. Family history  If you have a first-degree relative — a parent or sibling — with hemochromatosis, you're more likely to develop the disease. Ethnicity  People of Northern European descent are more prone

Risk factors Sex  Men are more likely than women to develop signs and symptoms of hemochromatosis at an earlier age. Because women lose iron through menstruation and pregnancy, they tend to store less of the mineral than men do. After menopause or a hysterectomy, the risk for women increases.

Onset Hereditary hemochromatosis is present at birth. But, most people don't experience signs and symptoms until later in life between the ages of 50 and 60 in men and after age 60 in women. Women are more likely to develop symptoms after menopause, when they no longer lose iron with menstruation and pregnancy.

Genetic Aspect A gene called HFE is most often the cause of hereditary hemochromatosis. You inherit one HFE gene from each of your parents. The HFE gene has two common mutations, C282Y and H63D.

Genetic Aspect One of the better characterized genes responsible for hereditary haemochromatosis is HFE on chromosome 6p21  which codes for a protein that participates in the regulation of iron absorption

Genetic Aspect The HFE gene has two common mutations, C282Y and H63D. The C282Y allele is a transition point mutation from guanine to adenine at nucleotide 845 in the HFE gene, resulting in a missense mutation that replaces the cysteine residue at position 282 with a tyrosine amino acid.

Proteins HFE code for The HFE gene codes for a 343 amino acid protein that is similar to class 1 MHC proteins. The C282Y mutation results in a mutant HFE protein which undergoes accelerated degradation and decreased expression on the cell surface.

C282Y (Major) According to Feder a study in 1996 two mutations in an MHC class I gene at chromosome 6p21 which is now named the 'HFE' gene and defines Type 1 HH. he 'major' mutation was a G to A substitution at nucleotide 845 which lead to a cysteine to tyrosine substitution at the amino acid 282, now commonly referred to a the 'C282Y' mutation. 

H63D (Minor) The 'minor' mutation was a C to G change at nucleotide 187 which resulted in a histidine to aspartic acid substitution at position 63 ('H63D').

Genotype Heterozygous: Having one copy of the abnormal HFE gene, for example C282Y or H63D – also known as a ‘carrier’. Homozygous: Two copies of the same gene abnormality, for example C282Y and C282Y. Compound heterozygous: Having one C282Y and one H63D abnormal gene. Compound heterozygotes usually have a milder form of haemochromatosis.

Genetic test result Explanation Risk of iron overload How many with the genotype? Homozygous C282Y 2 copies of the C282Y mutation Greatly increased risk 1 in 200 Compound heterozygous C282Y / H63D 1 copy of C282Y mutation and 1 copy of H63D mutation Increased risk 1 in 50 Homozygous H63D 2 copies of H63D mutation Very slightly increased risk 1 in 100 Heterozygous H63D 1 copy of H63D mutation and one normal gene Probably no increased risk 1 in 5 Heterozygous C282Y 1 copy of C282Y mutation and one normal gene 1 in 9 Normal genotype No mutations detected No increased risk 2 in 3

Different Forms Juvenile hemochromatosis This causes the same problems in young people that hereditary hemochromatosis causes in adults. But iron accumulation begins much earlier, and symptoms usually appear between the ages of 15 and 30. This disorder is caused by mutations in the hemojuvenile or hepcidin genes.

Genetic Aspect (Spoken) The function of DMT1 is to act as the mediator for iron absorption on the luminal aspect of the mature enterocyte located on duodenal villi. The expression of DMT1 in the mature, villous duodenal enterocyte is determined by the iron content of the immature duodenal crypt cell—low intracellular iron results in increased DMT1 expression and vice versa. Currently, a disease state related to germline mutations of genes coding for DMT1 is not known.

Genetic Aspect (Spoken) If you inherit 1 abnormal gene, you won't develop hemochromatosis. You are considered a gene mutation carrier and can pass the mutation on to your children. But, they wouldn't develop disease unless they also inherited another abnormal gene from the other parent. .

Treatment Prior to damage Organ Treatment of organ damage Phlebotomy Desferrioxamine Diet Treatment of organ damage Increasing intake of substances that inhibit iron

Phlebotomy Early diagnosis is vital as the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donations. Initiation of treatment is recommended when ferritin levels reach 500 mg/L Phlebotomy (or bloodletting) is usually done at a weekly interval until ferritin levels are less than 50 mg/L. In order to prevent iron reaccumulation, subsequent phlebotomies are normally carried out approximately once every three to four months for males, and twice a year for females.

Conditions ↓ intake or absorption & ↑ apoferritin production ↑ Cause Iron TIBC % Sat Ferritin MCV Iron deficiency anemia ↓ intake or absorption & ↑ apoferritin production ↓ ↓ ↑ ↓ ?? Hemolytic anemia RBC destruction ↓ -N N Pernicious anemia defective iron storage Hemochromatosis ↑ rate of absorption & ↓ ferritin production N- ↓ B-Thalessemia Ineffective erythropoiesis N- ↑ Lead Poisoning decreased RBC formation

Conditions Condition Cause Iron TIBC Ferritin Cirrhosis ↓ ferritin production ↓ Hepatitis ↑ release from stores & ↑ release of ferritin ↑

Treatment Desferrioxamine mesilate Where venesection is not possible, long-term administration of desferrioxamine mesilate is useful. Desferrioxamine is an iron- chelating compound, and excretion induced by desferrioxamine is enhanced by administration of Vitamin C. It cannot be used during pregnancy or breast-feeding due to risk of defects in the child.

Treatment Organ damage Treatment of organ damage (heart failure with diuretics and ACE inhibitor therapy). Diet Limiting intake of alcoholic beverages, vitamin C (increases iron absorption in the gut), red meat (high in iron) and potential causes of food poisoning (shellfish, seafood). Increasing intake of substances that inhibit iron absorption, such as high-tannin tea, calcium, and foods containing oxalic and phytic acids (such as collard greens, which must be consumed at the same time as the iron-containing foods in order to be effective).

References Haemochromatosis Australia: http://haemochromatosis.org.au/genetics/ Modern Pathology http://www.nature.com/modpathol/journal/v20/n1s/fig_tab/3800715f1.html#fig ure-title