Familial Hyperchylomicronemia Syndrome

Etiology

About 80% of familial hyperchylomicronemia syndrome results from inherited defects in both alleles of the lipoprotein lipase gene. The rest, 20%, is the result of a mutation in other genes related to the function of lipoprotein-lipase such as apolipoprotein C-II (APOC2), apolipoprotein A-V (APOA5), high-density lipoprotein binding protein 1 (GP1HBP1), and lipase maturation factor 1 (LMF1). Other unidentified mutations also exist.[1] These all mutations lead to the malfunctioning of the enzyme lipoprotein lipase.

Epidemiology

Familial hyperchylomicronemia syndrome is a rare and under-reported condition due to its vague symptoms. Therefore, one can only estimate and cannot state its true prevalence with high confidence. It is estimated to affect 3000 to 5000 patients globally and is present in 1 to 10 individuals per every one million population.[3] There is no correlation observed concerning gender or race. However, there have been higher incidences in certain geographical areas such as Quebec of Canada amongst French Canadians and also in South Afrikaners.[1][4][5]

Pathophysiology

The pathophysiology behindfamilial hyperchylomicronemia syndrome is a mutation in the enzyme lipoprotein lipase. Lipoprotein lipase is an enzyme that is present in the vascular endothelial surface. It degrades circulating triglycerides found in chylomicrons and other triglycerides-rich lipoproteins (TGRL) in the bloodstream. Generally, chylomicrons are degraded by lipoprotein lipase within 3 to 4 hours post-prandial. However, mutation of lipoprotein lipase leads to a non-functional enzyme that is unable to perform lipolysis.[6] This mutation results in severe triglyceridemia as chylomicrons persist in the circulation. Triglycerides may reach levels ten times higher than normal, even during fasting. An increase in triglycerides accumulation in the blood can cause impaired blood flow to organs such as the pancreas leading to symptoms of pancreatitis. Further, these triglyceride-rich chylomicrons also deposit in the skin causing eruptive xanthomas and may also be seen in the retina, referred to as lipemia retinalis. Hepatosplenomegaly is also present when macrophages in the liver and spleen uptake the excess chylomicrons causing fat-filled cells that cause liver and spleen enlargement.[7][8]

Histopathology

Xanthomas are found almost exclusively in the setting of elevated levels of chylomicrons in plasma. There is good evidence to support the fact the lipid found in xanthomas is typically the circulating lipid in highly concentrated amounts. Histopathological diagnosis is confirmed by the presence of form cells within the dermis. These cells are typically the macrophages that engulf lipid and stain positive for the lipid with special stains (Oil-red-O).

History and Physical

Detailed history, including family history and physical examination, is very crucial to establish a diagnosis of familial hyperchylomicronemia syndrome. The majority of symptoms are from increased levels of chylomicrons and can range from vague abdominal discomfort to multi-organ failure because of acute pancreatitis. Most patients may present in early childhood or adolescence, but they may present in later stages of life. Recurrent intermittent abdominal pain not associated with pancreatitis and fatigue are the most reported symptoms. Children may present with symptoms of colic as well as failure to thrive in infancy.[9][10] Few other reported symptoms are bloating, asthenia, indigestion, and joint pains. Acute pancreatitis is one of the severe manifestations reported. Patients can also present with symptoms of forgetfulness, depression, and difficulty in concentration.[6][2]

On physical examination, raised-red rashes called eruptive xanthomas are present on the skin. Lipemia retinalis, which is milky colored blood vessels due to increased chylomicrons, is seen in the retina while performing in-office ophthalmoscopy. In a few patients, hepatosplenomegaly can also occur. However, it is also possible that familial hyperchylomicronemia could be present in the absence of all these clinical signs discussed above.[11]

The physical examination associated with other conditions of hypertriglyceridemia such as obesity, acanthosis nigricans, cushingoid features (buffalo hump, purple striae, moon facies) can also give a clue to the diagnosis of familial hyperchylomicronemia.[1][3][12]

Evaluation

Evaluation of familial chylomicronemia syndrome is necessary if any patient presents with the signs and symptoms mentioned above. A complete, fasting lipid profile is essential. For diagnosis, blood triglycerides should be higher than 880 mg/dl for three consecutive blood draws. Though conditions other than FCS can cause elevated triglycerides levels, hypertriglyceridemia refractory to triglycerides lowering therapy should raise suspicion of familial chylomicronemia syndrome. One quick way to evaluate is to look for milky appearance and lipemic separation on refrigeration of the blood samples.[13][12]

