Chapter 69: Hemochromatosis

Hemochromatosis is a heterogeneous group of heritable disorders that increase the risk of developing iron overload due to increased dietary absorption of iron. Most hemochromatosis is due to mutation(s) in genes that alter the expression, structure, or ferroportin binding of hepcidin, a liver polypeptide that is the central regulator of iron absorption. Deleterious mutations that cause hemochromatosis include those of the HFE, HJV, TFR2, HAMP, and SLC40A1 genes. A rare mutation in the iron-responsive element of the FTH1 gene caused hemochromatosis due to decreased ferritin heavy-chain ferroxidase activity. Because mechanisms to excrete iron are limited, some persons with hemochromatosis develop iron overload and consequent target organ injury

Epidemiology

Prevalence

HFE hemochromatosis:

• 4–10 per thousand (western European whites)

• 4–5 per thousand (non-Hispanic whites in United States)

• 1 in 200 (U.S. Vietnamese)

Non-HFE hemochromatosis:

Rare, based on pathogenic mutations and cases discovered in population samples

Race/ethnicity:

HFE hemochromatosis:

Predominantly European whites; some Native Americans, U.S. Vietnamese, Hispanics, African Americans

Non-HFE hemochromatosis:

Predominantly European whites; some Asians, Native Africans, African Americans, Japanese, Pacific Islanders

Male-to-female ratios in HFE hemochromatosis diagnosed in medical care:

• Hemochromatosis genotype: 1:1

• Elevated serum iron measures: 1.3:1

• Elevated hepatic transaminase levels: 2:1

• Diabetes mellitus: 4:1

• Cirrhosis: 5:1

• Primary liver cancer: 5:1

Age:

HFE hemochromatosis:

Severe iron overload typically occurs in subjects 40–60 years old but is rare before age 30 years

Non-HFE hemochromatosis:

Severe iron overload is common in children, adolescents, or young adults with HJV, TFR2, or “gain-of-function” SLC40A1 hemochromatosis

Life expectancy:

Normal in treated patients without cardiomyopathy, cirrhosis, or diabetes mellitus, and in individuals who do not develop iron overload

Mortality rate in U.S. Adults:

• Men: 2.4/million

• Women: 1.2/million

• Whites: 1.9/million

• Nonwhites: 1/million

Barton JC et al. Genet Test 2007;11:269–275

Beutler E, Felitti VJ. Arch Intern Med 2002;162:1196–1197

Witte DL et al. Clin Chim Acta 1996;245:139–200

Yang Q et al. Ann Intern Med 1998;129:946–953

Etiology and Classification

Differential Diagnosis of Elevated Iron Measures

Non-hemochromatosis multiorgan iron overload:

1. Heritable anemias

   • Intermediate and severe β-thalassemia syndromes

   • X-linked sideroblastic anemia

   • Pyruvate kinase deficiency

   • Atransferrinemia

   • DMT-1 deficiency

   • Glutaredoxin deficiency

2. Hereditary aceruloplasminemia

3. Refractory anemia with ringed sideroblasts (myelodysplasia)

4. Transfusion iron overload

5. Chronic ingestion or injection of iron supplements

6. Excessive iron in total parenteral nutrition regimens

7. African iron overload

8. African American iron overload

9. Neonatal “hemochromatosis” (severe fetal liver injury because of maternal–fetal alloimmunity)

Liver disorders sometimes associated with iron overload:

1. Chronic viral hepatitis

2. Non-alcoholic fatty liver disease, including metabolic syndrome

3. Alcoholic liver disease

4. Porphyria cutanea tarda

5. Other advanced liver disease

Hyperferritinemia without iron overload:

1. Common liver disorders, especially non-alcoholic fatty liver, chronic viral hepatitis, and alcoholic liver disease

2. Other inflammation, tissue injury, or acute infection

3. Mean serum ferritin greater in healthy persons of Asian and Native sub-Saharan African descent than in European whites

4. SLC40A1 Q248H polymorphism in Native Africans, African Americans

5. Hyporegenerative anemia

6. Autonomous ferritin production by malignancy

7. Hereditary hyperferritinemia-cataract syndrome

Work-Up

1. CBC: Hemoglobin, MCV often slightly increased; some patients with cirrhosis and portal hypertension have thrombocytopenia

2. Serum chemistry profile: Hepatic transaminase levels often mildly increased

3. Serum iron measures: Transferrin saturation often increased; unbound iron-binding capacity elevated; ferritin always elevated in iron overload

