Iron Overload Flashcards
Define Haemosiderosis & Haemochromatosis
Haemosiderosis – state of iron deposition in various body tissues or organs
Haemochromatosis – clinical expression of iron-induced injury in the affected tissue
Discuss Hereditary/Primary haemochromatosis
Hereditary/Primary haemochromatosis – is a congenital cause that is due to abnormal increase in intestinal iron absorption.
Clinical presentation is between 40-60yrs but clinical penetrance is low.
Full phenotypic expression is enhanced by alcoholism, hepatitis, chronic hemolysis, chronic transfusion, exogenous iron etc.
Menstrual loss in women account for low frequency and delay onset.
Discuss haemochromatosis Type 1
Type 1 - is the most common genetic cause found in the Northern European population. It is an autosomal recesive trait
What are the possible mutations in HFE gene?
Mutation in HFE gene
- C282Y – G to A at nucleotide 845 (cysteine to tyrosine at 282). 10-13% are heterozygous, 1 in 200-250 are homozygous
- H63D – G to C at 187 (histidine to aspartate at 63). About 30% are heterozygous
S65C – A to T at 193 (serine to cysteine at 65). It is rare - C282Y/C282Y – homozygous state, account for 90% of clinical cases of hereditary hemochromatosis
- C282Y/WT – heterozygous state, only few develops clinical evidence of iron overload
- H63D/H63D – few develops clinical symptoms
- C282Y/H63D – compound heterozygous with mild subclinical iron overload
- H63D/WT – heterozygous, rarely develops clinical or biochemical evidence of iron overload
- Digenetic disease – heterozygote for C282Y and also mutation in HAMP gene (hepcidin gene)
Discuss the clinical features of haemochromatosis Type 1
Clinical features
Early symptoms – chronic fatigue, weakness, abdominal pain, arthralgia, elevated liver enzymes, arthritis/pseudogout
Endocrine complication – DM, hypothyroidism, gonadal failure
Heart failure, arrythmias
Iron induced liver damage, liver cirrhosis, HCC
Skin bronzing/grey skin pigmentation
How can iron status to tested be used to diagnose haemochromatosis Type 1?
Iron status
Transferrin saturation – most sensitive and cost effective initial screening test. Male > 60%, female > 45-50% is abnormal
Serum ferritin – surrogate marker of total iron stores. Male > 300µg/L, female > 200µg/L
How can a liver biopsy be used to diagnose haemochromatosis Type 1?
Liver biopsy – is the gold standard but less frequently done.
It gives information about iron content, distribution, degree of cirrhosis
It is done if ferritin >1000µg/L, in abnormal liver function test, in advanced age to evaluate liver cirrhosis
It is diagnostic of iron overload if there is
Perl’s stain grade ¾
Hepatic iron concentration > 80µmol/g dry weight(4.5mg/g)
Hepatic iron index score ≥ 1.9 (progressive increase in hepatic iron /age in years)
How can Desferrioxamine be used to teset for Type 1 Haemochromatosis?
Desferrioxamine-induced iron excretion – single IM injection is given. Urinary excretion of iron > 2mg in 24hrs indicates increased iron stores
Non-invasive methods os Type 1 Haemochromatosis diagnosis?
Non-invasive methods – semiconducting quantum interface device (SQUID), MRI
Discuss Phlebotomy in the management of Primary iron overload
Can iron chelation be used?
Phlebotomy is the key therapeutic modality. It prolongs life expectancy if goal is met.
Venesection:
1 unit of blood (200-250mg of iron & 30ng/ml of ferritin) is removed weekly until ferritin < 20µg/L & transferrin saturation < 16%. Hb levels should be measured weekly & the rate of venesection reduced if anaemia develops.
In normal individual, total iron store is 1g, 4-6 phlebotomies are required to make the patient iron deficiency
But patients with haemochromatosis will not become iron def until at least 4g of iron is removed i.e. 16 phlebotomies
In advanced case, total body iron stores could be as high as 20g ,thus, requires weekly phlebotomy for 1yr
After attaining the target ferritin value, maintenance is every 2-4 months phlebotomy/year
Iron chelation should only be considered in rare cases where phlebotomy is contraindicated e.g. anaemia, short term treatment in life threatening cardiac failure
Discuss Type 2 (juvenile) haemochromatosis
- Type 2 (juvenile) haemochromatosis – is autosomal recessive, with early onset iron overload.
- Clinical presentation is 2nd or 3rd decade of life (cardiomyopathy, cardiac failure, endocrine diseases, hypogonadism)
- It is characterized by mutation in haemojuvelin gene at chromosome 1q21
Intestinal iron absorption is greater than type 1 - Haemojuvelin modulates hepcidin expression & hepcidin levels are low in homozygous individuals
- Mutations in hepcidin gene (HAMP) have been described in several families with a type of juvenile haemochromatosis not linked to chromosome 1.
- affected subjects were homozygous for the mutation in each case
Discuss Type 3 haemochromatosis
Type 3 – is phenotypically similar to HFE-associated haemochromatosis
It due to transferrin receptor 2 gene mutation
Hepcidin level is low
Discuss Type 4 haemochromatosis
- Type 4 – is an autosomal dominant trait, due to heterozygous mutation in iron transporter, ferroportin 1 coded on chromosome 2q32 & deletion of valine at 162 has been found in some families
- Increased serum ferritin but normal transferrin saturation
- Liver biopsy shows increase in both hepatocytes & RES
Phenotype is similar to anaemia of chronic disorders
Discuss Neonatal haemochromatosis
Neonatal haemochromatosis – occur inutero with perinatal liver cirrhosis, thus, the only option is liver transplant
- Infusion of γ-globulin in pregnancy reduces severity
It has been linked in some cases to presence of maternal factor e.g. antiribonuclear antibody/alloantibody with unknown target antigen
What is Secondary causes of iron overload?
Chronic haemolytic anaemias -Thalassemia major, G6PD def, PKD def, dyserythropoietic anaemia, hereditary spherocytosis, sideroblastic anaemia (ALA-S def), megaloblastic anaemia
Due to increased erythroid destruction (hyperremia) & anaemia leads to increased intestinal absorption
Iatrogenic iron overload (chronic blood transfusion) e.g. aplastic anaemia, SCA, MDS, pure red cell aplasia
Endemic form of nutritional iron overload (African/Bantu siderosis) – results from combination of dietary component (brewing of beer in large iron kegs) & an unknown susceptibility gene probably ferroportin gene
Alcoholism
Hepatitis
NASH
Porphyria cutanea tarda
Chronic medicinal iron intake
Hereditary atransferrinaemia – iron deposition due to ineffective utilization of iron by erythroid cells
Hereditary aceruloplasminaemia – ceruloplasmin has ferroxidase activity to release iron from cells. Mutated gene result in accumulation of excess iron , normal transferrin, degeneration of retina, basal ganglia & DM
