Overview

Hypertriglyceridemia (HTG) is a health condition characterized by abnormally increased triglyceride levels in the blood. Triglycerides, also known as triacylglycerols (TAG), are the main constituents of body fat in humans. Ingested fats are divided into smaller parts within the intestines and afterward absorbed in the form of free fatty acids. Those acids bind to glycerol and form triglycerides that make  part of every lipoprotein in smaller or bigger amounts. A lipoprotein is a particle formed mainly from triglycerides and cholesterol, responsible for storing, transporting, and utilizing fats in the body. Usually, these particles get destroyed quickly and don't represent any risk, but once the concentration of triglycerides in the blood increases, the situation changes dramatically. High triglyceride levels are associated with atherosclerosis and damage of the vessels; they are also connected to a higher risk of developing ischemic heart disease, non-alcoholic fatty liver disease, or pancreatitis. 

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There are many clinical conditions hidden in the term hypertriglyceridemia. HTG itself is only one of three main groups forming dyslipidemias (= disorders of lipid metabolism). The whole classification is very complicated and comprehensive, but let us quickly mention it for the integrity of the article. According to the part of lipoprotein that is impaired, it's possible to differentiate:

1. Hypercholesterolemie - increased levels of cholesterol
2. Combined hyperlipoproteinemia - increased levels of both cholesterol and triglycerides
3. Hypertriglyceridemia - increased levels of triglycerides

All of the mentioned groups include both primary (genetically determined disease) and secondary (developing based on other health conditions or lifestyle) forms of diseases. 

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The desired level of TAG in the blood is < 1,7 mmol/l. Increased levels of TAG can be found in: 

• Familial hypertriglyceridemia (type IV familial dyslipidemia) - a typically autosomal dominant disorder characterized by an increased production of very low-density lipoprotein (VLDL) in the liver that can cause acute pancreatitis and usually manifests in adulthood. 
• Familial hyperlipoproteinemia type I - a rare form of the disease characterized by very high levels of TAG (20 - 200 mmol/l). It can clinically manifest as abdominal colics, pancreatitis, hepatomegaly, or splenomegaly. 
• Familial combined hyperlipidemia - the most common genetically determined dyslipidemia that can cause an early heart attack. TAG values are increased together with cholesterol blood values. 
• Secondary form of HTG is linked to:

1. Diabetic HTG - one of the most common forms of secondary HTG
2. Alcohol abuse
3. A diet rich in saccharides 
4. Obesity
5. Pregnancy
6. Multiple medications (diuretics, steroids, estrogen, beta-blockers, isotretinoin)

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Prevalence & Risk factors

Hypertriglyceridemia is a very common disease with its prevalence constantly increasing, especially within the younger population. Prevalence differs worldwide, but it's been estimated that approximately 25-30% of the world's population suffers from hypertriglyceridemia. The real numbers might be even higher, due to the disease's lack of clinical symptoms and low amounts of patients undergoing regular preventive checkups. Hypertriglyceridemia is closely associated with uncontrolled diabetes mellitus, obesity, non-alcoholic fatty liver disease, and unhealthy lifestyles, which are more prevalent in developed countries. 

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Some of the risk factors include: 

• Age over 70
• Sex - men are way more prone to develop HTG
• Family history 
• Smoking
• Unhealthy diet
• Alcohol abuse
• Diabetes mellitus
• Obesity
• Metabolic syndrome
• Lack of physical activity
• High blood pressure 

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Genetics

There are many types of HTG and therefore the genetics behind each type differs. Many specific gene mutations have been identified, and the research still continues.^[13] 

Primary HTG is a group of genetic disorders characterized by elevated triglyceride levels in the blood, caused by inherited factors.

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Secondary HTG are multifactorial - meaning that both, genetic and environmental factors, must occur for the disease to develop. Inheritance patterns are often unclear.^[15] 

‍The genetic basis of hypertriglyceridemia varies, some types involve single gene mutations, while others are influenced by multiple genes and environmental factors. Genetic testing and consultation with healthcare providers or genetic counselors can help identify the specific genetic basis in individual cases. 

