Primary hypertriglyceridemia
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Synonyms and keywords:: Primary hypertriglyceridemia; Familial hypertriglyceridemia; Type IV hyperlipoproteinemia; Type 4 hyperlipoproteinemia; Hyperlipoproteinemia type IV; Type 4 Hyperlipidemia

# Overview
Primary hypertriglyceridemia, or type 4 hyperlipidemia has high concentration of triglycerides in the blood. It is also known as hypertriglyceridemia (or pure hypertriglyceridemia). Hypertriglyceridemia denotes high (hyper-) blood levels (-emia) of triglycerides, the most abundant fatty molecule in most organisms. Triglyceride levels are usually not extremely elevated in cases of primary hypertriglyceridemia. Elevated levels of triglycerides can be detrimental to normal cardiac functioning. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia (high cholesterol levels). Very high triglyceride levels may also interfere with blood tests, hyponatremia may be reported spuriously (pseudohyponatremia). A related term is "hyperglyceridemia," or "hyperglyceridaemia," which refers to a high level of all glycerides, including monoglycerides, diglycerides, and triglycerides.

# Historical Perspective
- In 1967, Dr. Fredrickson classified lipoprotein disorders using paper electrophoresis.
- In 1964, Dr. Leverton explained the post-carbohydrate rise in triglycerides and the difference in the levels in patients with cirrhosis and metastasis.

# Classification
There is no single established classification system for primary hypertriglyceridemia. However, primary hypertriglyceridemia may be classified according to gene mutation or severity of triglyceridemia.

## Classification by Gene Mutation
Primary hypertriglyceridemia may be classified according to the following gene mutations:
- LPL gene: LPL is the primary enzyme involved in the catabolism of lipids rich in triglycerides. The mutations in LPL can be further classified on the basis of their specific substitutions such as:
Gly188Glu
Asp9Asn
Asn291Ser
Ser447Ter
- Gly188Glu
- Asp9Asn
- Asn291Ser
- Ser447Ter
- APOA5
- LMF1
- GPIHBP1

## Classification by Severity of Triglyceridemia
Hypertriglyceridemia may be classified according to the concentration  of triglycerides on the lipid profile. More marked elevations are usually seen in cases of hypertriglyceridemia resulting from secondary causes.
- Normal triglycerides: <150 mg/dL
- Borderline-high triglycerides: 150-199 mg/dL
- High triglycerides: 200-499 mg/dL
- Very high triglycerides: >500 mg/dL
To view the ATPIII guidelines for classification of triglyceride levels, click here.
For a detailed classification of hyperlipoproteinemia, click here.

# Pathophisiology

## Pathogenesis
The regulation of lipids in the body can be affected at any of the following three stages:
- Exogenous pathway that involves synthesis of chylomicrons in the intestines to transport triglycerides and cholesterol to be utilized by the body.
- Endogenous pathway that involves production of VLDL cholesterol and TG within the body and transportation to various tissues.
- The reverse cholesterol transport involves exchange of TGs (from LDL and VLDL) and HDL cholesteryl ester using cholesteryl ester transfer protein to remove peripheral cholesterol and supply it to the liver and other organs.
Primary hypertriglyceridemia can occur through various mechanisms involving abnormal mutations in the LPL gene, which can increase triglyceride levels up to 80%.
- Abnormal very low density lipoprotein (VLDL) production in liver (internal pathway) and synthesis of chylomicrons in the intestines (external pathway).
- Abnormal lipoprotein lipase (LPL)-mediated lipolysis.
- Abnornal remanant clearance
- Reduction of HDL-C levels (hypoalphalipoproteinemia), which predisposes patients to ischemic heart disease.
- Primary hypertriglyceridemia causes an increase in the ABCA-1 dependent efflux of cholesterol from macrophage to serum due to an increased amount of prebeta-HDL in serum, which leads to an increased risk of cardiac complications.

## Genetics
- The development of primary hypertriglyceridemia can follow either an autosomal dominant (AD) or autosomal recessive (AR) mode of inheritance.
- The LPL gene can have various mutations. Gly188Glu, Asp9Asn, Asn291Ser, and Ser447Ter substitutions can affect lipid metabolism and one's risk of developing ischemic heart disease (IHD). Heterozygous Gly188Glu carriers have an increased risk of IHD, while Ser447Ter carriers enjoy a protective effect.

# Causes
The primary cause of primary hypertriglyceridemia is a genetic mutation in the LPL gene, leading to abnormal metabolism of triglycerides in the body.

