Lipid Disorders



Lipid Disorders


Francis Q. Almeda

Susan DeLange



Coronary heart disease (CHD) is the major cause of mortality in industrialized nations, and despite impressive advances in cardiovascular care, the adverse event rates remain significant. Dyslipidemia is an important risk factor for the development and progression of atherosclerotic cardiovascular disease (ASCVD) [1], and diagnosis and treatment of patients with lipid disorders have been shown to significantly reduce the risk of future cardiac adverse outcomes. The intensity of risk-reduction therapy should be adjusted to the individual’s absolute risk [2], and the accurate assessment of the patient’s overall cardiovascular risk status is the central component for the optimal treatment of individuals with dyslipidemia (Grade A).

Lipid disorders can be classified into primary (genetic or inherited) (Table 7.1) or secondary (due to disease or environmental factors). Important secondary factors that result in altered lipid metabolism include hypothyroidism, diabetes mellitus, renal disease, obstructive liver disease, alcohol intake, and various medications, and the identification and modification of these secondary causes should be aggressively pursued.


LIPOPROTEIN METABOLISM

Lipoproteins are large complexes that transport lipids (mainly cholesterol esters, triglycerides [triacylglycerol; TAG], and fat-soluble vitamins) to and from the vasculature to various body tissues. The plasma lipoproteins are divided into five main classes based on their relative densities: chylomicrons, very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs).

Lipoprotein metabolism occurs through two basic mechanisms, which include the transport of dietary lipids to the liver and peripheral tissues (exogenous pathway) and the production and delivery of hepatic lipids into the circulation and peripheral tissues (endogenous pathway) [3]. In the exogenous pathway, dietary cholesterol is acted upon by the intestinal cells to form cholesterol esters through the addition of fatty acids. TAGs from the diet are hydrolyzed by pancreatic lipases within the intestine and emulsified with bile acids to form micelles.









Table 7.1. Inherited Lipid Disorders

































Condition

Mechanisms/Characteristics


Familial combined hypercholesterolemia (FCHL)

The most common primary lipid disorder may affect ≤2% of US population. Autosomal dominant. Increased secretion of apo B-100 with resulting in varying patterns of high LDL with moderate elevations of TAG and low HDL. Significantly increased risk of ASCVD. Common comorbidities include diabetes, hypertension, and obesity


Familial hypertriglyceridemia (FHTG)

Relatively common (1 in 500). Autosomal dominant. Usually with moderately to severely elevated TAG (250-1,000 mg/dl) with mildly increased cholesterol (<250 mg/dl) with low HDL due mainly to increased production and impaired clearance of VLDL, although more severe form has elevated chylomicrons


Familial hypercholesterolemia (FHC)

Occurs in 1 in 500. Deficient or defective LDL receptor resulting in reduced clearance and accumulation of LDL with normal TAG. Autosomal dominant. Heterozygous FHC (LDL range, 325-450 mg/dl). Homozygous FHC with very high LDL (500-1,000 mg/dl). Clinical clues include tendon xanthomas, childhood CHD, arcus cornea in young patients, premature ASCVD


Primary (familial) hypoalphalipoproteinemia

Most common genetic cause of low HDL. HDL <10th percentile with normal cholesterol and TAG levels after secondary causes of low HDL are excluded. Increased risk of premature ASCVD


Familial defective apo B-100

Occurs in 1 in 1,000. Autosomal dominant. Moderate elevation in LDL with normal TAG. Mutant apo B-100 poorly recognized by LDL receptor. Palmar and tuberoeruptive xanthomas, premature ASCVD. Clinically resembles heterozygous FHC


Familial dysbetalipoproteinemia (FDBL)

Occurs in 1 in 10,000. Mixed hyperlipidemia due to increased chylomicrons and VLDL remnants due to defective apolipoprotein E. Autosomal dominant. Tendon xanthomas, premature ASCVD


Familial chylomicronemia syndrome (FCS)

Occurs in ˜1 in 1,000,000. Autosomal recessive. Genetic deficiency of lipoprotein lipase or cofactor apo C-II resulting in extremely high TAG (>1,000 mg/dl) due to chylomicronemia. Recurrent pancreatitis, lipemia retinalis, eruptive xanthomas, hepatomegaly. Usually without premature ASCVD


Tangier disease

Rare disease manifested by very low HDL due to mutations in the gene ABCA1 results in rapid clearance of HDL from the circulation. Patients have cholesterol accumulation in the reticuloendothelial system with hepatomegaly and pathognomonic enlarged yellowish orange tonsils