Genetic testing allows us to detect whether you have the predisposition to develop this disease. In Macromo, we use polygenic risk scores and causative evidence-based genetic variants for evaluation. The polygenic risk score (PRS) represents the total number of genetic variants that increase an individual's risk of developing a particular disease. All variants across their genome are summed and ranked according to their effect on disease development.

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Signs & Symptoms

HTG remains silent for a long time and usually doesn't cause any symptoms until severely elevated blood levels are seen (defined as TAG level over 11,4 mmol/l). If severe hypertriglyceridemia develops, patients may experience some of the following symptoms or body changes: 

• Gastrointestinal: sudden abdominal pain, nausea, vomiting
• Difficulty breathing
• Eruptive xanthomas (lipid deposits in the skin)
• Lipaemia retinalis (abnormal color of the retinal arteries) 
• Corneal arcus (whitish or great arc around the cornea)
• Xanthelasma (yellowish deposits of fat around the eyes)

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Diagnosis

Although high glyceride levels are present in 20-30% of the adult population, there are usually no symptoms and the diagnosis is often incidental. The diagnosis and classification of HTG is purely based on the levels of TAG in the blood. It's important to realize that recommended values and values used for classification apply to fasting TAG levels.

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For a thorough examination, a so-called lipid profile should be obtained. It's a simple blood test, where medical specialists search for increased levels of all types of lipoproteins and cholesterol. Whenever a patient is diagnosed with HTG, the first step is to rule out secondary causes to settle a fitting treatment plan. 

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Therapy

The main goal of the HTG treatment is to lower the risk of developing cardiovascular disease or pancreatitis, both by non-pharmacological and pharmacological treatment.

The most effective ways to lower triglyceride levels are lifestyle modifications, including a healthy diet, exercise, and weight loss. The most profitable is alcohol abstinence and a reduced intake of simple carbohydrates. If those changes aren't sufficient alone, pharmacotherapy might be indicated. 

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Lifestyle changes

• Alcohol abstinence
• Exercise (at least 2,5 hours of aerobic exercise per week) 
• Avoiding simple carbohydrates 
• Weight loss (obesity is one of the causes of secondary hypertriglyceridemia) 
• Glucose control (diabetes mellitus hugely increases the risk of complications) 

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Pharmacotherapy

• Statins are the first-line drugs used to lower lipid levels by blocking the enzyme that the liver uses for lipid production.
• Non-statin lipid-lowering agents may be added if statins alone aren't sufficient in achieving treatment goals or the patient can't use statins.

• Fibrates 
• Niacin (vitamin B3)
• Ezetimibe
• Omega-3 fatty acids (often found in sardine, salmon, and mackerel; or used as supplements)
• PCSK9 inhibitors 

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Prevention

Lifestyle modifications are the foundation of preventing HTG, same as in other metabolic diseases (i.e., obesity, metabolic syndrome, diabetes mellitus). Introducing a healthy diet and regular exercise can be extremely beneficial and can not be replaced by medications. 

• Regular exercise (at least 2,5 hours of aerobic exercise per week)
• Avoid smoking
• Avoid alcohol abuse
• Diet changes

• Avoid simple carbohydrates (processed and refined sugars in candy, soft drinks)
• Introduce omega-3 fatty acids into your diet (can be found in salmon, mackerel, sardine)
• Avoid trans-fats (fast food, fried food, processed food) and saturated fats
• Eat regularly, optimally 5 times a day
• Stay hydrated

Adhering to preventive check-ups is necessary to avoid the development of complications since HTG stays silent for a long time. 

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Prognosis

Without sufficient management of the disease, the prognosis is unfortunately poor, especially in the presence of other risk factors (high blood pressure, uncontrolled blood sugar, obesity, lack of physical activity). Patients with hypertriglyceridemia are at an extreme risk of developing coronary artery disease (up to 30%) and pancreatitis. The prognosis differs in genetically determined forms of the disease, but it's important to realize that although some of the severe states require strong will and strict restrictions in diet and lifestyle, most elevated triglycerides can be controlled, at least partially.

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Recommendations

• Improve your health by regular exercise, at least 2,5 hours of aerobic exercise per week. 
• If you notice yellow-looking deposits around your eyes, get checked for high triglycerides. 
• Introduce omega-3 fatty acids into your diet. 
• Adhere to preventive checkups and blood tests to avoid the development of HTG complications.