SUN-231 - Extreme Hypertriglyceridemia ( >5,680 Mg/Dl) Associated with Hereditary Hemochromatosis

Severe hypertriglyceridemia (HTG) is a major risk factor for acute pancreatitis and is most commonly attributed to uncontrolled diabetes mellitus or secondary causes such as medications. Iron overload is an underrecognized contributor to HTG by impairing lipoprotein lipase activity. HFE gene mutations have been associated with an increased risk of primary HTG, and iron-reduction therapy has been shown to lower triglyceride levels in affected patients.
We present a 43-year-old Caucasian man with bipolar disorder treated with quetiapine and bupropion, and long-standing polycythemia (hemoglobin 17.8 g/dL since 2020), who developed rapidly progressive hypertriglyceridemia. Triglyceride levels increased from 154 mg/dL in early 2024 to >5,680 mg/dL by April 2025, despite being on treatment with rosuvastatin 20 mg daily. Notably, lipase remained normal at 15 U/L, and there were no clinical features of acute pancreatitis.
Further evaluation revealed markedly elevated ferritin at 2,421 ng/mL. Abdominal ultrasound demonstrated massive hepatomegaly with diffuse fatty infiltration. Genetic testing confirmed homozygous C282Y hereditary hemochromatosis. Concurrently, the patient was diagnosed with new-onset type 2 diabetes mellitus.
Initial management with high-intensity statin therapy, fenofibrate 160 mg daily, icosapent ethyl 2 g twice daily, and semaglutide resulted in limited improvement in triglyceride levels. Therapeutic phlebotomy was initiated on May 27, 2025, leading to a rapid decline in ferritin from 2,334 to 1,040 ng/mL (May 20–June 17), accompanied by a dramatic reduction in triglycerides to 182 mg/dL by June 3, 2025.
This case highlights iron overload as a key and underrecognized contributor to extreme hypertriglyceridemia in the setting of diabetes mellitus. The rapid normalization of triglyceride levels following phlebotomy, despite prior refractoriness to conventional lipid-lowering therapy, suggests restoration of metabolic lipid handling with iron reduction. Iron overload should be considered in patients with severe or refractory hypertriglyceridemia, particularly when accompanied by elevated ferritin or polycythemia. Early HFE testing and therapeutic phlebotomy may provide rapid and effective correction of lipid abnormalities when iron excess contributes to disease pathophysiology.

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