Introduction:

• It is a condition in which the amount of total body iron is markedly increased. (Normal is 3-4gms)
• It is also called as “Bronze diabetes”

Epidemiology:

• 4-5/1000 population in people with north European descent

Etiology:

• Hereditary
  • Type I hemochromatosis.
    • Autosomal recessive inheritance

Single point mutation (G to A at nucleotide 845) of HFF gene located on chromosome 6p, close to HLA gene locus

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Cysteine to tyrosine substitution at amino acid 282 (C282Y mutation)

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Decreased hepcidin release from liver

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No internalization/destruction of ferroportin

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Inappropriately increased intestinal absorption of iron

• Type II (Juvenile) Hemochromatosis
  • Autosomal recessive
  • Present at 2^nd-3^rd decade
  • Associated with cardiomyopathy
  • Hypogonadism

Hemojuvelin locus on Chr-1q 21 is mutated (G320V)

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Hemojuvelin is altered

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Decreased hepcidin levels

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Increased iron absorption

• Some are associated with mutation in HAMP gene which codes for Hepcidin
  • Type III Hemochromatosis
    • Mutation in transferrin receptor 2 gene
    • TFR2 binds to transferrin, but is not iron regulated.
  • Type IV hemochromatosis
    • Autosomal dominant inheritance
    • Associated with increased ferritin levels but normal transferrin      saturation
    • Liver biopsy shows increased iron in both RES &hepatocytes.
    • Mutation of Ferroportin 1 gene on chromosome 2q 32(Deletion of valine at position 162)
    • Treatment- Venesection with erythropoietin therapy
  • DMT1 associated hemochromatosis
    • Decreased hepcidin with high transferrin saturation
    • Normal or increased ferritin
    • Severe microcytic anemia
  • Atransferrinemia
    • Associated with hypochromic anaemia
    • Decreased hepcidin
    • Autosomal recessive inheritance
  • Aceruloplasminonemia
    • Decreased hepcidin
    • Autosomal recessive
    • Triad of 
      • Diabetes mellitus
      • Progressive neurological disease- dementia, dysarthria, dystonia
      • Retinal degeneration
  • Neonatal Hemochromatosis
    • Associated with heavy parenchymal deposition of iron in liver
    • Treatment- Liver transplantation.
    • Associated with anti ribonuclear antibody in mothers
    • Prevention- infusion of gamma globulins during pregnancy
  • Atransferrinemia
    • Associated with hypochromic anemia
    • Iron deposition in RES.
• Acquired:
  • Multiple blood transfusions/ chronic hypoxia. Iron content of each transfusion =volume in ml x hematocrit x 1.16mg.
    • Thalassemia
    • Sickle cell disease
    • Aplastic anemia
  • Dietary iron overload. (Bantu siderosis)
  • Multiple iron dextran injections
  • Ineffective erythropoiesis
    • β- thalassemia
    • Megaloblastic anemia
    • Sideroblastic anemia
    • Congenital dyserythropoietic anemia

Pathogenesis:

• Excess of iron is directly toxic to host tissue by
  • Lipid peroxidation through iron catalysed free radical reaction.
  • Stimulation of collagen synthesis
  • Direct interaction of iron with DNA
• Deposition occurs in various organs, with resulting fibrosis
  • Liver- Cirrhosis
  • Pancreas- Diabetes mellitus
  • Heart- Congestive cardiac failure
  • Joints- Arthritis
  • Hypogonadism- Secondary to derangement of hypothalamic pituitary axis

Clinical Features: Onset usually after age of 50 years

• Hepatic
  • Hepatomegaly- in 95% of symptomatic patient
  • Hepatic cirrhosis
  • Hepatocellular carcinoma
    • 30% of cirrhotics develop this
    • Most common cause of death in treated patient
• Systemic- Tiredness, weight loss, abdominal pain
• Diabetes mellitus- Seen in 65% of patient
• Heart failure –
  • Occurs due tocardiomyopathy and various cardiac arrhythmias
  • Most common cause of death in untreated patients.
• Leaden (Metallic slate) grey skin pigmentation.
  • Due to excessive formation of melanin especially in exposed parts, axillae, groin and genitalia.
• Arthritis mainly involving 2^nd and 3^rd metacarpophalangeal joints
• Deposition of Calcium pyrophosphate leads to chondrocalcinosis
• Hypogonadotropic hypogonadism- Due to impaired hypothalamic pituitary function secondary to deposition of iron in pituitary
  • Males- Testicular atrophy, loss of libido and impotence.
  • Females – Amenorrhea, Sparse body hair
• Infection with siderophilic organisms such as
  • Vibriovulnificus.
  • Listeriamonocytogenes
  • Yersiniaenterocolitica

Investigations:

