Severe Familial Hypertriglyceridemia

Successful Treatment With Insulin and a Modified Meal Plan

Ahila Ayyavoo; Palany Raghupathy; Meenal Agarwal; Paul Hofman


J Endo Soc. 2018;2(12):1357-1362. 

In This Article

Abstract and Introduction


Context: Mutations in genes encoding the lipoprotein lipase enzyme, its cofactor, or transport proteins can cause severe familial hypertriglyceridemia, resulting in serious complications, such as severe pancreatitis, hepatosplenomegaly, lipid encephalopathy, and failure to thrive. Current treatment includes a low-saturated-fat formula enriched with high medium-chain triglyceride (TGs), oral fibrates, omega-3 fatty acids, or plasmapheresis.

Case Description: A 71-day-old infant with very severe hypertriglyceridemia and recurrent pancreatitis associated with a likely pathogenic variant in the LPL gene was treated successfully with insulin infusion and a locally prepared low-fat formula feed after stopping breast milk. Subcutaneous insulin was administered daily from 9 to 30 months of age. His serum TG level was markedly lower, although higher than normal. No episodes of hypoglycemia were noted. Fenofibrate and omega-3 fatty acids were ineffective in this infant. At the last follow-up visit, he was 36 months old and growing normally. He was consuming a special meal plan and receiving insulin injections during high-fat meals. Two other young infants with severe hypertriglyceridemia were growing normally after a short course of insulin infusion and the same modified reduced long chain fat diet.

Conclusions: Insulin is an unusual and affordable therapeutic option for some patients with severe hypertriglyceridemia and can be helpful in the prevention of acute and chronic complications. Locally available cereals and millets with high crude fiber and a low glycemic index, along with medium chain TGs, was used to prepare an economical special formula at home to maintain TG concentrations in the acceptable limits.


The accumulation of circulating triglycerides (TGs) results in hypertriglyceridemia (HTG).[1] Dietary TGs are assembled into chylomicrons (large lipoprotein molecules) in the gut.[2] The enzyme lipoprotein lipase (LPL) and its cofactor apolipoprotein-CII are responsible for the clearance of chylomicrons that appear in circulation after the absorption of dietary fat.[3] LPL is produced by myocytes and adipocytes and transported to the luminal surface of capillaries for release of free fatty acids from TGs in chylomicrons and hepatic very-low-density lipoproteins.[1,4]

Factors contributing to elevated TGs include overweight status, insulin resistance, type 2 diabetes mellitus (T2DM), physical inactivity, and genetic disorders.[2] Using the serum TG levels, childhood HTG has been classified as mild (150 to 199 mg/dL), moderate (200 to 999 mg/dL), severe (1000 to 1999 mg/dL), and very severe (>2000 mg/dL).[2]

Primary LPL deficiency is a rare autosomal recessive disorder of lipoprotein metabolism, with a prevalence of ~1 per million.[5,6] It is caused by biallelic pathogenic or likely pathogenic variants (or mutations) in the LPL or APOC2 gene. Familial chylomicronemia can also be caused by mutations in APOA5, GPIHBP1, and LMF1 genes, the proteins of which interact with LPL and lead to low LPL activity.[6,7]APOCIII is an inhibitor of LPL and can increase TGs through a non-LPL mechanism.[8]

The clinical features associated with LPL deficiency include recurrent abdominal pain, failure to thrive, xanthomatosis, hepatosplenomegaly, and lipemic plasma.[6] Severe complications such as recurrent pancreatitis and lipid encephalopathy have been reported.[2,6,9] Available treatment options include dietary fat restriction, use of medium chain TGs (MCTs), fibrates, n-3 fatty acids, plasmapheresis, apolipoprotein-CIII inhibitor and alipogene tiparvovec (AAV1) gene therapy.[8,10] Alipogene tiparvovec (AAV1-LPLS447X gene variant in an adeno-associated viral vector of serotype 1) gene therapy for LPL deficiency has been associated with ≥40% reduction in fasting median serum TGs at 3 to 12 weeks in one-half of the patients participating in a trial.[10] These subjects might require immunosuppression to prevent potential capsid-related immune events.[10]

Secondary HTG seen in patients with T2DM is known to improve with insulin, dietary fat restriction, fibrates, or niacin.[11] Heparin and insulin infusions have been used to treat adult patients with HTG-induced acute pancreatitis by stimulating LPL activity.[12] Acquired LPL deficiency can be observed during insulin deficiency and will be improved with insulin therapy.[13] Hence, insulin was used to treat a young child from early infancy with very severe HTG and recurrent pancreatitis associated with a homozygous likely pathogenic variant in the LPL gene. Two other children with severe HTG, who had not undergone genetics analysis, were also treated with insulin infusion.