• Information
  1. Characteristics
  2. Disease Subtypes
  3. Pathogenesis of HC
  4. Screening and Evaluation
  5. Treatment

A. Characteristics [9]

1. Abnormal Iron Metabolism
   1. Abnormal regulation of intestinal iron absorption
   2. Iron (Fe) deposition in abnormal sites
   3. Genetic (most common) and sporadic forms
2. Organ Dysfunction [12]
   1. Due to abnormal iron deposition in various organs
   2. Cirrhosis - hepatocytes and Kupfer cells
   3. Diabetes - along with skin changes, often called "Bronze Diabetes"; late onset Type 1 [22]
   4. Skin pigmentation increases - due to abornormal deposition of melanin
   5. Endocrine failure - especially hypogonadism
   6. Cardiac - cardiomyopathy and conduction abnormalities
   7. Joint Disease - pseudogout, destructive distal arthritis
3. Presentation in Men and Women
   1. Most series report male predominance for clinical disease
   2. Men present more often than women with cirrhosis and diabetes
   3. Women present more often than men with skin pigmentation and fatigue
   4. Women present with lower iron levels, likely due to iron losses through menses
   5. Less commonly presents in children, usually distinct subtypes
4. Symptoms and Signs Present on Diagnosis [8]
   1. Arthritis 65% (physician diagnosed)
   2. Liver Disease 52%
   3. Extreme Fatigue 46%
   4. Arthalgia 44%
   5. Loss of libido 26%
   6. Therefore, diagnoses were made relatively late in disease course
5. Later Stage Symptoms [8]
   1. Splenic enlargement - usually due to portal hypertension from cirrhosis
   2. Hypogonadism / Testicular atrophy - impotence and testicular fibrosis
   3. Heart block
6. Disease diagnosis should be made on genotype, not on hepatic iron stores [15]
7. 0.5-1.0% of population has homozygous hereditary HC detectable on screening [5]

B. Disease Subtypes [18]

1. Hereditary Hemochromatosis (HHC) [11]
   1. Several different types of HHC
   2. Type 1: adult autosomal recessive HFE mutations
   3. Type 2: Juvenile hemochromatosis autosomal recessive (maps to chromosome 1q)
   4. Type 3: autosomal recessive TFR2 (transferrin receptor 2) mutations chr 7q22
   5. Type 4: autosomal dominant ferroportin1/IREG1/MTP1 mutations (SLC40A1) chr 2q32
   6. Type 5: autosomal dominant H-ferritin mutations
2. Type 1 HHC (85% of HHC) [8,13,15,21]
   1. Due to mutations in HFE gene (previously HLA-H) on chr 6p21.3 in HLA complex
   2. HFE heterozygous (carrier) 10-15% of Caucasian population
   3. Prevalance of Type 1 HHC <1% indicating poor penetrance of HFE mutations
   4. Most common HFE mutation in whites is Cys282Tyr (C282Y), ~0.5% homozygous [5,7]
   5. H63D mutation is homozygous in 1% and heterozygous (with C282Y) in 2-3% [21]
   6. About 1% of persons with diagnosed HHC lack either mutation
   7. Penetrance of HFE mutations is low and additional genes abnormalities present [11]
   8. C282Y mutation does not account for iron metabolism abnormalities in nonwhites [7]
   9. Homozygous C282 mutations in Caucasians associated with fatigue [5]
   10. Onset of symptomatic disease age 40-60 years
   11. In aysymptomatic persons with homozygous C282Y mutation, 28% of men and 1.2% of women developed iron-overload disease (symptoms/signs) [17]
3. Characteristics of Persons Heterozygous for Hemochromatosis [19]
   1. Unusual for these persons to develop clinical problems
   2. Mean serum iron and transferrin-saturation values are generally above normal range
   3. Ferritin values are also increased
   4. Liver biopsy essentially normal with some increased iron deposition
   5. Reduced prevalence of iron deficiency anemia in heterozygotes for major HFE mutation
4. Type 2 (Juvenile) Hemochromatosis [1,4]
   1. Type 2a: HVJ (HFE2) mutation chr 1q21, hemojuvelin gene, may modulate hepciden
   2. Type 2b: HAMP mutation chr 19q13.1, hepcidin gene, down regulation of iron release
   3. Both autosomal recessive
   4. High transferrin saturation
   5. Affects liver, endocrine glands, heart
   6. Excellent response to therapeutic phlebotomy
   7. Onset age by age 10-30 years
5. African Iron Overload
   1. Appears to be an acquired form of hemochromatosis
   2. Genetic component may be present
   3. In Sub-Saharan Africa, iron absorbed from home-brewed beer made in iron vats
   4. In USA, primary iron overload (unknown causes) has recently been described
   5. Hepatic iron deposition in both macrophages (Kupfer cells) and parenchymal cells
   6. Associated with ascorbic acid (Vitamin C) deficiency and osteoporosis
6. Acquired Hemochromatosis
   1. Alcoholism - increased iron deposition in liver
   2. Blood Transfusions - thalassemia, sickle cell anemia, hemolytic anemias
   3. Increased iron ingestion
   4. Hepatic iron deposition primarily in macrophages in acquired disease
7. Neonatal Hemochromatosis [3,4]
   1. Uncertain mechanism, may be autosomal recessive or nongenetic maternal factor
   2. Alloimmune mechanism has been proposed, and IVIg can be of some benefit [3]
   3. Presents as fulminant hepatic failure in newborn
   4. Hypoglycemia, bleeding diathesis, renal failure, non-immune hydrops
   5. Siderosis in liver, exocrine pancreas, heart with macrophage sparing
   6. Oral bile acid therapy may be useful in some patients
   7. Antioxidant "cocktails" may be of some benefit, reducing oxidative damage by free iron
   8. Vitamin E, selenium, acetylcysteine has been used
   9. Diuretics to control ascites
   10. Liver transplantation may be required
8. Aceruloplasminemia