# Differentiating Primary hypertriglyceridemia from Other Diseases
Primary hypertriglyceridemia must be differentiated from other diseases that cause abnormal increases in serum triglycerides, including:
- Familial hypercholesterolemia/Familial combined hyperlipidemia
- Dysbetalipoprotenemia
- Mixed hyperlipoprotenemia
Primary hypertriglyceridemia must also be differentiated from other diseases that may cause xanthomas such as:
- Sitosterolemia
- Cerebrotendinous Xanthomatosis (CTX) - CYP27A1 recesive  gene mutation
For a detailed differential diagnosis of hyperlipoproteinemia click here.

# Epidemiology and Demographics

## Prevalence
- The prevalence of type 4 hyperlipidemia (i.e., primary hypertriglyceridemia) is 5%10% in the general population.
- According to the NCEP-ATPIII definition of high triglycerides (>200 mg/dl), the prevalence of hypertriglyceridemia due to any cause (including the secondary causes) is about 16% of the adult population.

## Age
- Primary hypertriglyceridemia rarely presents in childhood.

## Gender
- Primary hypertriglyceridemia appears to affect men and women equally.

## Race
- Primary hypertriglyceridemia does not appear to have a racial predilection.

# Risk Factors
Positive family history is the most potent risk factor for primary hypertriglyceridemia. Other factors that can contribute to the manifestation and severity of the disease are:
- Obesity
- Diabetes melitis type 2 or Insulin resistance
- Hypertension
- Use of certain medications

# Screening
There are no recommendations for screening the young adult population for primary hypertriglyceridemia. USPSTF guidelines for 2016 show insufficient evidence to assess possible benefits of screening children and adolescents under 20 years old.

# Natural History, Complications, and Prognosis

## Natural History
If left untreated, primary hypertriglyceridemia may result in pancreatitis, which can become chronic and result in irreversible damage of the pancreas. Rarely, pancreatitis can be life-threatening.

## Complications
Approximately one in four citizens of the United States has a high level of triglycerides (>150mg/dl) that can predispose them to and directly lead to numerous complications, including:
- Cardiovascular diseases, particularly atherosclerosis of the coronary vessels
The prevalence of primary hypertriglyceridemia with hypoalphalipoproteinemia in patients less than 55 years of age undergoing coronary arteriography was found to be 15 percent, while an increased risk of ischemic heart disease was found in heterozygous carriers for Gly188Glu mutations in the LPL gene.
- The prevalence of primary hypertriglyceridemia with hypoalphalipoproteinemia in patients less than 55 years of age undergoing coronary arteriography was found to be 15 percent, while an increased risk of ischemic heart disease was found in heterozygous carriers for Gly188Glu mutations in the LPL gene.
- Non-alcoholic fatty liver disease (NAFLD)
- Pancreatitis caused by TG breakdown by pancreatic lipase and the release of free fatty acids, leading to production of free radicals.
- Non-insulin-dependent diabetes mellitus
Primary hypertriglyceridemia predisposes patients to the development of NIDDM.
- Primary hypertriglyceridemia predisposes patients to the development of NIDDM.

## Prognosis
Baseline triglyceride levels can predict mortality due to cardiovascular cause in first-degree relatives of affected patients,  without being influenced by total serum cholesterol concentration. 

# Diagnosis
The diagnosis of primary hypertriglyceridemia is based on the triglyceride levels in blood obtained by a lipid profile. It is preferable to estimate fasting triglyceride levels rather than non-fasting levels. Genetic studies can be done for confirmatory purposes after a proposed diagnosis of primary hypertriglyceridemia has been established in the presence of a positive family history.

## History and Symptoms
The hallmark of primary hypertriglyceridemia is elevated triglyceride levels. A positive family history of diagnosed primary hypertriglyceridemia and elevated triglyecride levels on a lipid profile are suggestive of familial hypertriglyceridemia. The symptoms of hypertriglyceridemia can vary in accordance with the severity of the condition. The most common symptoms include:

### Gastrointestinal
- Recurrent abdominal pain

### Ophthalmological
- Creamy appearance of the retina

### Dermatological
- Eruptive xanthomas: yellow papules with erythemtous base, demonstrating deposition of triglycerides in the cutaneous histiocytes
Primarily on the elbows and buttocks
- Primarily on the elbows and buttocks

### Musculoskeletal
- Lipid deposits on tendons
- Joint pain

### ENT
- Throat pain

## Physical Examination
Common physical examination findings of primary hypertriglyceridemia include:
General Appearance
- Increased body mass index (obesity)
- Lymphadenopathy

