What are the clinical features of hemochromatosis?

Clinical Features of Hemochromatosis

Most patients with hemochromatosis today are asymptomatic and identified through abnormal iron studies on routine screening, with approximately 75% lacking symptoms when diagnosed, representing a dramatic shift from the classic "bronze diabetes" presentation of advanced disease. 1

Evolution of Clinical Presentation

The clinical presentation of hemochromatosis has fundamentally changed over recent decades:

• Historical presentation (1950s-1980s): Patients typically presented with advanced disease showing the classic triad of cirrhosis, diabetes, and skin pigmentation 1
• Current presentation (1990s-present): Most patients are now identified through abnormal iron studies on routine chemistry panels or family screening, with approximately 75% being asymptomatic at diagnosis 1
• Incomplete penetrance: Only approximately 70% of C282Y homozygotes demonstrate elevated ferritin levels, and fewer than 10% develop full clinical manifestations with end-organ damage 1, 2, 3

Symptomatic Presentations

Nonspecific Systemic Symptoms

When symptoms occur, they are often vague and nonspecific:

• Weakness, lethargy, and fatigue: Reported in 19-83% of symptomatic patients across different series 1, 3
• Apathy and weight loss: Common but nonspecific complaints 1

Organ-Specific Manifestations

Hepatic involvement:

• Right upper quadrant abdominal pain: Present in 0-58% of patients, reflecting hepatomegaly 1, 3
• Hepatomegaly: Found in 3-83% of patients depending on disease stage 1, 3
• Cirrhosis: Documented in 3-94% of patients, with higher rates in older symptomatic cohorts 1, 3

Musculoskeletal manifestations:

• Arthralgias: Occur in 13-57% of patients, characteristically affecting the second and third metacarpophalangeal joints 1, 3
• Chondrocalcinosis: A specific finding that should raise suspicion for hemochromatosis 1
• Arthritis: Can be a presenting feature requiring rheumatology evaluation 4

Endocrine dysfunction:

• Diabetes mellitus: Present in 6-55% of patients due to pancreatic iron deposition 1, 3
• Sexual dysfunction: Loss of libido and impotence reported in 12-56% of male patients 1, 3
• Testicular atrophy: Found in 14-50% of affected men 1, 3
• Amenorrhea: Can occur in women with cirrhosis 1
• Hypogonadotropic hypogonadism: Results from pituitary dysfunction 1, 3

Cardiac manifestations:

• Congestive heart failure symptoms: Reported in 0-35% of patients 1, 3
• Cardiomyopathy and arrhythmias: Can be presenting features requiring cardiology referral 1, 3, 4

Dermatologic findings:

• Skin pigmentation: Present in 5-82% of patients, with higher rates in advanced disease 1, 3
• Changes of porphyria cutanea tarda: Should prompt evaluation for hemochromatosis 1

Other physical findings:

• Splenomegaly: Found in 13-40% of patients 1
• Loss of body hair: Reported in 6-32% of cases 1
• Gynecomastia: Occurs in approximately 8-12% of men 1

Critical Diagnostic Considerations

Key clinical pearls:

• The AASLD recommends evaluating patients with abnormal iron studies for hemochromatosis even in the absence of symptoms 1
• All patients with evidence of liver disease should be evaluated for hemochromatosis 1
• Women are often diagnosed later than men due to protective effects of menstrual blood loss 5
• The thoughtful clinician must consider hemochromatosis when patients exhibit these symptoms, as many features overlap with other disease processes 1

High-Risk Presentations Requiring Specialist Referral

Patients with the following features should be referred to hepatology or appropriate subspecialty 4:

• Ferritin >1,000 μg/L with elevated ALT/AST, hepatomegaly, platelet count <200, or age >40 years (approximately 80% probability of cirrhosis in C282Y homozygotes) 4
• Cardiac symptoms: Heart failure, cardiomyopathy, or atrial fibrillation warrant cardiology evaluation 4
• Endocrine manifestations: Diabetes, hypogonadism, or pituitary dysfunction require endocrinology referral 4
• Significant arthropathy: Particularly affecting metacarpophalangeal joints, warrants rheumatology consultation 4

Common Pitfalls

• Failing to distinguish genetic susceptibility from clinical disease: Most C282Y homozygotes never develop symptomatic disease 2
• Overlooking hemochromatosis in atypical populations: While rare, hemochromatosis can occur in African-Americans and women of childbearing age 6
• Attributing elevated ferritin solely to inflammation: Inflammatory conditions can elevate ferritin without true iron overload, requiring combined assessment with transferrin saturation 2
• Missing the diagnosis due to nonspecific symptoms: The absence of classic "bronze diabetes" in modern practice makes diagnosis challenging 1, 5