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BASICS

Description

  • Genetic disorder causing iron overload from increased intestinal absorption.
  • Surplus iron deposits in tissues including liver, pancreas, heart β†’ organ damage.
  • Patients often asymptomatic initially; late complications include diabetes, cirrhosis, skin pigmentation, cardiac issues.

Epidemiology

  • Clinical symptoms usually present in 3rd–5th decades for types 1, 3, 4; juvenile type 2 presents earlier.
  • More common clinical expression in men due to menstruation delaying onset in women.
  • Prevalence: ~5.4% carry C282Y mutation; homozygosity ~0.3% in US; type 1 accounts for >90% cases in US, mostly northern European descent.

ETIOLOGY AND PATHOPHYSIOLOGY

  • Genetic mutations:
  • Type 1: HFE gene (C282Y, H63D mutations) - most common
  • Type 2 (juvenile): HJV or HAMP genes
  • Type 3: TFR2 gene
  • Type 4: SLC11A3 gene (ferroportin disease)
  • Types 1–3 cause hepcidin deficiency β†’ increased ferroportin activity β†’ excessive iron absorption.
  • Type 4 involves ferroportin insensitivity or inactivity, causing iron accumulation in mesenchymal tissues.
  • Excess unbound plasma iron deposits in organs, leading to dysfunction.

Genetics

  • Autosomal recessive inheritance (types 1–3); type 4 is autosomal dominant.
  • Variable expressivity and incomplete penetrance.
  • ~75% men and 50% women with type 1 have increased transferrin saturation.

RISK FACTORS

  • Positive family history
  • Male sex (30–50 years typical onset)
  • Alcohol use (increases iron absorption and liver damage)
  • Menstruation and pregnancy delay symptoms in women.

PREVENTION

  • Screen first-degree relatives with fasting transferrin saturation and ferritin.
  • Genetic testing recommended for children of diagnosed parents.
  • Population screening not recommended due to low penetrance.

DIAGNOSIS

History

  • Fatigue, weakness
  • Arthralgia
  • Abdominal pain
  • Loss of libido or impotence
  • Diabetes symptoms
  • Skin hyperpigmentation or blistering

Physical Exam

  • Hepatomegaly, splenomegaly
  • Skin hyperpigmentation (bronze)
  • Hepatic tenderness, jaundice
  • Peripheral edema, ascites
  • Gynecomastia
  • Testicular atrophy

Differential Diagnosis

  • Other inflammatory liver diseases
  • Alcoholic or biliary cirrhosis
  • Repeated transfusions
  • Sideroblastic anemia
  • Ξ²-thalassemia major

DIAGNOSTIC TESTS & INTERPRETATION

  • Serum ferritin (SF): β‰₯300 Β΅g/L (men, postmenopausal women), β‰₯200 Β΅g/L (premenopausal women) suspicious.
  • Transferrin saturation (TS): β‰₯45% suspicious, but nonspecific.
  • Genetic testing for HFE mutations confirms diagnosis.
  • Liver enzymes (ALT, AST), CBC, hematocrit monitor complications.
  • Hepatic MRI (T2-weighted) to quantify liver iron if SF >1,000 Β΅g/L, hepatomegaly, or elevated enzymes.
  • Liver biopsy if fibrosis staging or uncertain diagnosis needed.

TREATMENT

General Measures

  • Phlebotomy (~500 mL/session) weekly or twice weekly initially, may take 2–3 years to deplete iron.
  • Maintenance phlebotomy 2–6 times/year to keep SF near 50 Β΅g/L.
  • Erythrocytapheresis alternative: removes RBCs only, less frequent treatments needed but costly.
  • Hydration before phlebotomy to avoid hypovolemia.

Medications

  • Chelation therapy (deferoxamine, deferasirox, deferiprone) for patients unable to undergo phlebotomy.
  • Proton pump inhibitors may reduce iron absorption and phlebotomy frequency.
  • Testosterone replacement in men may improve hypogonadism symptoms but risk hepatotoxicity.
  • Vaccinations: Hepatitis A/B if naive; pneumococcal if cirrhosis present.

ONGOING CARE

  • Monitor hemoglobin before phlebotomy; hold if <11 g/dL.
  • Check SF every 1–3 months during initiation phase; yearly during maintenance.
  • Avoid iron supplements, vitamin C supplements, iron-fortified foods.
  • Limit alcohol (<4 units/day) to reduce liver damage risk.

PROGNOSIS

  • Dependent on cirrhosis presence.
  • Early diagnosis and treatment normalize life expectancy.
  • Type 2 juvenile HH presents earlier and more severe.
  • Cirrhosis increases risk of hepatocellular carcinoma (~3–4% annual incidence).
  • Symptoms like diabetes, hypogonadism may persist despite treatment.

COMPLICATIONS

  • Arthritis, chondrocalcinosis
  • Osteoporosis
  • Diabetes mellitus
  • Hypogonadism
  • Arrhythmias
  • Congestive heart failure
  • Cirrhosis (20–45% in C282Y homozygotes with SF >1,000 Β΅g/L)
  • Hepatocellular carcinoma risk increased
  • Increased susceptibility to infections (Listeria, E. coli, Yersinia, Vibrio)

Clinical Pearls

  • Screening recommended in symptomatic or family history patients, not general population.
  • Elevated transferrin saturation is earliest marker.
  • Ferritin can be falsely elevated in inflammation.
  • Hepatic MRI and liver biopsy help evaluate organ damage.
  • Phlebotomy remains cornerstone of treatment.
  • PPI use may reduce phlebotomy frequency.
  • Testosterone replacement requires caution due to hepatotoxicity risk.

References

  1. Buzzetti E, Kalafateli M, Thorburn D, et al. Interventions for hereditary haemochromatosis: an attempted network meta-analysis. Cochrane Database Syst Rev. 2017;3(3):CD011647.
  2. Kowdley KV, Brown KE, Ahn J, et al. ACG clinical guideline: hereditary hemochromatosis. Am J Gastroenterol. 2019;114(8):1202-1218.