• Serum iron studies.
  • Serum ferritin levels.
    • Raised to >200 μg/L in women &> 300μg/L in men
    • Increase in 1 μg/L reflects 65mg increase in total body iron stores.
  • Plasma iron level-Raised
  • Plasma iron blinding capacity – Decreased.
  • Transferrin saturation->55%
• CT and MRI to assess hepatic iron content.
  • MRI shows Shortening of relaxation time and thus reduction in signal intensity with iron overload.
  • In case of cardiac overload T-2 value of MRI is less- <20ms.
• Liver biopsy for iron content
  • Indications - Elevated serum transaminases activity and hepatomegaly
  • Remove extraneous blood before wrapping in aluminium foil and drying.
  • In hemochromatosis iron content is more than 80 μmol/gm dry weight (>4.5mg/g dry weight).
  • Hepatic iron index – Iron content per gram of liver is converted to micromoles and is divided by patient’s age.It is more than 1.9 in hemochromatosis.
  • Histopathology
    • Golden yellow hemosiderin molecules in cytoplasm of periportalhepatocytes.
    • Deposition of iron is in the form of ferritin or hemosiderin, which can be demonstrated by Pearl’s Prussian blue reaction
    • Bile duct epithelium and Kupfer, cells also show pigmentation in later stages.
    • Then there is formation of fibrous septa and micronodular cirrhosis
    • Characteristically no inflammation is present
• Molecular techniques to detect HFE gene mutations.
• Measurement of urine iron content after IM injection of 0.5gm of deferoxamine.
  • More than 2gm excretion in 24 hours indicates hemochromatosis.
• Superconducting quantum interface device (SQUID)
  • Depends on paramagnetic properties of hemosiderin andferritin.
• Monitoring for iron induced tissue damage.  
  • Cardiac function: ECG +/- exercise, 24-h monitor, Echocardiography,MUGA+/- stress issue, Doppler echography
  • Liver structure and function- Liver functions tests, Liver histology
  • Bone- Bone density (Dexa scan) for osteoporosis
  • Endocrine system- 
    • Diabetes- Urine glucose, HbAIC, Glucose tolerance test
    • Growth and sexual Development- Sitting and standing height, Tanner staging, Radiography for bone age, Testosterone, oestradiol, LH, FSH, Pulsatile GNRH release, Sperm tests
    • Thyroid- T4, TSH
    • Parathyroid- Calcium, phosphate, PTH           

Treatment:

• Phlebotomy- To remove excess of iron
  • Should be done even for asymptomatic individuals.
  • 450ml removed each week – for at least 6months to remove total iron excess.
  • Initiate phlebotomy once ferritin is >300ng/ml in men and >200ng/ml in women
  • Until- serum ferritin is <20 μg/L and Transferrin saturation <16% (These have to be measured once a month). Hemoglobin also needs to be monitored every week, so that development of anemia can be avoided.
  • Then remove 2-4 units every year. This blood can be used for other patients.
  • To maintain- Ferritin- <50 μg/L, Transferrin-saturation <50% and HCt>33%.
• Iron chelation
  • Useful in short-term management of patient with life threatening cardiac failure.
  • Risk of mucormycosis increases after starting chelation therapy
  • Useful in transfusional overload in patients with thalassemia, CDA etc. Refer beta thalassemia section for details.
• Dietary modifications:
  • Avoid alcohol and iron containing medications
  • Avoid iron containing foods
  • Avoid raw seafood, undercooked pork and unpasteurized milk- as incidence of severe Vibriovulnificus and Yersiniaenterocolitica is high.
• Refer to hepatologist 
  • For fibrosis assessment if ferritin- >1000microg/L or raised transaminases.
  • For patients with confirmed cirrhosis, alfa fetoprotein levels and liver ultrasound must be done once in 6 months
• Siblings, parents and children must be offered testing for HFE gene mutation.

Related Disorders:

• Acute iron poisoning      
  • Present with
    • Severe necrotizing gastritis & enteritis.
    • Metabolic acidosis.
    • Cardiovascular collapse.
    • Liver damage.
  • Treatment
    • Deferoxamine
      • Orally- 5gm instilled into Stomach after 1% NaHCO₃ gastric lavage
      • Parenterally- 1-2gm IM
• Aceruloplasminemia.
  • Autosomal recessive
  • Gene on chromosome -3q
  • Presents with progressive degeneration of retina & basal ganglia and diabetes mellitus.
  • Iron accumulation in liver, pancreas & brain.
  • Serum iron- Decreased.
  • TIBC, ferritin- Normal
  • Treatment –Iron chelation with Deferoxamine

• Hallervorden- Spatz syndrome.
  • Autosomal recessive.
  • Fe accumulates in brain (Basal ganglia)
  • Present with extrapyramidal signs in childhood

Defect in pantothenate kinase gene.

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Accumulation of cysteine

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Iron binding by cysteine

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Oxidative stress

• Neuroferritinopathly
  • Autosomal dominant
  • Chromosome -19q 13.3
  • Ferritin light chain polypeptide gene mutation.(Adenine insertion at position 460-461)
  • Late onset basal ganglia disease.

• Friedrich’s ataxia.
  • Characterized by loss of sensory neurons in spinal cord & dorsal root ganglia.
  • There is mitochondrial iron overload with loss of iron – sulphur cluster containing enzymes.
  • Chromosome -9q 13 involved

Expansion of trinucleotide repeats within intron of FRDA gene.

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Reduced expression of frataxin m RNA & protein

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Oxidative damage when iron accumulates.