Hypertriglyceridemia Clinical Presentation

• Hypertriglyceridemia is usually asymptomatic until triglycerides are greater than 1000-2000 mg/dL.
• A history of recurrent episodes of acute pancreatitis is common in patients with severe and uncontrolled hypertriglyceridemia.^[6] Triglyceride levels often exceed 5000 mg/dL at the onset of pancreatitis.
• Severe hypertriglyceridemia may cause eruptive xanthomas, which is a benign condition.
• Patients with recurrent episodes of abdominal pain that is less severe than acute pancreatitis may experience the chylomicronemia syndrome^[7] .

  • These patients usually have triglyceride elevations greater than 2000 mg/dL at the onset of symptoms and provide a history of recurrent episodes of abdominal pain, sometimes with nausea, vomiting, or dyspnea.
  • Pancreatitis is not necessarily present.
  • Pain is commonly mid epigastric but may occur in other regions, including the chest or back.
  • The presentation of hyperchylomicronemia may be confused with conditions such as acute myocardial syndromes or biliary colic.

When triglycerides are less than 1000 mg/dL, the physical findings are normal unless the underlying condition is dysbetalipoproteinemia, type III hyperlipoproteinemia. In this condition, palmar xanthomas may be discerned infrequently.

When triglycerides are acutely and massively elevated, physical findings may be absent except on funduscopic examination. Therefore, physical findings in patients with severe hypertriglyceridemia are variable, ranging from normal to one or more of the following findings:

• Dermatological

  • Eruptive xanthomas (seen below) are sometimes found when sustained elevated triglycerides are well above 1000 mg/dL. These are 1- to 3-mm yellow papules on an erythematous base. They are most prominent on the back, buttocks, chest, and proximal extremities. The lesions are caused by accumulations of chylomicrons within macrophages and disappear gradually when triglycerides are kept below 1000 mg/dL. Eruptive xanthomas on the back of a patient admitted with a triglyceride level of 4600 mg/dL and acute pancreatitis. Close-up of eruptive xanthomas.
  • Patients with dysbetalipoproteinemia (type III) may have palmar xanthomas (yellowish creases of the palms). This type of xanthoma is considered pathognomonic for this disorder. Tuberous or tuberoeruptive xanthomas, which also may occur in other hyperlipidemias, may arise on the elbows, knees, or buttocks.
• Gastrointestinal

  • If pancreatitis or the chylomicronemia syndrome is present, the mid epigastric area or upper right or left quadrants are tender to palpitation.
  • Hepatomegaly and, less commonly, splenomegaly may be appreciated.
• Ophthalmologic: Triglyceride levels of 4000 mg/dL or higher may cause a condition known as lipemia retinalis, in which funduscopic examination reveals retinal blood vessels (and occasionally the retina) that have a pale pink, milky appearance.
• Neurological: Memory loss, dementia, and depression have been reported in patients with the chylomicronemia syndrome.

Hypertriglyceridemia has many causes, including familial and genetic syndromes, metabolic disease, and drugs.

• Genetic causes: Abnormalities of the enzyme pathway for chylomicron metabolism are the best-characterized genetic causes of hypertriglyceridemia. However, less clearly defined inheritable disorders are more frequent causes of elevated triglycerides.

  • Type I hyperlipoproteinemia is the best-characterized genetic cause of hypertriglyceridemia and is caused by a deficiency or defect in either the enzyme LPL or its cofactor, apo C-II.
    • LPL hydrolyzes triglycerides in chylomicrons and VLDL, releasing free fatty acids. The enzyme is found in the endothelial cells of capillaries and can be released into the plasma by heparin. LPL is essential for the metabolism of chylomicrons and VLDL, transforming them into their respective remnants. Apo C-II, an apolipoprotein present in both chylomicrons and VLDL, acts as a cofactor in the action of LPL.
    • The above pathway is affected by other genetic disorders, particularly type 1 or type 2 diabetes, because LPL requires insulin for full activity.
  • Two triglyceride disorders are genetically controlled, but the mechanisms are not clearly defined.
    • Familial combined hyperlipidemia is an autosomal dominant disorder characterized by patients and their first-degree relatives who may have either isolated triglyceride or LDL-c elevations or both. Diagnosis of the disorder in a particular patient requires a family history of premature coronary artery disease (CAD) in 1 or more first-degree relatives and a family history for elevated triglycerides with or without elevated LDL-c levels. The diagnosis is important for prognosis; 10-20% of patients with premature CAD have familial combined hyperlipidemia.
    • Familial hypertriglyceridemia is also an autosomal dominant trait.^[8] These patients and their families have isolated triglyceride elevations and may have an increased risk of premature coronary artery disease.
• Metabolic causes^[8]