C. Pathogenesis of HC [1,2,18]

1. Duodenal enterocytes are responsible for the majority of iron absorption
   1. Intestinal crypt cells store iron and "sense" body iron stores"
   2. HFE protein is found in highest concentrations in these crypt cells
   3. HFE is likely involved coupling of crypt sensing to enterocyte iron absorption
2. HFE Gene
   1. HFE is a class 1 MHC gene alpha chain that forms heterodimers with ß2-microglobulin
   2. HFE cannot bind peptides (unlike other MHC Class 1 molecules) and does not bind iron
   3. HFE forms complexes with receptor for iron-binding transferrin (regulates iron uptake)
   4. HFE is expressed on surface of many cells including duodenal crypt cells, macrophages
   5. Certain mutations of HFE cause it to lose its ability to bind ß2-microglobulin
3. HFE Binds Transferrin Receptor 1 (TFR1)
   1. HFE reduces the affinity of the TFR1 for iron-bound transferrin
   2. The C282Y mutation causes loss of HFE expression on the surface
   3. There is a paradoxical increase in transferrin receptor mRNA in HHC
   4. HFE regulates hepcidin (HAMP gene) expression
   5. HAMP gene expression is reduced <5X in HHC patients versus controls
   6. Hepatic IREG1 (iron transport) mRNA levels upregulated ~2X in HHC patients
   7. In C282Y homozygotes, ~45% develop iron overload and ~20% develop HHC symptoms [14]
4. Regulation of Iron Levels [16]
   1. Iron stores in body are highly regulated and sensed by intestinal crypt cells
   2. Hemochromatosis protein (HFE) expressed in crypt cell
   3. HFE protein likely couples sensing mechanism of crypt cell to absorption by enterocyte
   4. As transferrin saturation rises, crypt cell accumulates iron and reduces iron absorption
   5. HFE either inhibits uptake or inhibits release of iron from cells
   6. HFE function depends on level of transferrin saturation
   7. HFE binds to TFR1 and enhances uptake of iron or inhibits its release
   8. Mutations of HFE result in overabsorption of dietary iron
   9. HFE mutations usually poor penetration and additional genetic mutations for disease [11]
5. Other Genes Involved in Hemochromatosis
   1. TFR2 has 66% homology to TFR1 and can mediate uptake of transferrin-bound iron
   2. TFR2 has high level expression in hepatocytes
   3. Hepcidin is synthesized by hepatocytes in response to iron overload or inflammation
   4. Hepcidin appears to have key role in down-regulating intestinal iron absorption
   5. Hemojuvelin modulates hepcidin expression (little is known about it)
6. Organ Deposition of Iron
   1. Hepatic iron deposition is primarily in hepatocytes
   2. Women generally develop organ damage and symptoms later than men

