A. Characteristics [9]
- Abnormal Iron Metabolism
- Abnormal regulation of intestinal iron absorption
- Iron (Fe) deposition in abnormal sites
- Genetic (most common) and sporadic forms
- Organ Dysfunction [12]
- Due to abnormal iron deposition in various organs
- Cirrhosis - hepatocytes and Kupfer cells
- Diabetes - along with skin changes, often called "Bronze Diabetes"; late onset Type 1 [22]
- Skin pigmentation increases - due to abornormal deposition of melanin
- Endocrine failure - especially hypogonadism
- Cardiac - cardiomyopathy and conduction abnormalities
- Joint Disease - pseudogout, destructive distal arthritis
- Presentation in Men and Women
- Most series report male predominance for clinical disease
- Men present more often than women with cirrhosis and diabetes
- Women present more often than men with skin pigmentation and fatigue
- Women present with lower iron levels, likely due to iron losses through menses
- Less commonly presents in children, usually distinct subtypes
- Symptoms and Signs Present on Diagnosis [8]
- Arthritis 65% (physician diagnosed)
- Liver Disease 52%
- Extreme Fatigue 46%
- Arthalgia 44%
- Loss of libido 26%
- Therefore, diagnoses were made relatively late in disease course
- Later Stage Symptoms [8]
- Splenic enlargement - usually due to portal hypertension from cirrhosis
- Hypogonadism / Testicular atrophy - impotence and testicular fibrosis
- Heart block
- Disease diagnosis should be made on genotype, not on hepatic iron stores [15]
- 0.5-1.0% of population has homozygous hereditary HC detectable on screening [5]
B. Disease Subtypes [18]
- Hereditary Hemochromatosis (HHC) [11]
- Several different types of HHC
- Type 1: adult autosomal recessive HFE mutations
- Type 2: Juvenile hemochromatosis autosomal recessive (maps to chromosome 1q)
- Type 3: autosomal recessive TFR2 (transferrin receptor 2) mutations chr 7q22
- Type 4: autosomal dominant ferroportin1/IREG1/MTP1 mutations (SLC40A1) chr 2q32
- Type 5: autosomal dominant H-ferritin mutations
- Type 1 HHC (85% of HHC) [8,13,15,21]
- Due to mutations in HFE gene (previously HLA-H) on chr 6p21.3 in HLA complex
- HFE heterozygous (carrier) 10-15% of Caucasian population
- Prevalance of Type 1 HHC <1% indicating poor penetrance of HFE mutations
- Most common HFE mutation in whites is Cys282Tyr (C282Y), ~0.5% homozygous [5,7]
- H63D mutation is homozygous in 1% and heterozygous (with C282Y) in 2-3% [21]
- About 1% of persons with diagnosed HHC lack either mutation
- Penetrance of HFE mutations is low and additional genes abnormalities present [11]
- C282Y mutation does not account for iron metabolism abnormalities in nonwhites [7]
- Homozygous C282 mutations in Caucasians associated with fatigue [5]
- Onset of symptomatic disease age 40-60 years
- In aysymptomatic persons with homozygous C282Y mutation, 28% of men and 1.2% of women developed iron-overload disease (symptoms/signs) [17]
- Characteristics of Persons Heterozygous for Hemochromatosis [19]
- Unusual for these persons to develop clinical problems
- Mean serum iron and transferrin-saturation values are generally above normal range
- Ferritin values are also increased
- Liver biopsy essentially normal with some increased iron deposition
- Reduced prevalence of iron deficiency anemia in heterozygotes for major HFE mutation
- Type 2 (Juvenile) Hemochromatosis [1,4]
- Type 2a: HVJ (HFE2) mutation chr 1q21, hemojuvelin gene, may modulate hepciden
- Type 2b: HAMP mutation chr 19q13.1, hepcidin gene, down regulation of iron release
- Both autosomal recessive
- High transferrin saturation
- Affects liver, endocrine glands, heart
- Excellent response to therapeutic phlebotomy
- Onset age by age 10-30 years
- African Iron Overload
- Appears to be an acquired form of hemochromatosis
- Genetic component may be present
- In Sub-Saharan Africa, iron absorbed from home-brewed beer made in iron vats
- In USA, primary iron overload (unknown causes) has recently been described
- Hepatic iron deposition in both macrophages (Kupfer cells) and parenchymal cells
- Associated with ascorbic acid (Vitamin C) deficiency and osteoporosis
- Acquired Hemochromatosis
- Alcoholism - increased iron deposition in liver
- Blood Transfusions - thalassemia, sickle cell anemia, hemolytic anemias
- Increased iron ingestion
- Hepatic iron deposition primarily in macrophages in acquired disease
- Neonatal Hemochromatosis [3,4]
- Uncertain mechanism, may be autosomal recessive or nongenetic maternal factor
- Alloimmune mechanism has been proposed, and IVIg can be of some benefit [3]
- Presents as fulminant hepatic failure in newborn
- Hypoglycemia, bleeding diathesis, renal failure, non-immune hydrops
- Siderosis in liver, exocrine pancreas, heart with macrophage sparing
- Oral bile acid therapy may be useful in some patients
- Antioxidant "cocktails" may be of some benefit, reducing oxidative damage by free iron
- Vitamin E, selenium, acetylcysteine has been used
- Diuretics to control ascites
- Liver transplantation may be required
- Aceruloplasminemia
C. Pathogenesis of HC [1,2,18]
- Duodenal enterocytes are responsible for the majority of iron absorption
- Intestinal crypt cells store iron and "sense" body iron stores"
- HFE protein is found in highest concentrations in these crypt cells
- HFE is likely involved coupling of crypt sensing to enterocyte iron absorption
- HFE Gene
- HFE is a class 1 MHC gene alpha chain that forms heterodimers with ß2-microglobulin