Further, for those who present with recurrent pancreatitis, careful past medical and family history (as mentioned above in history and physical), medications history, and alcohol use history should be obtained. Serum lipase should be checked over amylase as amylase can be affected by elevated chylomicrons. Computed tomography should be obtained for patients with recurrent abdominal pain to look for pancreatitis and its complications. Ultrasound of the right upper quadrant should also be performed to look for gallstones as a possible cause of pancreatitis.[14] Further, complete blood count, a basic metabolic panel with liver enzymes, and the clinician should check hemoglobin A1c for evaluation of metabolic syndrome, alcoholic, and non-alcoholic fatty liver disease. Other endocrine conditions like hypothyroidism and Cushing syndrome should also be ruled out by checking thyroid stimulating hormones, free thyroxine (free T4), and 24-hour urine free cortisol, respectively. Furthermore, circulating apolipoprotein- B II levels can be checked to differentiate from other hypertriglyceridemias such as polygenic hyperchylomicronemia and combined hyperlipidemia (pCH). Patients with pCH have apolipoprotein B II levels above 120 mg/dl, whereas FCS patients will have less than 100 mg/dl.[15]

Post-heparin lipoprotein lipase activity assay and genetic mutation analysis are diagnostic tests but are only available at specialized laboratories. In post-heparin LPL assay, injection of intravenous heparin fails or inadequately releases lipoprotein lipase from endothelial capillaries. Genetic tests are expensive, and some mutations can be overlooked since not all genetic mutations have been identified.[16][17]

Treatment / Management

Management of FCS is usually via an interprofessional team, including an endocrinologist or lipidologist, dietician, patient’s support group, and primary care. Dietary modification is the mainstay management of familial chylomicronemia syndrome. Lipid-lowering therapy such as fibrates, niacin, and omega-3 fatty acids have little to no role in the treatment as they act by either decreasing VLDL or increasing lipoprotein lipase activity. Both mechanisms will not affect the chylomicrons in FCS. Therefore, patients should follow a very-low-fat diet with a fat intake of less than 10% to 15% of daily calories (i.e., no more than 20 to 30 gm fat per day). Patients should be encouraged to use medium-chain triglycerides because they are water-soluble, not incorporated in the chylomicrons, and readily absorbed in the portal vein. They should also take essentials fatty acids such as alpha-linolenic acid and linolenic acid in addition to fat-soluble vitamins. Moreover, they should avoid alcohol intake and take caution with certain medications that can increase triglycerides levels, such as beta-blockers, thiazide diuretics, and exogenous estrogen.[2]

The goal of the dietary modification is to keep the triglycerides levels below the threshold for acute pancreatitis (i.e., in the range of 750 mg/dl to 880 mg/dl.) Often, the diet regimen is so rigid that patients are unable to maintain it regularly. Therefore, counseling and close follow-up with a dietician along with an endocrinologist or lipidologist are necessary. In settings of complicated acute pancreatitis, plasmapheresis may be an option in selected cases, especially in pregnant patients.[7]

Alipogene tiparvovec is the first gene therapy approved in Europe and was thought to decrease the triglyceride by 40% within 12 weeks post-therapy. However, it was then discontinued in 2017. Further, volanesorsen, an Apo C-III ASO, has been shown to reduce triglyceride by 50 to 80% in phase II and III trials and is pending approval right now.[16][18]

Differential Diagnosis

Differential diagnoses of clinical picture pancreatitis and elevated triglycerides, which are manifestations of familial hyperchylomicronemia syndrome, are given below. These conditions should be in the differential diagnosis.[12]

• Gall stones pancreatitis
• Alcoholic pancreatitis
• Insulin resistance
• Severe hypothyroidism
• Metabolic syndrome
• Glycogen storage disease
• Partial lipodystrophies
• Type III dysbetalipoproteinemia
• Polycystic ovary syndrome[19]

Prognosis

Patients often have a delay in diagnosis due to its heterogeneous symptoms and significantly affect the quality of life. Common complications include recurrent acute pancreatitis, chronic pancreatitis leading to loss of exocrine function, pancreatic pseudocyst, and necrotizing pancreatitis. Acute severe pancreatitis can also cause multiorgan failure and increases morbidity and mortality.

Some reported complications are lead to anxiety related to recurrent pancreatitis attacks. 

Despite adherence to a low-fat diet, some patients continue to suffer from the symptoms of fatigue, indigestion, abdominal pain, and confusion. The symptoms cause a significant clinical and psychosocial burden that leads to limited social interaction and increased unemployment.[3] Along with this, hypertriglyceridemia is also an independent risk factor for cardiovascular diseases.[20]

Complications

The most common complication is acute and recurrent pancreatitis and hospitalizations. Acute severe pancreatitis can also cause multi-organ failure and increases morbidity and mortality. It can also cause chronic pancreatitis leading to loss of exocrine function, pancreatic pseudocyst, or necrotizing pancreatitis. Further, hypertriglyceridemia can cause significant cardiovascular disease. Some other complications include anxiety, depression, social anxiety, change in mentation, loss of memory, and difficulty concentrating.[3]