### Dermatological
- Eruptive xanthomas
- Tuberous xanthomas
- Palmar xanthomas

### Ophthalmology
- Lipemia retinalis
- Xanthelasmas (yellow plaques near the inner part of the eyelids)
- Corneal arcus (clouding of the cornea)

### Musculoskeletal
- Arthritis
- Tendon xanthomas
- Eruptive Xanthomas on an elbow.

### Gastrointestinal
- Hepatosplenomegaly
- Pancreatitis

### ENT
- Enlarged (cholesterol deposited) tonsils
- Eruptive xanthoma.

### Central nervous system
- Peripheral neuropathy

## Laboratory Findings
An elevated concentration of triglycerides on fasting lipid profile in patient with a positive family history is diagnostic of primary hypertriglyceridemia. The laboratory findings consistent with primary hypertriglyceridemia include:

## Imaging Findings
There are no specific findings associated with primary hypertriglyceridemia.

## Other Diagnostic Studies
There are no other diagnostic studies associated with the diagnosis of primary hypertriglyceridemia.

# Treatment
The mainstay of treatment of primary hypertriglyceridemia is lifestyle modification (e.g., diet and exercise). Medical therapy shows benefits in patients in whom lifestyle modifications fail to control triglyceride levels. Gene therapy is an emerging treatment option. Supportive clinical trial data for pharmacological therapies for treatment of hypertriglyceridemia includes:
- Niacin data
- Niacin AIM HIGH trial
- Omega 3 data

## Non-Pharmacological
- The mainstay of therapy for hypertriglyceridemia includes lifestyle modifications to lower the triglyceride levels to below 150 mg/dl.
A reduction of weight by 5-10% can help decrease the triglyceride levels by 20%.
- A reduction of weight by 5-10% can help decrease the triglyceride levels by 20%.
- Other measures include steps to reduce dietary fat and limit the consumption of high glycemic index foods.
Appropriate dietary changes, coupled with an increase in aerobic activity, can substantially decrease triglyceride content in the body.
Diet adjustment and weight loss can cut triglyceride levels by up to 25%.
In conjunction with other lifestyle modifications, the daily consumption of 4 grams of omega 3 fatty acids can also be helpful in reducing plasma levels by up to 20%.
- Appropriate dietary changes, coupled with an increase in aerobic activity, can substantially decrease triglyceride content in the body.
- Diet adjustment and weight loss can cut triglyceride levels by up to 25%.
- In conjunction with other lifestyle modifications, the daily consumption of 4 grams of omega 3 fatty acids can also be helpful in reducing plasma levels by up to 20%.
- Other factors that may be secondarily increasing triglyceride levels, including diabetes and/or hypothyroidism, should be treated; alcohol consumption should be minimized; and medications like beta blockers, isotretinoin, glucocorticoids may have to be held to help with decreasing excessively increased triglyceride levels.

## Medical Therapy
The means of treating elevated triglyceride levels varies according to the severity of the condition.
- A moderate increase (i.e., >500 but 1000) or isolated hypertriglyceridemia needs to be treated by using a fibrate as the primary treatment.
- Extended release niacin (Nicotinic acid) can be used in patients with low HDL and elevated triglyceride levels. 
- Lomitapide is used to treat genetic hypertriglyceridemia and recurrent refractory acute pancreatitis.
The following table demonstrates features of various pharmacological therapies aimed at decreasing serum triglyceride levels:
-  - Increase
-  - Decrease

## Emerging treatment options
- Gene therapy has been recently introduced for patients with LPL deficiency and recurrent or severe pancreatitis.
- Rimonabant a cannabinoid-1 (CB1) receptor antagonist works by decreasing appetite and consumption of food.
- Glitazar drugs have dual agonists on peroxisome proliferator-activated receptor- (like fibrates) and - (like thiozolidinidiones).
- LPL gene therapy may  be helpful by treating monogenic LPL (lipoprotein lipase) deficiency.

## Surgery
- Surgical intervention is not recommended for the management of primary hypertriglyceridemia.
- Xanthomas may be surgically removed for cosmetic purposes.

## Prevention

### Primary Prevention
As primary hypertriglyceridemia is a genetic disease, no recommendations have been established proposed for its primary prevention.

### Secondary Prevention
Measures for the secondary prevention of primary hypertriglyceridemia include:
- Genetic counseling
- The NCEP proposes dietary and behavioral measures to reduce the burden of atherosclerosis.
Clinical approach includes lifestyle modifications.
Population-based approach includes the reduction of individual risk of the patient.
- Clinical approach includes lifestyle modifications.
- Population-based approach includes the reduction of individual risk of the patient.