- HFE cannot bind peptides (unlike other MHC Class 1 molecules) and does not bind iron
- HFE forms complexes with receptor for iron-binding transferrin (regulates iron uptake)
- HFE is expressed on surface of many cells including duodenal crypt cells, macrophages
- Certain mutations of HFE cause it to lose its ability to bind ß2-microglobulin
- HFE Binds Transferrin Receptor 1 (TFR1)
- HFE reduces the affinity of the TFR1 for iron-bound transferrin
- The C282Y mutation causes loss of HFE expression on the surface
- There is a paradoxical increase in transferrin receptor mRNA in HHC
- HFE regulates hepcidin (HAMP gene) expression
- HAMP gene expression is reduced <5X in HHC patients versus controls
- Hepatic IREG1 (iron transport) mRNA levels upregulated ~2X in HHC patients
- In C282Y homozygotes, ~45% develop iron overload and ~20% develop HHC symptoms [14]
- Regulation of Iron Levels [16]
- Iron stores in body are highly regulated and sensed by intestinal crypt cells
- Hemochromatosis protein (HFE) expressed in crypt cell
- HFE protein likely couples sensing mechanism of crypt cell to absorption by enterocyte
- As transferrin saturation rises, crypt cell accumulates iron and reduces iron absorption
- HFE either inhibits uptake or inhibits release of iron from cells
- HFE function depends on level of transferrin saturation
- HFE binds to TFR1 and enhances uptake of iron or inhibits its release
- Mutations of HFE result in overabsorption of dietary iron
- HFE mutations usually poor penetration and additional genetic mutations for disease [11]
- Other Genes Involved in Hemochromatosis
- TFR2 has 66% homology to TFR1 and can mediate uptake of transferrin-bound iron
- TFR2 has high level expression in hepatocytes
- Hepcidin is synthesized by hepatocytes in response to iron overload or inflammation
- Hepcidin appears to have key role in down-regulating intestinal iron absorption
- Hemojuvelin modulates hepcidin expression (little is known about it)
- Organ Deposition of Iron
- Hepatic iron deposition is primarily in hepatocytes
- Women generally develop organ damage and symptoms later than men
D. Screening and Evaluation [9,10,13,14]
- Routine screening in general population is not recommended [13,14]
- Disease is common with potential to cause substantial morbidity
- Very long subclinical phase without evidence that early intervention modfies outcomes
- Variable penetrance of genetic defects
- Greatest risk in C282Y homozygotes, but <30% develop symptomatic HC [14]
- For patients at increased risk, screening consists of iron, ferritin, transferrin saturation
- Normal Male Transferrin Saturation <60%
- Normal Female Transferrin Saturation <50%
- Phenotypic screening with ferritin, transferrin, iron is preferred over genotyping
- Serum Ferritin may be most sensitive method
- If abnormal Transferrin Saturation, measure ferritin levels
- Ferritin corresponds to total body iron stores
- Abnormal ferritin (for example, >300) levels should prompt liver biopsy
- Normal ferritin levels should be followed up with screening tests every 2 years
- Screening for transferrin saturation and ferritin levels does not detect all homozygotes [19]
- Serum ferritin levels predict advanced hepatic fibrosis in HC patients [6]
- If all tests normal, no need to repeat screening
- Abnormal test results should be followed up with a fine needle liver biopsy
- However, diagnosis of hemochromatosis should not rely on hepatic iron stores
- Previously, hepatic iron index >1.9 mmol/kg/year has been used as diagnostic
- Hepatic iron stores can be estimated non-invasively by T2 weighted gradient echo MRI [23]
- Genotyping verification of disease is the gold standard diagnosis [15]
- Investigation for HC in Community
- Suspicion for HC must be high
- Most diagnoses of hemochromatosis are delayed
- Abnormal laboratory tests initiated investigation in 45% of cases
- Symptoms initiated investigation in 35% of cases
- Diagnosis of a relative initiated investigation in 20% of cases
- Must evaluate for HC-related conditions [20]
- Critical in patients with HC and in relatives of patients with HC
- Liver: transaminase elevations, cirrhosis, hepatic fibrosis
- Joint Disease: hemochromatic arthropathy
- Diabetes mellitus: late onset type 1 form (typically >30 years) [22]
- Iron overload (preclinical, presymptomatic)
- Note that relatives of patients with HC are at high risk for these conditions [20]
- Cirrhosis [6]
- Major concern in patients with HC
- Serum ferritin level predicts risk for advanced hepatic fibrosis
- Cirrhosis unlikely to be present if serum ferritin levels <1000µg/L
- However, patients with intermediate levels (300-1000µg/L) still have significant risk
- Therefore, liver biopsy to rule out cirrhosis should be considered in many patients
E. Treatment
- Phlebotomy is mainstay
- Usually 500cc removed every 1-2 weeks
- Follow transerrin saturation and ferritin levels, which should fall to normal range
- Once in normal range, phlebotomy is done every 2-4 months
- Goal is to maintain low normal ferritin and transferrin saturation levels
- Iron binding agents may be used if phlebotomy is contraindicated
- Deferoxamine - given intraperitoneally (also for aluminum toxicity in CAPD)
- Deferiprone - oral chelation therapy, questionable longer term efficacy
- Arthritis
- Nonsteroidal anti-inflammatory drugs (NSAIDs) useful
- Poor response to systemic disease therapy
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