What is the diagnosis and treatment for an adult with suspected hemochromatosis (iron overload disorder) and associated diabetes, also known as bronze diabetes?

Bronze Diabetes: Diagnosis and Management of Hemochromatosis with Diabetes

Bronze diabetes is hemochromatosis-associated diabetes, and the definitive treatment is therapeutic phlebotomy initiated before cirrhosis develops to reduce morbidity and mortality, with the goal of depleting iron stores to a ferritin level of 50-100 µg/L. 1

What is Bronze Diabetes?

Bronze diabetes refers to the classic triad of hemochromatosis: cirrhosis, diabetes mellitus, and skin pigmentation (bronze or gray-brown discoloration). 1 This term describes the end-stage manifestation of hereditary hemochromatosis (HH), an autosomal recessive disorder most commonly caused by C282Y homozygosity in the HFE gene. 1, 2

• The pathophysiology involves iron-induced pancreatic beta-cell damage leading to impaired insulin synthesis and secretion, combined with insulin resistance. 3, 4, 5
• Approximately 50% of patients with hemochromatosis will develop either type 1 or type 2 diabetes due to selective beta-cell destruction from iron overload. 3
• The degree of glucose intolerance correlates directly with the stage of iron overload and accompanying liver disease. 4

Diagnostic Approach

Suspect hemochromatosis in any adult presenting with:

• Fatigue, right upper quadrant pain, arthralgias (especially 2nd and 3rd metacarpophalangeal joints), impotence, decreased libido, or symptoms of heart failure or diabetes. 1
• Physical findings: hepatomegaly, skin pigmentation, testicular atrophy, congestive heart failure, or arthritis. 1

Confirm diagnosis with:

• Transferrin saturation (TSAT) >45% in females or >50% in males combined with elevated ferritin (>200 µg/L in females, >300 µg/L in males). 1
• HFE genetic testing showing C282Y homozygosity confirms hereditary hemochromatosis. 1, 2
• If non-HFE genotype, hepatic iron overload must be demonstrated by MRI or liver biopsy. 1

Critical pitfall: Do not treat elevated hemoglobin and high iron saturation as iron deficiency anemia—this represents iron overload, not deficiency. 6

Treatment: Phlebotomy Protocol

Phlebotomy is the mainstay of treatment and must be initiated before cirrhosis and diabetes develop to significantly reduce morbidity and mortality. 1

Induction Phase

• Remove 500 mL of blood (one unit) weekly or twice weekly as tolerated. 1
• Each unit contains approximately 200-250 mg of iron. 1
• Check hemoglobin/hematocrit before each session—do not allow hematocrit to fall below 80% of baseline. 1, 7
• Monitor ferritin every 10-12 phlebotomies (approximately every 3 months). 1, 7
• Target ferritin: 50-100 µg/L (AASLD) or <50 µg/L (EASL). 1, 8
• Treatment may take 2-3 years in patients with total body iron stores >30 g. 1

Maintenance Phase

• Once iron stores are depleted, assess need for maintenance phlebotomy—not all patients reaccumulate iron. 1
• Frequency varies: some require monthly phlebotomy, others only 1-2 units per year. 1, 7
• Target ferritin <100 µg/L during maintenance. 1, 8

Expected Response to Treatment

Responsive features (will improve with phlebotomy): 1

• Malaise and fatigue
• Skin pigmentation
• Insulin requirements for diabetics (improved control, not cure)
• Abdominal pain
• Cardiac function

Less responsive or non-responsive features: 1

• Arthropathy (minimal improvement)
• Hypogonadism (less responsive)
• Advanced cirrhosis (no reversal)
• Testicular atrophy (no reversal)

Critical caveat: Once diabetes or cirrhosis develops, phlebotomy cannot reverse these conditions, though it may improve diabetes control and prevent further progression. 1, 4, 2 This underscores the importance of early diagnosis and treatment.

Diabetes Management Specifics

• Early intervention with phlebotomy before diabetes develops can prevent its occurrence. 3, 4, 2
• In established diabetes, phlebotomy may reduce insulin requirements but does not cure diabetes, especially if beta-cell damage is advanced. 1, 4, 5
• The pathogenesis is multifactorial: decreased insulin secretion, insulin resistance, cirrhosis, and metabolic syndrome all contribute. 5
• Standard diabetes management (insulin or oral agents) should continue alongside phlebotomy. 3

Monitoring and Lifestyle Modifications

• Avoid vitamin C supplements—they accelerate iron mobilization and can increase toxic free iron. 1, 7, 8
• Minimize alcohol consumption—it increases iron absorption and worsens liver damage. 7
• Avoid iron-fortified foods and iron supplements. 8
• No specific low-iron diet is necessary, as dietary modification has minimal impact (2-4 mg/day). 1

Screening for Complications

In patients with established cirrhosis:

• Continue hepatocellular carcinoma (HCC) screening even after adequate phlebotomy, as HCC risk persists. 1
• HCC accounts for 30% of hemochromatosis-related deaths, and cirrhosis complications account for another 20%. 1
• HCC is exceptionally rare in non-cirrhotic hemochromatosis, providing strong rationale for preventive therapy. 1

Prognosis

Survival is dramatically improved if treatment begins before cirrhosis and diabetes develop. 1 Early identification through family screening or incidental laboratory findings allows treatment of asymptomatic patients with iron overload markers, preventing end-organ damage entirely. 1