What are the symptoms of Haemochromatosis (iron overload disease)?

Symptoms of Haemochromatosis

Most patients with haemochromatosis are now diagnosed while asymptomatic through screening or incidental laboratory findings, but when symptoms occur, they range from nonspecific systemic complaints like fatigue and weakness to specific organ-related manifestations including characteristic joint disease, diabetes, cardiac dysfunction, and sexual health problems. 1

Asymptomatic Presentation (Most Common Today)

• The majority of patients with hereditary haemochromatosis are currently identified before developing symptoms, through abnormal serum iron studies on routine screening, evaluation of abnormal liver tests, or family screening. 1
• Approximately 70% of C282Y homozygotes demonstrate elevated ferritin levels, but fewer than 10% develop full clinical manifestations of end-organ disease. 2, 3

Nonspecific Systemic Symptoms

When symptoms do occur, the most common nonspecific complaints include:

• Weakness, lethargy, and fatigue: Reported in 19-83% of symptomatic patients across multiple studies, making this the most frequent symptom when present. 1, 2
• Abdominal pain: Occurs in 0-58% of patients, typically related to hepatomegaly. 1
• Apathy and weight loss: Less commonly reported but recognized systemic manifestations. 1

Musculoskeletal Symptoms (Highly Characteristic)

Joint disease is one of the most characteristic and debilitating manifestations of haemochromatosis, affecting specific joints in a distinctive pattern:

• Arthralgias: Present in 13-57% of patients, with a characteristic distribution affecting the 2nd and 3rd metacarpophalangeal joints, ankles (69.3%), hips (56.8%), and hands/wrists (46.9%). 1
• Haemochromatosis arthropathy: Distinguished from typical osteoarthritis by younger age of onset, characteristic joint involvement (especially 2nd and 3rd MCP joints and ankles), exuberant osteophytes, and rapid progression to cartilage loss. 1
• Chondrocalcinosis: Present in approximately 50% of cases with joint involvement. 1
• Patients have significantly increased risk of hip replacement (HR 2.77) and knee replacement (HR 2.14) compared to those without haemochromatosis mutations. 1

A critical pitfall: Haemochromatosis arthropathy does not respond to phlebotomy and can develop even on maintenance therapy, significantly affecting quality of life. 1

Endocrine and Sexual Health Symptoms

• Loss of libido and impotence: Reported in 12-56% of male patients, related to pituitary hypogonadism or cirrhosis. 1, 2
• Menstrual problems: Affect 62.9% of females with haemochromatosis. 1
• Sexual health issues: Reported in 57.3% of patients overall. 1
• Testicular atrophy: Physical finding in 14-50% of symptomatic patients. 1

Hepatic Manifestations

• Hepatomegaly: Present in 3-83% of patients depending on disease stage at presentation. 1, 2
• Right upper quadrant abdominal pain: Related to liver enlargement. 1
• Cirrhosis: Found in 3-94% of patients, with higher rates in those diagnosed based on symptoms rather than screening. 1

Cardiac Symptoms (Particularly in Severe/Juvenile Forms)

In severe haemochromatosis, especially juvenile forms (HJV and HAMP-related), cardiac manifestations are particularly prevalent and life-threatening:

• Congestive heart failure symptoms: Reported in 0-35% of adult-onset cases but much more common in juvenile forms. 1
• Cardiomyopathy: Myocardial iron accumulation induces restrictive cardiomyopathy with early diastolic dysfunction that may progress to dilated cardiomyopathy with impaired systolic function. 1
• Arrhythmias: Including extreme bradycardia, tachycardia, atrial fibrillation, ventricular arrhythmias, atrioventricular blocks of any degree, and sudden death. 1
• If untreated, patients with juvenile haemochromatosis can develop severe heart failure before age 30, possibly resulting in death or need for heart transplant. 1

Metabolic Symptoms

• Diabetes mellitus: Clinical diabetes present in 6-55% of patients, related to pancreatic iron deposition. 1, 2
• This contributes to the classic triad of "bronze diabetes" (cirrhosis, diabetes, and skin pigmentation) in advanced disease. 2

Dermatologic Manifestations

• Skin pigmentation: Greyish-brown discoloration present in 5-82% of symptomatic patients, with higher rates in those with advanced disease. 1, 2
• Skin problems: Reported in 70.4% of patients in recent surveys. 1

Neuropsychiatric Symptoms

• Depression: Affects 38% of patients with haemochromatosis. 1
• Brain fog: Reported in 60.4% of patients. 1

Key Clinical Pearls

The thoughtful clinician should consider haemochromatosis when patients present with:

• Unexplained fatigue combined with abnormal liver tests 1
• Characteristic arthropathy affecting 2nd/3rd MCP joints and ankles in younger patients 1
• Early-onset diabetes with hepatomegaly 2
• Male sexual dysfunction with elevated liver enzymes 2
• Family history of haemochromatosis or unexplained cirrhosis 1

Males are affected significantly more frequently than females, and disease prevalence increases with age. 1