Detailed history, including family history and physical examination, is very crucial to establish a diagnosis of familial hyperchylomicronemia. 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. 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 and difficulty in concentration.  

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 preforming 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. 

The physical examination that is associated with other conditions of hypertriglyceridemia such as obesity, acanthosis nigricans, cushingoid features (buffalo hump, purple striae, moon facies), also can give a clue to the diagnosis of familial hyperchylomicronemia.[1][2][7]

Evaluation of for familial chylomicronemia is necessary if any patient presents with the signs and symptoms mentioned above. A complete, fasting lipid profile is essential. For diagnosis, blood triglycerides levels should be higher than 880 mg/dl for three consecutive blood draws. Though conditions other than FCS can cause elevated triglycerides level, 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. 

Further, 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 are also necessary. 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 right upper quadrant should also be performed to look for gall-stones as a possible cause of pancreatitis. 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.  

Finally, 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.[1][7][8][9]

Management of FCS is usually via a multidisciplinary 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 consisting of less than 10 to 15% of total fat intake of total daily calorie intake (i.e., no more than 20 to 30 gm fat per day). Patients should be encouraged using 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.

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 880mg/dl.) Often, the diet regimen is so rigid that patients are unable to maintain it regularly. Therefore, counseling and close follow up with dietician along with endocrinologist or lipidologist is necessary. In settings of complicated acute pancreatitis, plasmapheresis may be an option in selected cases, especially in pregnant patients.[1][2]

Alipogene tiparvovec is the first gene therapy that had been 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 shown to reduce triglyceride by 50% to 80% in phase II and III trials and is pending approval right now.[1][10]

Differential diagnoses of clinical picture pancreatitis and elevated triglycerides, which are manifestations of FCS syndrome, are given below. These conditions should be in the differential diagnosis.[7]

• Gall stones pancreatitis
• Alcoholic pancreatitis
• Insulin resistance
• Severe hypothyroidism
• Metabolic syndrome
• Glycogen storage disease
• Partial lipodystrophies
• Type III dysbetalipoproteinemia
• Poly-cystic ovary syndrome

Patients often have a delay in diagnosis due to its heterogeneous symptoms and have significant effects on 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 multi-organ 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 significant clinical and psychosocial burden that leads to limited social interaction and increased unemployment.[2] Along with this, hypertriglyceridemia is also an independent risk factor for cardiovascular diseases.[8]

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 s significant cardiovascular diseases. Some other complications include anxiety, depression, social anxiety, change in mentation, such as loss of memory, and difficulty in concentration.[2]

Patient education and counseling are an integral part of the management of type 1 familial hyperlipidemia since the majority of management consist of dietary and lifestyle modification. The patient should be equally involved in decision making so that they can choose the changes they can implement. Patient education has shown to improve adherence to lifestyle modification and dietary changes.[1]

Management of type 1 familial hyperlipidemia should be an interprofessional spanning across the patient’s primary care doctor, endocrinologist, lipidologist, dietician, gastroenterologist, and patient support group.

Dietary modification is the mainstay management of familial chylomicronemia syndrome. Patients should understand that 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. A dietitian consult should be obtained to educate the patient on a very low-fat diet consisting of less than 10 to 15% of total fat intake of total daily calorie intake [i.e., no more than 20 to 30 g of fat per day). Patients should be encouraged using 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, the pharmacist should inform the patient to avoid alcohol intake and take caution with certain medications that can increase triglycerides levels such as beta-blockers, thiazide diuretics, and exogenous estrogen. Nursing can also help by assessing patient compliance with drug, dietary, and other lifestyle measures, and reporting their findings to the treating clinician for further evaluation and action.

Effective communication and interprofessional team effort will decrease the morbidity and mortality associated with type 1 familial hyperlipidemia.[1] [Level 5]