Primary hypertriglyceridemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]; Tarek Nafee, M.D. [3]

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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.[1] 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

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:[4][5]

  • 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:[6]
    • 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.[7]

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:[8]

Primary hypertriglyceridemia can occur through various mechanisms involving abnormal mutations in the LPL gene, which can increase triglyceride levels up to 80%.[9][10][11]

Genetics

  • The development of primary hypertriglyceridemia can follow either an autosomal dominant (AD) or autosomal recessive (AR) mode of inheritance.[6][13]
  • 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.[10]

Causes

The primary cause of primary hypertriglyceridemia is a genetic mutation in the LPL gene, leading to abnormal metabolism of triglycerides in the body.[14][15][16]

Differentiating Primary hypertriglyceridemia from Other Diseases

Primary hypertriglyceridemia must be differentiated from other diseases that cause abnormal increases in serum triglycerides, including:

Primary hypertriglyceridemia must also be differentiated from other diseases that may cause xanthomas such as:[17]

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.[15]
  • 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.[18]

Age

  • Primary hypertriglyceridemia rarely presents in childhood.[19]

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:[14][15]

Screening

There are no recommendations for screening the young adult population for primary hypertriglyceridemia.[20] USPSTF guidelines for 2016 show insufficient evidence to assess possible benefits of screening children and adolescents under 20 years old.[21]

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.[22]

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:[23]

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. [29]

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.[1] 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:[17][30][31][32]

Gastrointestinal

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

Musculoskeletal

ENT

  • Throat pain

Physical Examination

Common physical examination findings of primary hypertriglyceridemia include:[32][33]

General Appearance

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

Gastrointestinal

  • Hepatosplenomegaly
  • Pancreatitis

ENT

  • Enlarged (cholesterol deposited) tonsils

Central nervous system

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:[33][34][35][36]

Lab Tests Biomarker Result
Lipid Profile VLDL Elevated
Serum Triglycerides Elevated
HDL Prebeta HDL Elevated
HDL-C Decreased
LDL
Total Cholesterol Normal or Elevated
Plasma appearance Clear to cloudy
CMP Fasting Insulin levels May be elevated

(Metabolic Syndrome)

LFTs usually abnormal
CBC Cell indices,

Peripheral smear

Pancytopenia

Pseudo-Niemann pick cells

Other Glucose Tolerance usually abnormal
Carbohydrate Inducibility usually abnormal
Fat Intolerance Normal

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:

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%.[23]
  • Other measures include steps to reduce dietary fat and limit the consumption of high glycemic index foods.[37]
    • 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%.[38]
    • 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%.[39][40]
  • 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.

The following table demonstrates features of various pharmacological therapies aimed at decreasing serum triglyceride levels:

Drug Mechanism of benefit Dosage Advantages Side-effects Contraindication
Niacin/Nicotinic acid 1.5 - 2 gm once daily
  • Flushing
  • Pruritus
  • Nausea
  • Hepatitis (higher doses)
Omega-3 fatty acids
  • Bleeding at high doses
  • Fishy smell, can be reduced by
    • Freezing of medication
    • Trying different formulation
    • Taking medication with food
  • Nausea

(approximately 4 % of individuals at < 3 gm/d, and 20% at > 4gm/d experiences git side-effects)[43]

  • Hypersensitivity
Fibrate
  • ↑ - Increase
  • ↓ - Decrease

Emerging treatment options

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.[7][51][52]
    • Clinical approach includes lifestyle modifications.
    • Population-based approach includes the reduction of individual risk of the patient.

References

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