What are the diagnostic criteria and methods for hemochromatosis?

Diagnostic Criteria and Methods for Hemochromatosis

Causes and Pathophysiology

Hereditary hemochromatosis is a genetic disorder of iron metabolism caused primarily by mutations in the HFE gene, with the C282Y mutation present in approximately 90% of affected patients, transmitted in an autosomal recessive pattern. 1 The disease results from increased intestinal iron absorption leading to progressive iron deposition in the liver, heart, pancreas, and other organs. 1 If left untreated, this causes cirrhosis, hepatocellular carcinoma, cardiomyopathy, diabetes, arthritis, and hypogonadism. 1

The H63D mutation may also be associated with hemochromatosis, though its clinical significance is uncertain, and compound heterozygotes (C282Y/H63D) can occasionally develop iron overload. 1

Initial Diagnostic Testing: The Two-Test Approach

For case-finding and diagnosis of hemochromatosis, both fasting transferrin saturation (TS) and serum ferritin must be measured simultaneously—never rely on a single test. 1, 2 This represents the essential first step in the diagnostic algorithm.

Transferrin Saturation (TS)

• TS ≥45% is the primary screening threshold that triggers further investigation, offering high sensitivity for detecting C282Y homozygotes. 1, 2
• TS is calculated as: (serum iron ÷ total iron-binding capacity) × 100. 2
• Fasting samples are required for accuracy. 1

Serum Ferritin

• Diagnostic thresholds for case-finding are >200 µg/L in women or >300 µg/L in men. 1
• Ferritin >1,000 µg/L accurately predicts cirrhosis risk in confirmed hemochromatosis. 1
• Critical caveat: Ferritin can be falsely elevated by inflammation, chronic liver disease, malignancy, metabolic syndrome, and alcohol use—these must be excluded before attributing elevation to iron overload. 2

Genetic Testing: When and What to Order

If either TS ≥45% or ferritin exceeds the upper limit of normal, proceed immediately to HFE gene mutation analysis for C282Y and H63D mutations. 1, 2 This represents step 2 of the diagnostic algorithm.

Pre-Test Counseling Requirements

Before ordering genetic testing, discuss with patients: 1

• Treatment efficacy (phlebotomy)
• Costs of testing and monitoring
• Implications for insurability and employment
• Psychological impact of disease labeling
• Family screening implications
• Possibility of uncertain or variant genotypes

Interpretation of Genetic Results

• C282Y homozygotes (C282Y/C282Y): Confirms HFE-related hemochromatosis diagnosis. 2
• Compound heterozygotes (C282Y/H63D): Rarely cause significant iron overload; manage based on phenotype (iron studies), not genotype alone. 2, 3
• H63D homozygotes or heterozygotes: Can be reassured they are not at risk for progressive iron overload. 3

Assessment for Advanced Disease and Cirrhosis

In confirmed C282Y homozygotes, liver biopsy should be considered if any of the following are present: 1, 2

• Serum ferritin >1,000 µg/L
• Elevated liver enzymes (ALT or AST)
• Hepatomegaly on examination
• Age >40 years
• Platelet count <200

The combination of ferritin >1,000 µg/L, elevated aminotransferases, and platelet count <200 predicts cirrhosis in approximately 80% of C282Y homozygotes. 2 Conversely, ferritin <1,000 µg/L accurately predicts absence of cirrhosis. 1, 2

Role of Liver Biopsy

Liver biopsy is useful to: 1

• Document presence of cirrhosis (if not evident from imaging)
• Rule out significant iron overload when iron markers are equivocal
• Investigate other possible causes of liver disease
• Assess hepatic iron concentration and fibrosis staging

However, with the advent of genetic testing, liver biopsy is no longer widely used solely to confirm the diagnosis. 1

Clinical Presentations Warranting Testing

Consider testing in patients with: 1

• Type 2 diabetes
• Cardiac arrhythmias or cardiomyopathy
• Liver failure, hepatomegaly, or cirrhosis
• Elevated liver enzymes of unclear etiology
• Hepatocellular carcinoma
• Arthritis or chondrocalcinosis
• Hypogonadotropic hypogonadism
• Skin pigmentation changes
• Fatigue and joint pain (though nonspecific)
• Family history of hereditary hemochromatosis

Family Screening

First-degree relatives of patients with confirmed hemochromatosis should undergo both phenotypic testing (TS and ferritin) and HFE genetic testing after appropriate counseling. 2

Population Screening: Not Recommended

Routine population-wide screening for hemochromatosis is not recommended due to low penetrance, uncertain benefit of early treatment in asymptomatic genotype-positive individuals, and potential for false positives. 2 However, one-time phenotypic screening of asymptomatic non-Hispanic white men may have the highest yield if clinicians choose to screen. 1

Important Diagnostic Pitfalls

• Normal TS with elevated ferritin may still indicate iron overload in non-HFE hemochromatosis or compound heterozygotes—do not dismiss based on a single normal parameter. 2
• The TS threshold of 45% has high sensitivity but lower specificity, potentially identifying secondary iron overload requiring further evaluation. 2
• Combined interpretation of TS and ferritin is essential; normal ferritin with TS <45% has 97% negative predictive value for excluding iron overload in individuals <35 years. 2
• Always exclude secondary causes of hyperferritinemia (inflammation, alcohol, NAFLD, malignancy) before attributing elevation to hemochromatosis. 2

Diagnostic Algorithm Summary

1. Measure fasting TS and serum ferritin simultaneously in patients with suggestive symptoms, abnormal liver tests, or family history. 1, 2
2. If TS ≥45% and/or ferritin elevated (>200 µg/L women, >300 µg/L men), order HFE genetic testing for C282Y and H63D mutations. 1, 2
3. If C282Y homozygous with ferritin >1,000 µg/L, elevated liver enzymes, age >40, or platelets <200, consider liver biopsy to assess for cirrhosis. 1, 2
4. Screen first-degree relatives with both phenotypic and genetic testing. 2