4. Liver biopsy: “Gold standard” for ascertaining occurrence, severity of iron overload. Recommended for patients with serum ferritin level >1,000 μ/L. Evaluate for morphology (hematoxylin and eosin stain), fibrosis (trichrome stain), and iron grade (Perls'/Prussian blue stain). Perform quantitative iron measurements, compute hepatic iron index

5. Diabetes mellitus: Use standard diagnostic criteria; type 2 diabetes is typical; evaluate for vascular, ophthalmic, and neurologic complications

6. Anterior pituitary gland: Evaluate gonadotroph function with testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone levels; evaluate pituitary iron content with MRI scanning

7. Osteoporosis: Evaluate patients with hypogonadism using DEXA scans

8. Cardiac biopsy: Endomyocardial biopsy indicated in young persons with cardiomyopathy attributed to iron overload; evaluate morphology as described for liver

9. Imaging studies: Use T2 or T2^✫ MRI images of liver, heart, or pituitary to semiquantify iron content. Plain films of hands, hips, or knees detect arthropathy. In patients with cirrhosis, use CT scanning or liver ultrasonography to survey for primary liver cancer

10. DNA-based testing: HFE mutation analysis to detect alleles C282Y, H63D, and S65C is commercially available; testing for other HFE alleles or mutations in other hemochromatosis genes may be available from dedicated research or non-U.S. commercial laboratories

11. Family screening: Test first-degree family members of probands with transferrin saturation, serum ferritin. Perform DNA-based testing of family members with elevated iron measures

12. HLA-A and -B typing: For HFE hemochromatosis only. Persons HLA-identical to their sibling probands are assumed to have identical HFE genotypes and should be evaluated for iron overload

Regimen: Therapeutic Phlebotomy

Barton JC et al. Ann Intern Med 1998;129:932–939

Brissot P, de Bels F. Hematology Am Soc Hematol Educ Program 2006;36–41

Indications:

1. Iron overload due to hemochromatosis or other iron overload unassociated with severe anemia

2. Initiate treatment if ferritin level ≥300 ng/mL (men) and ≥200 ng/mL (women)

Treatment

Before therapy:

1. Verify that venous access is adequate. Use implanted ports for phlebotomy only if venous access is inadequate

2. If anemia is present, correct if possible

3. Routine erythropoietin therapy is unnecessary unless relative or absolute deficiency of erythropoietin is demonstrated

Achieving iron depletion:

1. Ensure adequate hydration before and after each session

2. Evaluate CBC each treatment day to ensure hemoglobin >11.0 g/dL

3. Use personnel skilled in therapeutic phlebotomy

4. Use butterfly needle (19 gauge) connected to an extension tubing set and collect blood in an evacuated bottle

5. Large needles (14 gauge, 16 gauge) are less well tolerated than smaller needles; use extension tubing and gravity to collect blood in bags

6. For port phlebotomy, use a 19-gauge Huber needle connected to an extension tubing set and collect blood in an evacuated bottle

7. Remove 300–450 mL/session from average women, older patients; 450–500 mL/session from men, larger women

8. Repeat every 5–14 days according to iron overload severity, patient tolerance

Toxicity

1. Local discomfort of venipuncture

2. Transient hypovolemia

3. Mild fatigue

4. Iron deficiency (if phlebotomy is excessive)

Efficacy

1. 95% of patients comply to achieve iron depletion

2. Each unit of blood (450–500 mL) contains 200–250 mg Fe (∼1 mg Fe/1 mL erythrocytes)

3. Serum ferritin ∼20 μg/L indicates that iron depletion has been achieved and that potentially harmful iron deposits have been removed

4. Aggressive iron depletion of patients with cardiac siderosis can be lifesaving

5. Hypogonadotrophic hypogonadism improves or resolves in some cases

6. Hepatic fibrosis or cirrhosis improves in some cases

7. Improved control of diabetes mellitus or joint symptoms, or in fatigue and weakness in some cases

8. Maintaining normal body iron levels (serum ferritin <300 μg/L in men, <200 μg/L in women) after achieving iron depletion would prevent future iron overload complications, but health benefits may not accrue to all asymptomatic patients

