👤 Takanari Gotoda

Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher.PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-of-function mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive.The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life.Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease.Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options. Show less

Objective- APOA5 variants are strongly associated with hypertriglyceridemia, as well as increased risks of cardiovascular disease and acute pancreatitis. Hypertriglyceridemia in apo AV dysfunction often aggravates by environmental factors such as high-carbohydrate diets or aging. To date, the molecular mechanisms by which these environmental factors induce hypertriglyceridemia are poorly defined, leaving the high-risk hypertriglyceridemia condition undertreated. Previously, we reported that LXR (liver X receptor)-SREBP (sterol regulatory element-binding protein)-1c pathway regulates large-VLDL (very low-density lipoprotein) production induced by LXR agonist. However, the pathophysiological relevance of the finding remains unknown. Approach and Results- Here, we reconstitute the environment-induced hypertriglyceridemia phenotype of human APOA5 deficiency in Apoa5 Show less

Rare monogenic and severe hypertriglyceridemia usually results from genetic abnormalities that lead to severely reduced activity of lipoprotein lipase (LPL), a crucial player in the hydrolysis of triglyceride(TG)-rich lipoproteins. These include mutations in the genes for LPL, APOC2, GPIHBP1, LMF1 and APOA5. On the other hand, recent results from genome-wide association studies(GWAS) or resequencing studies have revealed that common polygenic and mild hypertriglyceridemia results from accumulation of both common as well as rare risk variants under the influence of classical environmental conditions. Interestingly, some primary hyperlipoproteinemiae appear to share a common genetic basis, providing a recent interesting and unique hypothesis. Genetic analysis also could provide novel candidates for therapeutic targets and fundamental basis of establishment of more rational genetic risk scoring for hypertriglyceridemia. Show less