D. Screening and Evaluation [9,10,13,14]

1. Routine screening in general population is not recommended [13,14]
   1. Disease is common with potential to cause substantial morbidity
   2. Very long subclinical phase without evidence that early intervention modfies outcomes
   3. Variable penetrance of genetic defects
   4. Greatest risk in C282Y homozygotes, but <30% develop symptomatic HC [14]
2. For patients at increased risk, screening consists of iron, ferritin, transferrin saturation
   1. Normal Male Transferrin Saturation <60%
   2. Normal Female Transferrin Saturation <50%
   3. Phenotypic screening with ferritin, transferrin, iron is preferred over genotyping
3. Serum Ferritin may be most sensitive method
   1. If abnormal Transferrin Saturation, measure ferritin levels
   2. Ferritin corresponds to total body iron stores
   3. Abnormal ferritin (for example, >300) levels should prompt liver biopsy
   4. Normal ferritin levels should be followed up with screening tests every 2 years
   5. Screening for transferrin saturation and ferritin levels does not detect all homozygotes [19]
   6. Serum ferritin levels predict advanced hepatic fibrosis in HC patients [6]
4. If all tests normal, no need to repeat screening
5. Abnormal test results should be followed up with a fine needle liver biopsy
   1. However, diagnosis of hemochromatosis should not rely on hepatic iron stores
   2. Previously, hepatic iron index >1.9 mmol/kg/year has been used as diagnostic
   3. Hepatic iron stores can be estimated non-invasively by T2 weighted gradient echo MRI [23]
   4. Genotyping verification of disease is the gold standard diagnosis [15]
6. Investigation for HC in Community
   1. Suspicion for HC must be high
   2. Most diagnoses of hemochromatosis are delayed
   3. Abnormal laboratory tests initiated investigation in 45% of cases
   4. Symptoms initiated investigation in 35% of cases
   5. Diagnosis of a relative initiated investigation in 20% of cases
7. Must evaluate for HC-related conditions [20]
   1. Critical in patients with HC and in relatives of patients with HC
   2. Liver: transaminase elevations, cirrhosis, hepatic fibrosis
   3. Joint Disease: hemochromatic arthropathy
   4. Diabetes mellitus: late onset type 1 form (typically >30 years) [22]
   5. Iron overload (preclinical, presymptomatic)
   6. Note that relatives of patients with HC are at high risk for these conditions [20]
8. Cirrhosis [6]
   1. Major concern in patients with HC
   2. Serum ferritin level predicts risk for advanced hepatic fibrosis
   3. Cirrhosis unlikely to be present if serum ferritin levels <1000µg/L
   4. However, patients with intermediate levels (300-1000µg/L) still have significant risk
   5. Therefore, liver biopsy to rule out cirrhosis should be considered in many patients

E. Treatment

1. Phlebotomy is mainstay
   1. Usually 500cc removed every 1-2 weeks
   2. Follow transerrin saturation and ferritin levels, which should fall to normal range
   3. Once in normal range, phlebotomy is done every 2-4 months
   4. Goal is to maintain low normal ferritin and transferrin saturation levels
2. Iron binding agents may be used if phlebotomy is contraindicated
   1. Deferoxamine - given intraperitoneally (also for aluminum toxicity in CAPD)
   2. Deferiprone - oral chelation therapy, questionable longer term efficacy
3. Arthritis
   1. Nonsteroidal anti-inflammatory drugs (NSAIDs) useful
   2. Poor response to systemic disease therapy

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