  • Diabetes: Uncontrolled diabetes mellitus, both type 1 and type 2, is one of the most common causes of hypertriglyceridemia, and it is often severe in patients presenting with ketosis.
    • Patients with type 1 diabetes mellitus are insulin deficient, and LPL is largely ineffective. Control of these patients' diabetes mellitus with insulin will restore LPL function, reducing triglyceride levels and restoring diabetes mellitus control.
    • In patients with uncontrolled type 2 diabetes mellitus and hyperinsulinemia, triglycerides are elevated for several reasons. (1) LPL is less effective in the insulin-resistant state. (2) Overproduction of VLDL by the liver is common in patients with diabetes who are often overweight. (3) Diabetes mellitus is one of the conditions that leads to incomplete metabolism of VLDL, causing increased remnant VLDL or IDL observed in dysbetalipoproteinemia (see Dysbetalipoproteinemia).
  • Obesity: Mild-to-moderate elevations in triglycerides are common in obese patients, largely secondary to reduced efficacy of LPL and overproduction of VLDL.
  • Hypothyroidism: It commonly causes LDL-c elevations but also may lead to mixed hyperlipidemia or isolated triglyceride elevations. Reduced hepatic lipase activity slows VLDL remnant catabolism. As with diabetes mellitus, untreated hypothyroidism may cause dysbetalipoproteinemia in patients with homozygous apolipoprotein E-2.
  • Nephrotic syndrome: It is thought to increase hepatic synthesis of VLDL and also may slow catabolism of both LDL and VLDL. As in hypothyroidism, elevated LDL-c levels are more common in this condition, but mixed hyperlipidemia or isolated triglyceride elevations may be observed. Higher levels of proteinuria are correlated with more severe hyperlipidemia.
• Drugs

  • High-dose thiazide diuretics or chlorthalidone
  • High-dose beta-adrenergic blocking agents, excluding those with intrinsic sympathomimetic activity.
  • Unopposed oral estrogen replacement therapy
  • Oral contraceptives with high estrogen content
  • Tamoxifen
  • Glucocorticoids
  • Oral isotretinoin
  • Antiretroviral therapy (including some protease inhibitors, nonnucleoside reverse transcriptase inhibitors)
  • Atypical antipsychotics
• Other causes of hypertriglyceridemia

  • Alcohol: Excessive alcohol intake and high-carbohydrate diets (>60% of caloric intake) are frequent causes of hypertriglyceridemia.
  • High-carbohydrate diets (>60% of caloric intake)
  • Acute pancreatitis: It may cause substantial elevations in triglycerides by unknown mechanisms. However, much more frequently, severe hypertriglyceridemia causes acute pancreatitis. In patients presenting with acute pancreatitis and triglycerides greater than 1000 mg/dL, not assuming that the triglycerides are the cause of the pancreatitis is prudent. Other causes, such as common bile duct obstruction and alcoholism, must be considered as possible etiologies.
  • Pregnancy: In patients with mildly-to-moderately elevated triglycerides in the nonpregnant state, hypertriglyceridemia (sometimes severe) may occur. Such patients should be monitored closely, particularly in the third trimester. In fact, simply looking for laboratory notation of lipemic serum in routine blood tests during pregnancy will avoid unexpected complications resulting from unrecognized and untreated hypertriglyceridemia during pregnancy.