9. Compliance with phlebotomy to maintain iron depletion decreases ∼7% yearly

Monitoring Therapy

1. Initiation: CBC, serum ferritin, liver profile

2. Each phlebotomy session: CBC

3. Serum ferritin every 4 phlebotomy sessions in patients undergoing therapy to achieve iron depletion

4. After serum ferritin <200 μg/L, measure serum ferritin after every 1–2 phlebotomy sessions

5. When serum ferritin 20–50 ng/mL: discontinue phlebotomy, compute quantity of iron removed

6. Once-twice yearly after iron depletion: serum ferritin, liver profile

7. Start maintenance therapy when serum ferritin >300 μg/L (men) and >200 μg/L (women)

Notes

1. Do not monitor therapy using serum iron or transferrin saturation

2. Patients with greater iron burdens at diagnosis usually need more frequent maintenance phlebotomy. Some patients, especially women and older men, require little maintenance phlebotomy, if any

3. Many patients with “loss-of-function” ferroportin mutations have anemia, slow recovery of hemoglobin level after phlebotomy, and intolerance of normal iron stores; permit higher levels of ferritin in these cases than recommended for other types of hemochromatosis

4. Healthy patients can be voluntary blood donors in some circumstances, especially during maintenance therapy

5. Phlebotomy diminishes severity of hepatic fibrosis or cirrhosis, but it is unknown if risk of primary liver cancer is also reduced

6. Consider repeating liver biopsy 6–12 months after iron depletion in patients with hepatic fibrosis or cirrhosis at diagnosis to re-evaluate liver morphology

7. Primary liver cancer is presently unreported in non-HFE hemochromatosis but occurs in some patients with severe non-hemochromatosis iron overload

Regimen: Iron Chelation Therapy with Deferoxamine Mesylate (DFO)

Barton JC. Curr Gastroenterol Rep 2007;9:74–82

De Gobbi M et al. Haematologica 2000;85:865–867

Fabio G et al. Blood 2007;109:362–364

Nielsen P et al. Br J Haematol 2003;123:952–953

Indications:

1. Adjunct management of cardiomyopathy due to cardiac siderosis in patients undergoing concurrent therapeutic phlebotomy

2. Treatment of severe iron overload due to hemochromatosis in patients unable to tolerate or unwilling to undergo therapeutic phlebotomy

Treatment

Before therapy:

1. Verify that renal function is normal

2. Educate patients about the importance of compliance with DFO infusion schedules and manifestations of toxicity

Achieving iron depletion:

1. Subcutaneous DFO: Infuse deferoxamine mesylate 40 mg/kg by continuous subcutaneous infusion for 8–12 hours nightly for 5–7 nights weekly using a portable (ambulatory) pump

2. Intramuscular DFO: Deferoxamine mesylate 500–1000 mg by intramuscular injection, daily

3. Oral vitamin C: Ascorbic acid 200 mg on each day of DFO administration enhances iron excretion. DO NOT exceed this dose

Toxicity

1. Local reactions (eg, discomfort, pruritus, erythema)

2. Systemic allergic or hypersensitivity reactions (eg, urticaria, angioedema, musculoskeletal pain, anaphylaxis)

3. Diverse ocular and auditory adverse effects (eg, high-frequency hearing loss, deafness, retinal damage)

4. Neutropenia, agranulocytosis, thrombocytopenia

5. Increased susceptibility to Yersinia sp. infections and mucormycosis

6. Zinc deficiency

Efficacy

1. Deferoxamine mobilizes iron from parenchymal cells and macrophages; iron removal from heart is less rapid than from other sites

2. Urinary iron excretion, typically 5–40 mg/24 hours. Elimination often wanes after several consecutive days of therapy

3. Deferoxamine half-life is very short a stringent infusion routine is required for optimal efficacy

4. Hypogonadotrophic hypogonadism or cardiomyopathy due to HJV or TFR2 hemochromatosis improves or resolves in some cases

5. Hepatic fibrosis or cirrhosis regresses in some cases

6. In 3 HFE hemochromatosis patients who were unable to tolerate phlebotomy, subcutaneous deferoxamine treatment removed hepatocyte iron at a rate similar to that of weekly 500-mL phlebotomy

Monitoring Therapy

1. Initiation: CBC, serum ferritin, liver, and renal profiles

2. Monthly: Reevaluate patient; measure CBC, renal, liver profiles, serum ferritin; indicated cardiac assessment in patients with cardiomyopathy

3. Every 6 months: Serum luteinizing hormone, follicle-stimulating hormone, and testosterone or estradiol

4. When ferritin <300 ng/mL (men) and <200 ng/mL (women): Discontinue deferoxamine

5. Once or twice yearly after iron depletion: Reevaluate patient; serum ferritin, liver profile

6. Once or twice yearly in patients treated for prolonged intervals or those with new symptoms:

   Visual acuity tests, slit-lamp examinations, funduscopy, audiometry

Notes

1. Therapy must be individualized to maximize compliance and iron excretion

2. Red or rusty urine indicates a satisfactory level of iron excretion

3. Iron excretion after 8–12 hours of deferoxamine infusion is the same as with the same deferoxamine dose given over 24 hours in many patients

