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Hereditary Hemochromatosis - Diagnosis

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Hereditary Hemochromatosis
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The initial diagnosis of hemochromatosis does not establish risk for complications; that is a secondary diagnostic issue once the primary diagnosis is established. (LOE=B)

Diagnostic Testing and Evaluation

Physical exam findings may include increased pigmentation (“skin bronzing”), weight loss, arthritis in the small joints of the hand.

Diagnostic Criteria

  • Transferrin saturation > 45% on two occasions (at least one fasting) establishes iron overload (sensitivity ? 94%). (LOE=B)
  • Increased specificity can be obtained with a lower sensitivioty by raising the saturation criteion
  • Transferrin Saturations >55% have been associated with increased all-cause mortality (hazard ratio 1.6). (LOE=B)
  • Genetic testing for specific gene mutations (C282Y and H63D) confirms the diagnosis.

First steps

Do transferrin saturation, preferably fasting. Two elevations establishes iron overload, and genetic testing can be undertaken.

Testing Strategy

  • Do transferrin saturation; if elevated, repeat. If second abnomal do genetic testing.
  • If diagnosis established, get fasting blood sugar, echocardiogram, TSH, ferritin, and liver enzymes.
  • If either transferrin normal, hemochromatosis less likely, but if borderline, may be accumulating iron, but not high enough to diagnose yet.

Tests that are not helpful

  • Elevated ferritin is NOT helpful for diagnosis because it is also a non-specific marker of inflammation; is drawn for prognostic reasons and to monitor therapy (see Management)
  • Other variations in the gene are not clearly associated with clinical manifestations, so only the specific mutations should be tested for.

Subsequent Evaluation

  • Physical exam findings include increased pigmentation only. The arthritis is non-inflammatory and thus has no findings.
  • There are many testing abnormalities associated with complications, including elevated TSH (hypothyroidism), elevated blood sugars (Type 2 diabetes), liver enzyme abnormalities (alone, or due to cirrhosis or hepatocellular carcinoma), abnormal echocardiogram (cardiomyopathy).

Clinical Features (LOE = A)



Lab Abnormalities

Other findings

Abdominal Pain

Weight loss

Hepatitis/transaminase elevation

Hepatocellular carcinoma


Increased pigmentation

Type 2 diabetes mellitus

Cardiomyopathy or Cardiac Arrhythmia



Arthralgia or arthritis (especially small joints of the hand)




Loss of Libido



Lifestyle/Environmental Contributors to Disease

  • Dietary intake of iron, vitamins containing iron, and pharmacologic doses ( >RDA of 200 mg) of Vitamin C can all increase total iron uptake and thus iron accumulation.
  • Alcohol intake can also exacerbate iron accumulation and appears to increase the amount of liver damage.

Differential Diagnosis

  • Other hereditary iron overload conditions
  • Secondary iron overload

Consensus Statements and Guidelines

Screening: USPSTF, American College of Physicians

All aspects: American Association for the Study of Liver Diseases (AASLD)