Management of hyperlipidemias: An update

Indian Journal of Dermatology, Venereology and Leprology, Sep/Oct 2009 by Ranjan, Nitin

Introduction

Cholesterol serves not only as an essential component of the cell membrane but also as the precursor molecule from which steroid hormones, bile salts, and vitamin D are synthesized. It is both derived from the diet and synthesized within the body, mainly in the liver. Cholesterol circulates as a component of lipoproteins. The principal plasma lipoproteins are the chylomicrons (CMs), very low density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). The principal fat in the diet is the triglycerides (TG), which are absorbed in the intestine. The lipoproteins are transported in combination with apoproteins (apo), like apo-A, apo-B, and apo-C.

The Pathways

Transport of lipoproteins can be divided into:

Exogenous transport

From ingested food to intestine to peripheral cells and liver [Figure 1]

Products of fat digestion from the gut (cholesterol, TG) are packaged with intestinal apo-B48 to form nascent CMs. This process is mediated by microsomal triglyceride transfer protein (MTP). [1] In the circulation, nascent CMs acquire cholesteryl esters (ChE), apo-C, and apo-E from HDL to form CMs. These CMs come in contact with lipoprotein lipase (LPL) located on the luminal surface of vascular endothelium of skeletal muscle and adipose tissue. LPL breaks down the triglyceride component of CMs into free fatty acids (FFA) and monoglycerides, in the process converting the CMs to smaller particles called CM remnants. The cholesterol-rich CM remnants are taken up by the liver via LDL-receptor-like-protein (LRP) receptors or Apo-E receptors. [2] In this way, dietary cholesterol finally reaches the liver.

Endogenous transport

From liver to peripheral tissues: the apo-B100 lipoprotein system [Figure 2]

Analogous to the secretion of nascent CMs by the gut, liver synthesizes and secretes nascent VLDL, by complexing TG and apo-B100 under the mediation of MTP. [1] Triglyceride-rich nascent VLDL serves as an efficient acceptor of ChE from HDL. This transfer takes place under the agency of cholesteryl ester transfer protein (CETP) in the plasma and leads to the formation of mature VLDL. [3] During circulation, LPL hydrolyses the TG of VLDL to FFA and monoglycerides, in the process converting VLDL to smaller lipoproteins called intermediate density lipoproteins (IDL), and further to still smaller ChE-rich LDL. LDL supplies tissues with cholesterol. Thus the liver serves as the major site for both cholesterol synthesis and LDL catabolism.

From peripheral tissues to liver: the apo-A 1 lipoprotein system [Figure 3]

Nascent HDL particles are synthesized by apolipoprotein-phospholipid complexes in plasma, and also by intestine and the liver. Peripheral tissues (including liver) transfer unesterified cholesterol to nascent HDL by the membrane protein ATP-binding cassette protein A1 (ABCA1). [4] Lecithin-cholesterol acyltransferase (LCAT), an enzyme present on HDL, esterifies this cholesterol, leading to the formation of ChE. VLDL and CMs transfer TG to nascent HDL, which leads to formation of mature HDL. HDL is taken up directly by hepatocytes via the scavenger receptor class BI (SR-BI). [5] The transfer of excess cholesterol from the tissues back to the liver via HDL is called 'reverse cholesterol transport.'

Hyperlipidemias

Hyperlipidemias are classified as primary or secondary. Patients with primary hyperlipidemia have been classified into 5 major groups according to plasma lipoprotein patterns [Table 1],[Figure 4]. [6],[7] Conditions causing secondary hyperlipidemia include obstructive liver disease, various hematopoietic diseases (myeloma, Waldenstrom's macroglobulinemia, cryoglobulinemia, hemochromatosis), chronic renal failure, myxedema, pancreatitis, and drugs like estrogens, corticosteroids, and retinoids. [8]

Dermatologic Markers of Lipid Derangement

Abnormalities of lipid metabolism may favor lipid deposition in the skin and present as xanthomas. [9] Xanthelasma palpebrarum is the commonest type of cutaneous xanthoma and typically involves the upper eyelids as symmetrical, soft, yellowish papules and plaques near the medial canthi. [10],[11] The major lipid stored in xanthomas is esterified cholesterol. [12],[13] Xanthelasma is a marker of dyslipidemia, requiring a complete lipid profile to detect patients potentially at increased risk of cardiovascular disease. [14] However, only about half of the patients with xanthelasma are hyperlipidemic. [15] The most frequent hyperlipidemia associated with xanthelasma is type IIa. [16] Less frequently, types IIb, III, and IV are found. [16] Isolated xanthelasmata are often treated with destructive modalities, like trichloroacetic acid, electrocautery, surgical excision, [17] carbon dioxide laser, [18] pulsed dye laser, [19] and erbium:YAG laser. [20] A brief review of various other types of xanthomas is presented in [Table 2].

Management

Traditional foods and herbal therapies

Dietary advice has a small but significant role to play in normalizing abnormal serum lipids in those at high risk of cardiovascular disease, and reductions in serum total cholesterol levels of the order of 3% to 6% are to be expected. [21],[22] Replacement of saturated fats by unsaturated fats leads to improved lipid levels.[23] However, it is not clear whether polyunsaturated or monounsaturated fats are most cardioprotective. [24] Rapeseed oil, which is rich in omega-3 fats, is especially useful. [25] Soluble fiber (in oats, pectin, psyllium, guar gum) results in a significant but very modest lipid-lowering effect.[26],[27],[28] Unrealistic (47g per day) intake of purified soy protein will lower total cholesterol levels by about 0.6 mmol L. [29] A recent review of the efficacy of garlic as an antihyperlipidemic agent found it difficult to recommend garlic as an antihyperlipidemic agent owing to the low methodological quality of the studies. [30] Stanol esters and plant sterols reduce cholesterol in those on an average diet, but may lack efficacy in those already on a low fat diet. [25]