4. Improvement in survival or disease-related symptoms has not been established for persons with hemochromatosis

5. Possible role of DFO therapy for “maintenance” of normal serum ferritin levels in persons with HFE hemochromatosis is unknown

6. Safety and efficacy of DFO when administered with other iron chelation agents have not been established in patients with HFE hemochromatosis

Regimen: Iron Chelation Therapy Deferasirox (DFX)

Barton JC. Curr Gastroenterol Rep 2007;9:74–82

Phatak P et al. Hepatology 2010;52:1671–1679

Adams PC, Barton JC. Blood 2010;116:317–325

Exjade (deferasirox) tablets, for oral suspension; product label May 2013. Novartis Pharmaceuticals Corporation, East Hanover, NJ

Indications:

Treatment of iron overload with DFX should be considered in persons with HFE hemochromatosis who have anemia, severe heart disease, poor venous access, or poor compliance with phlebotomy

The U.S. Food and Drug Administration has licensed deferasirox for management of chronic iron overload:

1. Caused by transfusion in persons ≥2 years of age

2. In patients ≥10 years of age with non–transfusion-dependent thalassemia syndromes and with liver iron concentration ≥5 mg Fe/g of liver dry weight and serum ferritin >300 μg/L

Treatment

Before therapy:

1. Select target serum ferritin level

2. Exclude:

   • Males with hemoglobin <13 g/dL

   • Females with hemoglobin <12 g/dL

   • Current treatment with deferoxamine (DFO) or deferiprone (DFP)

   • Serum creatinine levels above the upper reference limit of normal range

   • Alanine aminotransferase (ALT) levels ≥2 × the upper reference limit of normal range

   • Diagnosis of hepatic cirrhosis

Achieving iron depletion:

1. Deferasirox 10 mg/kg per day orally, continually, is suggested for starting treatment (Deferasirox 5 mg/kg per day was less effective than 10 or 15 mg/kg per day in decreasing serum ferritin. Daily doses of deferasirox 15 mg/kg did not increase the rate of iron loss but caused more adverse events than 10 mg/kg per day)

2. Doses of DFX for iron overload because of HFE hemochromatosis are typically less than those used for other indications

Toxicity

1. Increased serum levels of ALT/AST

2. Increased serum creatinine level

3. Diarrhea, abdominal pain, nausea

4. Headache, fatigue, back pain, arthralgia

5. Bone marrow suppression, gastrointestinal bleeding are rare but potentially fatal

Efficacy

1. DFX mobilizes iron from parenchymal cells and macrophages; iron removal from heart is less rapid than from other sites

2. DFX and metabolites are primarily excreted in the feces (∼84% of dose)

3. Renal excretion of DFX and metabolites is minimal (∼8% of administered dose)

4. Mean elimination half-life ranges from 8–16 hours after oral administration

5. After 48 weeks of treatment, median serum ferritin levels in patients with HFE hemochromatosis decreased by 64%, 75%, and 74% in cohorts of patients who received deferasirox 5, 10, or 15 mg/kg per day, respectively

6. In all cohorts, median serum ferritin decreased to <250 μg/L after 48 weeks of treatment

Monitoring Therapy

1. Initiation: CBC, serum ferritin, and liver and renal function profiles

2. Monthly: Reevaluate patient; measure CBC, renal and liver function profiles, serum ferritin

3. Discontinue or interrupt therapy if serum ALT/AST or serum creatinine levels increase, or if unfavorable changes in neutrophil or platelet counts or hemoglobin levels occur

4. Risk of hepatic or renal toxicity may be increased in patients with low serum ferritin levels

5. Discontinue DFX when target serum ferritin level is reached

6. Once-twice yearly after iron depletion is completed: Reevaluate patient; serum ferritin, liver function profile

Notes

1. Approximately 30% of patients with HFE hemochromatosis do not tolerate or continue DFX therapy because of adverse events

2. Improvement in survival or disease-related symptoms has not been established

3. Possible role of DFX therapy for “maintenance” of normal serum ferritin levels in persons with HFE hemochromatosis is unknown

4. Safety and efficacy of DFX when administered with other iron chelation agents have not been established