What is Familial Hyperchylomicronemia Syndrome?
Familial hyperchylomicronemia syndrome (FCS), a rare hereditary disorder, is caused by changes in a gene involved in fat metabolism known as lipoprotein lipase. This condition leads to an excessive amount of triglycerides, a type of fat, and chylomicrons, a type of large fat particle, in the bloodstream. These high levels can cause various symptoms. One serious symptom could be episodes of acute pancreatitis, which is a sudden inflammation of the pancreas.
What Causes Familial Hyperchylomicronemia Syndrome?
About 80% of a syndrome called familial hyperchylomicronemia is caused by inherited problems with a gene known as lipoprotein lipase. The remaining 20% is down to mutations in other genes that work with lipoprotein-lipase, including apolipoprotein C-II (APOC2), apolipoprotein A-V (APOA5), high-density lipoprotein binding protein 1 (GP1HBP1), and lipase maturation factor 1 (LMF1). There may also be some unknown mutations contributing to this syndrome. All these mutations interfere with the normal functioning of an enzyme called lipoprotein lipase. Genes are like instruction manuals for our bodies, and a defective gene can cause a defect in the body. Mutation is a change in the DNA sequence of a gene. Enzymes, such as lipoprotein lipase in this case, are proteins that speed up or facilitate specific reactions within our bodies.
Risk Factors and Frequency for Familial Hyperchylomicronemia Syndrome
Familial hyperchylomicronemia syndrome is a rare condition that’s often not reported because its symptoms are not obvious. Because of this, it’s hard to determine how many people truly have this condition. Estimates suggest that between 3000 to 5000 people worldwide have it. This means that for every one million people, there are likely 1 to 10 individuals with this syndrome. Importantly, it doesn’t seem to favor one gender or race over another.
Interestingly, some areas have reported higher rates of the syndrome. For instance, it’s more common among French Canadians in Quebec, Canada, and among South Afrikaners.
Signs and Symptoms of Familial Hyperchylomicronemia Syndrome
Familial hyperchylomicronemia syndrome is a health condition that requires careful study of personal and family medical history to diagnose. Symptoms are caused by higher than normal levels of fat particles called chylomicrons. These symptoms can be as mild as a vague tummy discomfort, but in severe cases, it can lead to organ damage due to sudden inflammation of the pancreas (acute pancreatitis).
The symptoms typically show up in early childhood or adolescence, but it can also occur in adults. Commonly reported symptoms include recurring tummy pain not related to pancreatitis, fatigue, and general weakness. In babies, the syndrome can cause colic symptoms and slow growth. Other symptoms like bloating, general bodily weakness, indigestion, and joint pain have also been reported. The condition can also lead to acute pancreatitis, which is a severe complication. Furthermore, some patients may have issues like memory lapses, depression, and concentration difficulties.
- Recurring tummy pain not related to pancreatitis
- Fatigue
- General weakness
- Colic symptoms and slow growth in babies
- Bloating
- Indigestion
- Joint pain
- Acute pancreatitis (severe case)
- Memory lapses
- Depression
- Concentration difficulties
During a physical check-up, patients may have noticeable, raised-red rashes on the skin, known as eruptive xanthomas. Eye doctors might find milky-colored blood vessels in the retina, a condition called lipemia retinalis, due to the increased chylomicrons. Some patients may also have an enlarged liver and spleen. However, it’s important to note that a person can have familial hyperchylomicronemia syndrome without these physical signs.
Physicians also look for physical indications linked to other high-triglyceride conditions such as obesity, dark and velvety skin changes (acanthosis nigricans), and physical features related to Cushing’s syndrome like a fatty hump between the shoulders (buffalo hump), purple stretch marks, and a rounded face. These symptoms can provide clues for the diagnosis of familial hyperchylomicronemia syndrome.
Testing for Familial Hyperchylomicronemia Syndrome
If people experience the signs and symptoms previously mentioned, they might need to be tested for familial chylomicronemia syndrome. This involves fasting before having a blood test to check your lipid (fat) levels. For diagnosis, your blood triglycerides (a type of fat) should be higher than 880 mg/dl for three consecutive blood tests. When triglyceride levels remain high regardless of therapies to lower them, it could suggest familial chylomicronemia syndrome. A quick way to check for this is to look for a milky appearance and fat separation when the blood samples are stored in the fridge.
If individuals have recurrent pancreatitis (inflammation of the pancreas), doctor needs to know their past medical history, family history, medication use, and alcohol consumption. Blood tests should include checking your lipase levels (an enzyme produced by the pancreas) because amylase (another pancreatic enzyme) can be influenced by increased levels of chylomicrons. If you have recurrent abdominal discomfort, they may order a computed tomography (CT) scan to check for pancreatitis and any related complications. You might also need an ultrasound of your upper abdomen to look for gallstones, which could potentially cause pancreatitis.
Furthermore, your doctor may order a complete blood count and a standard metabolic panel (which includes liver tests), and they may check your hemoglobin A1c to evaluate for metabolic syndrome, alcoholic, and non-alcoholic fatty liver disease. They might also evaluate you for other conditions related to your endocrine system (ie, glands that produce hormones), like hypothyroidism (an underactive thyroid) and Cushing’s syndrome, by checking your thyroid stimulating hormone levels, free thyroxine (a thyroid hormone), and a 24-hour urine free cortisol test respectively. In addition, your apolipoprotein- B II levels can be checked to determine whether your hypertriglyceridemia, or elevated triglyceride levels, is due to other causes such as polygenic hyperchylomicronemia and combined hyperlipidemia. People with these conditions have apolipoprotein B II levels above 120 mg/dl, whereas people with familial chylomicronemia syndrome will have less than 100 mg/dl.
