AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
A Favorable Response to Semaglutide in Advanced Hepatic Fibrosis Secondary to Familial Hypobetalipoproteinemia
By Gerlt D, Huerta C, Nguyen N et al.
Introduction: Familial hypobetalipoproteinemia (FHBL) is an autosomal semi-dominant disorder caused by truncating APOB variants that impair hepatic secretion of apolipoprotein B-containing lipoproteins resulting in low LDL-C. While low LDL-C is generally cardioprotective, FHBL predisposes to hepatic steatosis and fat-soluble vitamin deficiencies. Heterozygous FHBL has an estimated prevalence of 1 in 1,000 to 3,000 but remains an uncommon clinical diagnosis. Patient Information: A 45-year-old man with type 2 diabetes mellitus presented with unexplained hypocholesterolemia. He had a family history of low cholesterol in his brother, father, and grandfather. He was previously recommended to adhere to a high-fat diet. Clinical Findings & Timeline: Over a decade of follow-up his LDL-C remained below 30 mg/dL with chronic idiopathic elevated liver enzymes. Diagnostic Assessment & Reasoning: At age 54, viral and autoimmune etiologies were excluded as a cause of elevated liver enzymes. Liver biopsy showed 70% macrovesicular steatosis, nonalcoholic fatty liver disease, and stage 3 fibrosis. Further evaluation revealed deficiencies in fat-soluble vitamins despite adequate intake. His bone densitometry progressed from osteopenia to osteoporosis. At age 59 he was referred to clinical genetics where FHBL was diagnosed with a pathogenic monoallelic APOB frameshift variant (c.10848del; p.Gly3617Alafs*6). Therapeutic Intervention(s): Semaglutide 1 mg weekly was initiated in addition to fat-soluble vitamin supplementation and alendronate. Follow-up, Outcomes & Adverse Events: Over 18 months the patient achieved 30-pound weight loss, improved diabetes control (A1c 8.0% to 6.6%) and near-normalization of liver enzymes. Repeat elastography showed stable stage 3 fibrosis. Treatment was well tolerated without new side effects. Discussion & Synthesis: This case presents a decade-long delay in the diagnosis of FHBL. Persistently unexplained hypocholesterolemia with concurrent hepatic steatosis should prompt genetic evaluation. Additionally, a high-fat diet may paradoxically worsen steatosis by increasing the lipid burden on a liver unable to export apoB-containing lipoproteins. The favorable response to semaglutide suggests glucagon-like peptide-1 (GLP-1) receptor agonists may benefit FHBL-associated liver disease. However, their potential to further reduce intestinal fat absorption warrants caution given the risk of worsening fat-soluble vitamin malabsorption. Early genetic testing, hepatic and bone density surveillance, and vitamin supplementation are pillars of management. Disease-specific trials of GLP-1 receptor agonists in FHBL may provide further insight.