I. Pathophysiology

    1. Definition of condition = systemic excess of iron in the body, resulting in tissue damage and dysfunction
  1. Iron accumulates as ferritin and hemosiderin
    1. Liver-All iron absorbed from intestine passes through liver; any that exceeds binding capacity of transferrin is deposited
    2. Accumulation with dysfunction also occurs in pancreas, heart, gonads, thyroid, hypothalamus, pituitary, and joints
  1. Hereditary form
  1. Characterized by excessive intestinal absorption of iron, not regulated by iron stores as is normally the case
  2. Genetics
    1. Most forms are autosomal recessive
    2. The gene known as HLA-H (aka HFE) is most commonly responsible; other genes may be involved as well (hemojuvelin, hepcidin, feroportin)
    3. Most common mutation is known as Cys282Tyr (aka C282Y); Accounts for 80-90% of white patients with hemochromatosis in U.S.; Also associated with increased risk of colorectal cancer
    4. Less common mutation is His63Asp (aka H63D)
    5. A more severe (but less common), autosomal dominant, juvenile-onset, genetic form has been identified in Italy
  3. Most common in individuals of Northern European ancestry (prevalence of heterozygosity is about 10%)
  4. Clinical manifestations occur after years of excess absorption (usually after age 30 in men; later in women)
  5. Women homozygous for the hereditary defect express the disease 1/10 as often as men, prob. b/c of menstrual loss of iron
  6. Ethanol abuse or hepatitis accelerates liver and pancreatic damage, probably due to high serum levels of ferritin after hepatocyte injury
  1. Secondary causes include:
  1. Chronic anemias, e.g. homozygous beta-thalassemia
  2. Multiple transfusions (iron excess tends to occur first in the reticuloendothelial cells, in contrast to hereditary hemochromatosis; treated with iron chelation)
  3. Porphyria cutanea tarda (a skin & liver disease that can be hereditary; associated with decrease in activity of hepatic uroporphyrinogen decarboxylase; may be associated with hepatitis C virus infection)
  4. Portocaval shunt
  5. Ingestional iron overload (documented in Africa from drinking beer fermented in steel drums)
  6. Other genetic conditions leading to iron overload or high ferritin levels:
    1. Transferrin receptor 2 mutation (phenotype similar to hereditary hemochromatosis)
    2. Ferroportin mutations (involved in movement of iron across enterocytes and macrophages-Iron accumulation is primarily in Kupffer cells)
    3. Aceruloplasminemia (mutation of ceruloplasmin gene, characterized by anemia, iron overload, diabetes mellitus, and neurodegeneration; usually treated with iron chelation because of  anemia)
    4. H-ferritin mutation
    5. Hyperferritinemia without iron overload (autosomal dominant genetic disorder causing high ferritin levels without iron overload; associated with bilateral congenital cataracts)
    6. Neuroferritinopathy (autosomal dominant genetic disorder affecting basal ganglai; clinical onset in adulthood, iron and ferritin deposits in the brain, ferritin levels usually normal or low)

II. Clinical manifestations

  1. Common presenting symptoms:
  1. Fatigue, often severe (75% of patients with heretditary hemochromatosis)
  2. Arthralgias 
  3. Abdominal discomfort
  4. Insulin resistance and diabetes mellitus (50% of patients with hereditary hemochromatosis)
  5. Erectile dysfunction in men (45% of patients with heretditary hemochromatosis)
  6. Amenorrhea
  7. Skin hyperpigmentation (like suntan) on both exposed and nonexposed areas; slate gray in late stages (75% of patients with hereditary hemochromatosis)
  1. Other manifestations
  1. Hepatosplenomegaly and hepatic dysfunction, including cirrhosis
  2. Hepatocellcular carcinoma
  3. Ascites leading to acute peritonitis or septicemia
  4. Arthritis
    1. Associated with calcium pyrophorphate crystal deposition i.e. pseudogout,
    2. Most commonly 2nd and 3rd MCP joints, knees, and hips
    3. Usually does not respond to iron removal treatment
    4. Treatable with salicylates or NSAIDS)
  5. Restrictive cardiomyopathy with heart failure and/or dysrhythmias
  6. Hypothyroidism
  7. Adrenal insufficiency
  8. Testicular atrophy
  9. Parkinsonism
  10. Osteoporosis
  11. Hearing loss
  12. Pleural effusion
  13. Hair loss

III. Diagnosis

  1. Laboratory abnormalities
  1. Iron studies
  1. Transferrin saturation (Fe/TIBC) > 60% (nl 20-50%)
  2. This can also occur with taking exogenous iron or OC's
  1. If % Sat is elevated and confounding factors ruled out, check ferritin
  1. In advanced hemochromatosis will be >500ug/l, often much higher
  2. But it's also an acute phase reactant so will be high in chronic disease, malignancy, etc., as well as alcohol abuse
  1. Often get macrocytosis ("due to liver dysfunction"-?)
  2. Genetic screens (for hereditary hemochromatosis-See above)
  1. Genetic screening is useful in testing relatives in families known to carry mutant alleles of HLA-H, to distinguish homozygotes from heterozygotes in families with hereditary hemochromatosis, or when hereditary hemochromatosis is suspected.
  1. Liver biopsy
    1. Gives semiquantitative estimation of iron overload (Hepatic Iron Concentration; us. divided by age to give "Hepatic Iron Index"); HII 1.9 or higher seems to be highly sensitive & specific for homozygous hereditary hemochromatosis diagnosed according to clinical & biochemical criteria (Gastroenterology 113:1270, 1997-JW)
    2. Consider for C282Y homozygotes > 40yo with (serum ferritin > 1,000 mg/L, abnormal hepatic transaminases, or hepatomegaly)
  2. Bone marrow examination not helpful; may or may not show increased hemosiderin content
  3. X-rays show joint changes which may be confused with osteoarthritis or rheumatoid arthritis, e.g. small cysts and osteophytes
  4. Screening
    1. Screening not yet advised in general population as of 2012
    2. Consider screening siblings of patients with hereditary hemochromatosis with %sat and serum ferritin

IV. Management and prognosis

  1. Monitoring
    1. Asymptomatic patients with proven homozygosity for C282Y
      1. Yearly exam of skin, heart, liver, joins, and (in men) testes + iron %sat
    2. Patients with hereditary hemochromatosis + hepatic cirrhosis
      1. Q6mo serum AFP and liver ultrasound recommended by American Association for the Study of Liver Diseases, 2011
  2. Median survival 2y after dx without treatment; if treatment begins before onset of signs/sx, survival is same as general population
  3. In general, organ dysfunction is not reversed by treatment but progression may be halted; the exception is cardiac dysfunction, which often substantially improves; hypogonadism may also improve
  4. Mortality is most commonly from complications of liver disease (subacute baterial peritonitis, bleeding from varices, hepatocellular Ca)
  5. Treatment of choice is repeated phlebotomy
    1. Usually 1.5-2 units/wk for non-elderly men without cardiovascular disease, 0.5 units/wk for others
    2. Continue until iron stores are normalized and transferrin sat is < 50%
    3. Most patients need phlebotomy Q2-4mos for maintenance
  6. Alcohol abstinence improves outcomes (alcohol increases iron absorption, in addition to its direct hepatotoxic effects)
  7. Avoid vitamin C supplements (may increase risk of cardiac dysrhythmias)
  8. Avoid eating uncooked seafood due to increased risk for infections by "siderophilic bacteria" which are common in seafoods.
  9. Liver transplant may be necessary in advanced cases

(Sources include Cecil's 20th ed.; Core Content Review of Family Medicine, 2012))