Lastly, there are diagnostic tests that can be done including the post-heparin lipoprotein lipase activity assay and genetic mutation analysis. In this first test, a shot of heparin is given intravenously, and it is expected to release lipoprotein lipase made by the cells lining your blood vessels. For the genetic test, it’s expensive and not all the genetic mutations may be found as they have not all been identified yet. Both these tests are only available at specialized labs.
Treatment Options for Familial Hyperchylomicronemia Syndrome
Managing Familial Chylomicronemia Syndrome (FCS) requires a team of specialists, including an endocrinologist or lipidologist who specialize in hormonal and fat disorders respectively, a dietitian, a support group, and your regular doctor. The main treatment is altering your diet.
A common tactic for dealing with high fat levels in the blood is taking lipid-lowering drugs like fibrates, niacin, or omega-3 fatty acids. However, in the case of FCS, these aren’t effective because they lower Very-Low-Density Lipoprotein (VLDL) or increase an enzyme activity that breaks down fat, both of which don’t affect the specialized fat droplets called chylomicrons in FCS.
Because of this, patients with FCS are advised to follow a strict diet with very low fat content. Ideally, fat should compose less than 10% to 15% of the daily calories intake (no more than 20 to 30 grams of fat per day). Medium-chain triglycerides, a type of fat, are recommended because they are water-soluble and breakdown directly in the liver. Other recommended dietary additions include essential fatty acids (like alpha-linolenic acid and linolenic acid), fat-soluble vitamins, and they should avoid alcohol and certain medications that can elevate triglyceride levels, such as beta-blockers, thiazide diuretics, and exogenous estrogen (a form of estrogen).
The objective of this diet modification is to keep the fat level, particularly a type of fat called triglycerides, below the level that may trigger a painful inflammation of the pancreas (pancreatitis). The target range is between 750 to 880 milligrams per deciliter (mg/dl). The diet is arduous to follow and requires constant counseling and monitoring by a dietician and a specialist.
In more severe cases like in acute pancreatitis, plasma exchange (plasmapheresis), a process that filters the blood, can be deployed, especially in pregnant patients.
Alipogene tiparvovec, the first approved gene therapy in Europe, was used previously as it reported a significant reduction in triglycerides level by 40% within the first 12 weeks after therapy. However, its usage was stopped in 2017. Currently, a new drug called volanesorsen, which has shown promising results in reducing triglyceride levels in clinical trials, is awaiting approval.
What else can Familial Hyperchylomicronemia Syndrome be?
When a patient shows signs of pancreatitis and high levels of triglycerides, these could be signs of a condition called familial hyperchylomicronemia syndrome. However, it’s also possible that they have one of the following conditions, which can present with similar symptoms:
- Gall stones pancreatitis
- Alcoholic pancreatitis
- Insulin resistance
- Severe hypothyroidism
- Metabolic syndrome
- Glycogen storage disease
- Partial lipodystrophies
- Type III dysbetalipoproteinemia
- Polycystic ovary syndrome
These possibilities should be considered and ruled out through appropriate testing to ensure an accurate diagnosis is made.
What to expect with Familial Hyperchylomicronemia Syndrome
The diagnosis for pancreatitis often gets delayed because its symptoms vary significantly from person to person and it greatly impacts one’s quality of life. Common complications that could arise from pancreatitis include repeated episodes of acute pancreatitis, chronic pancreatitis resulting in the decreased function of the pancreas, a build-up of fluid-filled sacs in the pancreas called pseudocysts, and a severe form of pancreatitis where parts of the pancreas die, called necrotizing pancreatitis.
Acute, or sudden, severe pancreatitis can also lead to the failure of other organs in the body, increasing the risk of further health complications and even death.
It is also reported that these complications often lead to worries concerning repeated attacks of pancreatitis.
Despite diligently following a diet low in fat, some patients continue to experience the symptoms of fatigue, indigestion, abdominal pain, and confusion. These symptoms often cause both medical and emotional distress, leading to decreased social interaction and increased unemployment. In addition, having high levels of fat (triglycerides) in the blood, known as hypertriglyceridemia, independently increases the risk for heart diseases.
Possible Complications When Diagnosed with Familial Hyperchylomicronemia Syndrome
The complications of hypertriglyceridemia, or high levels of fats in the blood, often involve problems with the pancreas. The most common issues include the sudden and constant onset of pancreatitis – inflammation of the pancreas – causing hospitalization. Severe cases of this inflammation can lead to multi-organ failure, increasing risks of serious illness and death. If this condition persists, it can turn into chronic pancreatitis, leading to a reduction in the pancreas’s ability to digest food, and resulting in pancreatic pseudocyst or a severe form of inflammation called necrotizing pancreatitis.
Through hypertriglyceridemia, there is also a considerable risk for heart disease. Other complications are emotional and cognitive in nature. These may include feelings of anxiety and depression, social anxiety, changes in mental status, memory loss, and difficulty focusing.
Common Complications include:
- Acute and recurrent pancreatitis
- Hospitalizations
- Chronic pancreatitis
- Disorder of pancreas functioning
- Pancreatic pseudocyst
- Necrotizing pancreatitis
- Cardiovascular disease
- Anxiety and depression
- Social anxiety
- Change in mental condition
- Memory loss
- Difficulty in concentrating
Preventing Familial Hyperchylomicronemia Syndrome
Teaching and advising patients is crucial in treating familial hyperchylomicronemia syndrome, a condition that often requires changes in diet and lifestyle. The patients should be actively involved in the decision-making to make sure they’re comfortable with the alterations they need to make in their lives. Studies show that when patients understand what they need to do and why, they’re more likely to follow through with changes to their diet and lifestyle.[1]
