SUN-234 - Severe Hypertriglyceridemia Unmasked by Bile Acid Sequestrant Therapy in A Patient with A CREB3L3 Variant Unknown Significance

Introduction: Severe hypertriglyceridemia (HTG) is a major risk factor for acute pancreatitis and can result from the interaction of genetic susceptibility and secondary triggers. Bile acid sequestrants are known to raise triglyceride levels and can precipitate severe HTG in susceptible individuals. CREB3L3 loss-of-function variants have recently been implicated in severe HTG. We present a case of extreme hypertriglyceridemia unmasked by colestipol in a patient found to carry a variant of uncertain significance in CREB3L3.

Case Description: A 37-year-old woman with a history of hepatic steatosis and chronic diarrhea was referred for evaluation of severe hypertriglyceridemia. She had mild to moderate triglyceride elevations since 2016 without prior pancreatitis. While taking colestipol for diarrhea, her triglycerides acutely increased to >2,000 mg/dL, though she remained asymptomatic. After dietary counseling, discontinuation of colestipol, and initiation of fenofibrate, triglycerides improved to the 500-600 mg/dL range. Genetic testing was pursued given the degree and persistence of hypertriglyceridemia in the absence of other obvious metabolic risk factors, and revealed a variant of uncertain significance in CREB3L3. While off lipid-lowering therapy, triglycerides again increased to 1,437 mg/dL. She subsequently initiated prescription fish oil and a strict low-fat diet, with improvement of triglycerides to the 300-400 mg/dL range.

Discussion: Although classified as a variant of uncertain significance, the patient’s clinical phenotype strongly suggests pathogenicity of the CREB3L3 variant. She demonstrated marked and recurrent triglyceride elevations, sensitivity to triglyceride-raising medications, and persistence of hypertriglyceridemia despite removal of secondary factors, all of which support an underlying genetic contribution. The dramatic rise in triglycerides following colestipol exposure, followed by partial improvement after discontinuation, further strengthens the likelihood that this variant contributes meaningfully to her phenotype. CREB3L3 plays a key role in hepatic lipid metabolism, and loss-of-function variants have been associated with severe hypertriglyceridemia. In this context, genetic testing provided important diagnostic insight by helping clarify the etiology of her severe and medication-sensitive hypertriglyceridemia.

Conclusion: This case demonstrates severe hypertriglyceridemia unmasked by colestipol in a patient with a CREB3L3 variant of uncertain significance, underscoring the importance of considering genetic susceptibility in patients with unexplained or medication-sensitive hypertriglyceridemia.

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