Hyperchylomicronaemia

Hyperchylomicronaemia, also known as familial chylomicronemia syndrome, is a rare genetic disorder that prevents the body from properly breaking down fats in the blood, leading to dangerously high levels of triglycerides that can cause serious complications including life-threatening inflammation of the pancreas.

Table of contents

• What is hyperchylomicronaemia?
• Other names for this condition
• What causes hyperchylomicronaemia?
• How common is hyperchylomicronaemia?
• Signs and symptoms
• How is hyperchylomicronaemia diagnosed?
• Treatment and management
• Possible complications
• Living with hyperchylomicronaemia

What is hyperchylomicronaemia?

Hyperchylomicronaemia is a rare genetic disorder that affects how the body processes fats from food. When you have this condition, your body cannot break down certain fat particles called chylomicrons (structures that carry fats through the bloodstream). These particles help move triglycerides (a type of fat) to different parts of your body where they are needed for energy and fat storage.^[1]

In people with hyperchylomicronaemia, chylomicrons build up in the blood plasma, causing triglyceride levels to become extremely high—often ten times higher than normal, even when fasting. Normal triglyceride levels are less than 150 milligrams per deciliter (mg/dL), but with this condition, levels commonly exceed 1,000 mg/dL and can reach levels as high as 2,000 mg/dL or more.^[1][8]

The condition causes significant health problems and distress for patients, as the buildup of fat particles can lead to serious complications.^[1]

Other names for this condition

familial chylomicronemia syndrome, familial hyperchylomicronemia, familial hyperchylomicronemia syndrome, familial lipoprotein lipase deficiency, lipoprotein lipase deficiency, chylomicronemia, chylomicronemia syndrome, type I hyperlipoproteinemia, hyperlipoproteinemia type Ia

What causes hyperchylomicronaemia?

Hyperchylomicronaemia is caused by mutations in genes that affect an enzyme called lipoprotein lipase (LpL). This enzyme normally sits on the surface of blood vessels and breaks down triglycerides found in chylomicrons and other fat-carrying particles in the bloodstream. Under normal circumstances, chylomicrons are broken down by lipoprotein lipase within 3 to 4 hours after eating.^[1]

About 80% of cases result from inherited defects in both copies of the lipoprotein lipase gene itself. A person must inherit the defective gene from both parents to have the disorder. If you inherit only one mutated gene, you become a carrier but will not have the disorder yourself, although you may be at higher risk for other health problems related to abnormal fat levels in the blood.^[1][8]

The remaining 20% of cases result from mutations in other genes related to the function of lipoprotein lipase, including genes that encode apolipoprotein C-II (APOC2), apolipoprotein A-V (APOA5), high-density lipoprotein binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1). Other unidentified mutations also exist.^[1]

When lipoprotein lipase is missing or not working properly, the body cannot break down fat properly. Chylomicrons persist in the circulation instead of being cleared, leading to severe increases in triglyceride levels. This accumulation of triglycerides in the blood can cause impaired blood flow to organs such as the pancreas, leading to symptoms of pancreatitis (inflammation of the pancreas).^[1]

How common is hyperchylomicronaemia?

Hyperchylomicronaemia is a rare and under-reported condition due to its vague symptoms. It is estimated to affect between 3,000 to 5,000 patients globally and is present in 1 to 10 individuals per every one million population.^[1][8]

The condition affects all genders, races, and ethnicities equally. However, there have been higher incidences reported in certain geographical areas, such as Quebec, Canada among French Canadians, and in South Afrikaners.^[1]

Because hyperchylomicronaemia is inherited, symptoms can develop as early as infancy or childhood. Around 25% of people with the condition receive their diagnosis in their first year of life. While it is more common to receive a diagnosis before age 10, some patients do not present with symptoms until adulthood.^[3][8]

Signs and symptoms

The symptoms of hyperchylomicronaemia are caused by extremely high levels of triglycerides in the bloodstream. The condition often presents in infancy with colicky pain, failure to thrive, and other signs. In women, the use of estrogens or first pregnancy can trigger initial symptoms.^[3]

At all ages, the most common clinical manifestation is recurrent abdominal pain and acute pancreatitis. The abdominal pain may be felt in the upper central part of the belly and may spread to the back, or it may be diffuse, appearing as an acute emergency. This pain can range from mild to severe and typically comes in episodes.^[3][8]

Other typical symptoms include:^[3][5][8]

• Eruptive xanthomas: Yellow deposits of fatty material in the skin that may appear on the face, shoulders, back, buttocks, soles of the feet, ankles, knees, and elbows. These occur in about 50% of patients and are not usually painful unless rubbed frequently.
• Lipemia retinalis: A creamy or pale appearance of blood vessels in the retina of the eye, visible during an eye examination.
• Hepatosplenomegaly: Enlargement of the liver and spleen.
• Loss of appetite
• Nausea and vomiting
• Pain in the muscles and bones
• Failure to thrive in infants
• Yellowing of the eyes and skin (jaundice)

Less common symptoms may include emotional problems, unexpected weight loss, memory loss, depression, joint pain, weakness and fatigue, bloating and indigestion, and in rare cases, abscesses around the anus.^[8]

Lab tests typically show massive accumulation of chylomicrons in the plasma and corresponding severe elevation of triglycerides. The plasma in a fasting blood sample appears creamy or milky due to the high fat content.^[3]

How is hyperchylomicronaemia diagnosed?

