Signs and Symptoms of Hereditary Hemochromatosis
Most patients with hereditary hemochromatosis today are asymptomatic and identified through abnormal iron studies on routine screening, family screening, or evaluation of abnormal liver tests, rather than presenting with classic end-organ manifestations. 1
Current Clinical Presentation Pattern
The clinical presentation of hemochromatosis has dramatically shifted over recent decades. While historical series from the 1950s-1980s showed patients presenting with advanced disease, approximately 75% of patients identified through modern screening methods are asymptomatic without end-stage manifestations. 1 Only about 70% of C282Y homozygotes even develop elevated ferritin levels, and fewer than 10% develop full clinical disease with end-organ damage. 2, 3
Symptomatic Presentations to Recognize
Nonspecific Systemic Symptoms
When symptoms do occur, the most common presentations include:
- Weakness, lethargy, and fatigue (reported in 19-83% of symptomatic patients depending on the series) 1, 3
- Abdominal pain, particularly right upper quadrant pain related to hepatomegaly (0-58% of patients) 1
- Weight loss and apathy 1
Specific Organ-Related Symptoms
Arthralgias are a hallmark symptom, particularly affecting the second and third metacarpophalangeal (MCP) joints (13-57% of patients). 1, 3 This characteristic arthropathy pattern, sometimes called the "iron fist," should immediately raise suspicion for hemochromatosis. 1
Endocrine manifestations include:
- Loss of libido and impotence in men (12-56% of patients) related to pituitary dysfunction or cirrhosis 1, 3
- Amenorrhea in women with cirrhosis 1
- Diabetes mellitus (6-55% of patients) due to pancreatic iron deposition causing beta-cell damage 1, 3, 4
Cardiac symptoms include:
Physical Examination Findings
Hepatic Manifestations
- Hepatomegaly (3-83% of patients, with higher rates in older series of symptomatic patients) 1, 3
- Cirrhosis on biopsy (3-94% depending on disease stage at presentation) 1, 3
- Extrahepatic manifestations of chronic liver disease 1
Dermatologic Findings
- Skin pigmentation/melanoderma - the classic "bronze diabetes" appearance (5-82% of patients) 1, 3, 5
- Changes of porphyria cutanea tarda 1
Other Physical Findings
- Testicular atrophy (14-50% of men) 1, 3
- Loss of body hair (6-32%) 1
- Gynecomastia (8-12%) 1
- Splenomegaly (13-40%) 1
- Arthritis with chondrocalcinosis 1
Critical Clinical Pitfalls
A major pitfall is the long diagnostic delay that occurs because early symptoms are nonspecific. Fatigue and joint pain are common complaints that may be attributed to other conditions for years. 6, 7 In one French study, 23-29% of patients with arthropathy or hepatopathy experienced diagnostic delays of 1-15 years. 6
The classic triad of cirrhosis, diabetes, and bronze skin pigmentation represents advanced, end-stage disease and should not be the target for diagnosis. 3, 5 Waiting for these manifestations means missing the opportunity to prevent irreversible organ damage through early phlebotomy.
Women typically present later than men because menstrual blood loss delays iron accumulation, with symptoms often appearing after menopause. 8, 7 Women also report more severe fatigue than men when symptomatic. 7
When to Suspect Hemochromatosis
Maintain a high index of suspicion in patients presenting with:
- Unexplained persistent fatigue, especially with elevated ferritin 1, 7
- Arthropathy affecting the 2nd and 3rd MCP joints 1
- Type 2 diabetes with hepatomegaly or elevated liver enzymes 3, 4
- Early-onset cardiac disease or male sexual dysfunction 3
- Any combination of liver disease, diabetes, and skin changes 1, 5
- First-degree relatives of confirmed hemochromatosis cases 1, 3
All patients with abnormal liver function tests should have iron studies performed as part of their evaluation. 1