Alan Brown, Vadzim Chyzhyk, Andres Gelrud, Joyce Ross, Alan Gilstrap, Andrew Hsieh, and Karren Williams
The familial chylomicronemia syndrome (FCS), also known as hyperlipoproteinemia type 1, lipoprotein lipase deficiency, lipase D deficiency, familial hyperchylomicronemia, familial chylomicronemia, chylomicronemia syndrome, idiopathic hyperlipemia, Burger-Grutz syndrome1
is an extremely rare genetic disorder.
It is inherited in autosomal recessive fashion, hence both parents must be carriers of the genetic defect and/or affected by the disease in order for their child to manifest with FCS. The prevalence of the disease is approximtely 1 in 1 milllion individuals.2
Most frequently severe hypertriglyceridemia is the clinical manifestation due to mutations affecting the gene responsible for production of lipoprotein lipase (LPL). More rarely, the disease can be due to a mutation causing th absence of apoproteinn C-II, which is the activator of lipoprotein lipase.4
Patients with FCS have plasma triglycerides ranging from 10 to 100 times the normal value (1500 to 15000 mg per deciliter).5
Clinical manifestations include recurrent pancreatitis, starting from an early age, eruptive xanthomas on the trunk and extremities, xerostomia, xerophthalmia, behavioral abnormalities, lipemia retinalis, hepatosplenomegaly, and joint pains.2,4
Recurrent bouts of pancreatitis can lead to chronic pancreatitis, which is the most serious manifestation of FCS with a mortality of 5-6%. The highest mortality has been linked to the development of pancreatic necrosis, infected pancreatic abscesses and multiorgan failure.2
Patients frequently experience failure to thrive, abdominal pains, intermittent nausea and vomiting. Standart of care during bouts of pancreatitis is fasting, intravenous hydration and pain control with opioids, which potentially can lead to development of substance dependance in FCS patients.
Therapeutic plasmapheresis or plasma exchange is required only rarely, but is extremely effective in removal of triglycerides from plasma of affected patients.3,4
The current standard of care includes lifestyle modifications including a diet very low in fat (15-25% of caloric intake from fat), which translates to approximately 30-50 g of fat daily. Patients who follow this diet experience improvement of their symptoms, including resolution of hepatosplenomegaly and decreased risk of pancreatitis.
Unfortunately, a low fat diet is not very palatable and adherence is difficult for many patients. Oils that are high in medium-chain triglycerides such as coconut oil can increase palatability of the diet.3,4
Lifestyle modifications, including avoidance of alcohol, exogenous corticosteroids, retinoids, beta-blockers, thiazide diuretics, bile acid resins, antipsychotics and antiretroviral drugs, as well as controlling secondary factors such as hypothyroidism, obesity, diabetes mellitus and nephrotic syndrome are essential.3
The currently available lipid lowering medications, including fibrates, niacin, statins and high doses of ω-3 fatty acids have minimal utility in treatment of FCS.3
New potential therapeutic approaches include the microsomal triglyceride transfer protein (MTTP) inhibitor lomitapide, gene therapy with alipogene tiparvovec, diacylglycerol O-acetyltransferases (DGATs), antisense oligonucleotides targeting APOC3 mRNA and others show promising results in lowering triglycerides levels in patients with FCS. 2,3,5
FCS and Quality of Life Panel
In order to assess the impact of FCS on both patients and caregivers with regard to quality of life (QOL) issues, ten patients were assembled and asked to participate in a question and answer panel. Eight out of ten spouses or caregivers who were responsible for the care of these patients were also in attendance to offer insights.
The median age of the patients was 48 years old (range 26-67) with average age at onset of symptoms 15.5 years old ( range about 2 mos to 49). The symptoms reported in patients with FCS were primarily gastrointestinal in origin and included abdominal pain, nausea, diarrhea, constipation, and bloating. The most common reported symptoms were fatigue and abdominal pain. Most of the patients noted that the frequency of symptom occurrence increased with age. Several patients commented on either the lack of a definitive diagnosis for their severe hypertriglyceridemia or misdiagnosis, such as cholecystitis.
The most common medical complication of FCS was acute pancreatitis (AP). Fatty liver, development of type 2 diabetes mellitus, and hepatosplenomegaly were also common. 100% of the patients had suffered acute pancreatitis with all having recurrent episodes, 80% reported fatty livere and 70% had undergone cholecystectomy usually due to misdiagnosis. Half of the patients had developed Type 2 Diabetes Mellitus and a similar number had developed hepatosplenomegaly.
Several factors contributed to a reduced quality of life in these patients with the low fat diet being a significant issue. 80% of patients found the diet “very difficult” to follow and 90% of patients continued to have some symptoms despite adherence to the diet.
FCS affected other quality of life issues also including it’s impact on employment. The patients reported that the pain and fatigue sometimes limited job performance and the frequent absences due to illness and hospitalizations had a negative impact on performance reviews and potential promotions. The ability to train for and perform the work for specific types of careers was limited by FCS and the need for recurrent healthcare and insurability issues also limited employment opportunities.
Finally, the impact of FCS on friends and relationships was a major issue. Friends and family often did not understand the seriousness of FCS, an issue that could be compounded by lack of correct diagnosis. Social life was restricted due to fatigue and symptoms which often caused pressure on relationships. The patients described that without their spouse’s/caregiver’s strong support, they likely would not have survived. They expressed concern, however, regarding how having FCS has affected the lives of their loved ones.
Patients and caregivers uniformly expressed the wish for effective treatment to reduce their symptoms, improve their quality of life, and be effective in lowering their triglycerides so they could enjoy a more normal social and personal life.
All were hopeful that new drug therapy in development will turn out to be effective for patients with FCS and help them realize a much brighter future.
- Genetic and Rare Diseases Information Center. rarediseases.info.nih.gov/diseases/12241/familial-lipoprotein-lipase-deficiency. March 8, 2016. Accessed October 31, 2017
- Brahm A.J., Hegele R.A.Chylomicronaemia - current diagnosis and future therapies. Nat Rev Endocrinol. 2015 Jun;11(6):352-62. DOI: 10.1038/nrendo.2015.26. Epub 2015 Mar 3.
- Gaudet D, Alexander VJ, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med 2015; 373:438-447. DOI: 10.1056/NEJMoa1400283
- Genest J, Libby P. Lipoprotein disorder and cardiovascular disease. In: Braunwald’ Heat Disease: A textbook of cardiovascular medicine. 10th edition. Editors: Douglas L. Mann, Douglas P. Zipes, Robert O. Bonow, Peter Libby, Eugene Braunwald. Elsevier/Saunders; Philadelphia, PA: 201
- Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J Med 2014; 371:2200-2206 DOI: 10.1056/NEJMoa1400284