Hyperchylomicronaemia is diagnosed through a combination of clinical signs and symptoms, extreme elevations in triglyceride levels, and genetic testing. The diagnosis should be suspected when certain features are present.^[13]

Healthcare providers will consider the diagnosis when patients have:^[3][13]

• A history of frequent episodes of acute pancreatitis
• Recurrent bouts of abdominal pain
• Fasting triglyceride levels above 885 mg/dL on several occasions, likely to be treatment-resistant
• Severely elevated fasting plasma triglycerides, often exceeding 2,000 mg/dL
• Absence of secondary causes for elevated triglycerides (such as diabetes, alcohol use, certain medications including estrogens, glucocorticoids, antidepressants, or isotretinoin, certain blood pressure medications, or other disorders)
• Early-onset of symptoms in childhood, adolescence, or early adulthood

A physical examination will look for enlarged liver and spleen, fatty deposits under the skin, and fatty deposits in the retina of the eye. Blood tests will show milky, lipemic plasma revealing severe accumulation of chylomicrons.^[3][5]

Special blood tests may be performed after blood thinners are given through a vein to look for lipoprotein lipase activity, which will be low or absent in people with this condition. The mass level of lipoprotein lipase in the blood will also be reduced or absent.^[3][5]

Genetic testing can be performed to confirm the diagnosis. More than 220 mutations in the lipoprotein lipase gene have been found to cause the condition. The diagnosis is finally confirmed by detection of either homozygous (both copies affected) or compound heterozygous (two different mutations) pathogenic gene variants in lipoprotein lipase or related genes, combined with low or absent lipoprotein lipase enzyme activity. However, cost and access to genetic testing may limit its use.^[3][13]

Regardless of whether or not genetic testing is performed, appropriate management should be implemented when hyperchylomicronaemia is suspected.^[13]

Treatment and management

Treatment of hyperchylomicronaemia aims to control symptoms and reduce blood triglyceride levels. The primary way to manage the disorder is through dietary changes. There is currently no cure for the condition.^[5]

The cornerstone of treatment is following a very low-fat diet. Healthcare providers typically recommend eating no more than 20 grams of fat per day to prevent symptoms from returning. To put this in perspective, 20 grams of fat equals approximately two 8-ounce glasses of whole milk, 4 teaspoons of margarine, or a 4-ounce serving of meat. This is in stark contrast to the average diet, which may contain up to 45% of total calories from fat.^[5]

Because a very low-fat diet can lead to deficiencies, fat-soluble vitamins (A, D, E, and K) and mineral supplements are recommended. Patients should discuss their diet needs with their healthcare provider and work with a registered dietitian to ensure proper nutrition while maintaining the low-fat requirements.^[5]

When pancreatitis develops, it responds to treatments specific for that disorder. Conditions such as dehydration and diabetes can make symptoms worse, so if present, these conditions need to be treated and controlled.^[5]

Standard cholesterol-lowering medications such as fibrates (like fenofibrate) and omega-3 fatty acids are often tried but typically have limited effectiveness in this condition.^[4][9]

Newer pharmacologic therapies are being developed to specifically target the underlying mechanisms of the disease, though these remain limited and are often part of clinical research.^[9]

Possible complications

Patients with hyperchylomicronaemia are at high risk of acute pancreatitis, which can be life-threatening. Pancreatitis is the most serious complication of the condition. When left untreated or poorly controlled, the excess chylomicrons may lead to repeated bouts of pancreatitis.^[3][5]

Triglyceride-induced pancreatitis has an overall worse prognosis and causes more health problems than pancreatitis from other causes, such as gallstones or alcohol. Recurrent pancreatitis can lead to chronic pancreatic insufficiency (when the pancreas cannot properly digest food) and diabetes.^[3][9]

Xanthomas (fatty deposits in the skin) are not usually painful unless they are rubbed frequently, but they can affect quality of life and cause distress.^[5]

The condition also correlates with significant emotional and psychological distress among patients, including depression, anxiety, and challenges with social activities due to the strict dietary restrictions required.^[1]

Living with hyperchylomicronaemia

People with hyperchylomicronaemia who strictly follow a very low-fat diet can live into adulthood and manage their symptoms. The key to living well with this condition is maintaining the dietary restrictions consistently.^[5]

Following a very low-fat diet can dramatically reduce symptoms and prevent the most serious complication—pancreatitis. The level of triglycerides in the blood can change drastically based on how much fat is consumed in the diet, making dietary adherence critical.^[5][8]

Patients should work closely with their healthcare team, including specialists in metabolic disorders, dietitians, and other support professionals. Regular monitoring of triglyceride levels and symptoms is important for ongoing management.^[5]

Genetic counseling is recommended for anyone with a family history of this disease. Contact a healthcare provider for screening if someone in your family has lipoprotein lipase deficiency. Awareness of risks may allow early detection and management.^[5]

There is no known way to prevent this rare, inherited disorder, as it is passed down through families. However, following treatment recommendations can prevent complications and improve quality of life.^[5]