Lecithin-cholesterol Acyltransferase (LCAT) deficiency

Rare disorder of low HDL due to lecithin/cholesterol acyltransferase deficiency. Increased catabolism of HDL. Corneal opacities due to accumulation of cholesterol in lens (“fish-eye disease”)



Longer-chain fatty acids are incorporated into TAGs and complexed with other particles such as cholesterol esters and phospholipids to form chylomicrons (which have a high concentration of TAGs). These particles are acted on by lipoprotein lipase along the capillary endothelium, and the TAGs are hydrolyzed, releasing free fatty acids, most of which are taken up by adjacent adipocytes or myocytes, and the remaining particles (chylomicron remnants) are transported to the liver. In the endogenous pathway, VLDL is transformed into IDL and then into LDL through hepatic metabolism. VLDL particles are similar to chylomicrons but have a higher ratio of cholesterol to TAGs and contain apolipoprotein B-100. The TAG of VLDL is hydrolyzed by lipoprotein lipase, and the particles continue to become smaller and denser and transform into IDL, which is composed of similar amounts of cholesterol and TAG. The hepatic cells remove approximately half of VLDL remnants and IDL. The remainder of IDL is modified by hepatic lipase to form LDL. LDL is composed of a core of primarily cholesterol esters, surrounded by a surface of phospholipids, free cholesterol, and apolipoprotein B. The majority of circulating LDL is cleared through LDL-mediated endocytosis in the liver. Modified (oxidized) plasma LDL accumulates in the intima and is acted on by activated macrophages (foam cells) and through complex mechanisms involving cytokines, growth factors, smooth cell proliferation, and inflammation, and results in atheroma formation [4]. The process of transferring cholesterol from peripheral cells to the liver for removal from the body by biliary secretion is called reverse cholesterol transport. The role of HDL in enhancing reverse cholesterol transport is one of the mechanisms by which HDL protects against the process of atherosclerosis. The major protein of HDL is apo A-I.

The major lipid abnormalities of clinical significance result in an alteration in the levels of LDL, HDL, and TAG, and these disorders are the primary focus of this chapter. Other associated abnormalities that have been investigated include abnormal levels of serum lipoprotein(a) and homocysteine, although the data surrounding these and other emerging risk factors remain controversial [5].


LOW-DENSITY LIPOPROTEIN CHOLESTEROL


Trials

The largest body of evidence exists for improved outcomes with LDL lowering, and thus, LDL remains the major therapeutic target for intervention [2]. Large epidemiologic studies such as the Seven Countries Study [6] confirmed the association of total serum cholesterol and CHD. In addition, the Multiple Risk Factor Intervention Trial [7] demonstrated that this relation was continuous and graded, without a threshold level. Large, placebo-controlled, randomized trials confirmed the benefit of LDL lowering on reducing long-term cardiac event rates [8, 9, 10].


Primary Prevention Trials

The central principle of management of the patient without established atherosclerotic vascular disease is that the intensity of risk reduction should be commensurate with the individual’s absolute cardiovascular risk (Table 7.2) (Grade A). The major risk factors (exclusive of LDL cholesterol) include age older than 45 years in men and older than 55 years in women, cigarette smoking, hypertension (defined as ≥140/90 mm Hg or on antihypertensive medication), low HDL cholesterol (<40 mg/dl), and a family history of premature CHD in firstdegree relatives (younger than 55 years in male relative, and younger than 65 years in female relative) [2]. The LDL cholesterol is not included among the risk factors because the reason for assessing these risk factors is to treat the LDL. A high HDL (≥60 mg/dl) is regarded as a “negative” risk factor and removes one other risk factor from the total count.









Table 7.2. Updated ATP III LDL-C Goals and Cut-Points for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories






























Risk Category

LDL-C Goal (mg/dl)

Initiate TLC (mg/dl)

Consider Drug Therapy (mg/dl)


High risk: CHD or CHD risk equivalents (10-year risk, >20%)*

<100 mg/dl (optimal goal <70 mg/dl)†

≥100 mg/dl‡

≥100 mg/dl (<100 in selected high-risk populations)†


Moderately high risk: 2+ risk factors (10-year risk, 10%-20%)**

<130 mg/dl

≥130 mg/dl

≥130 mg/dl (100-129, consider drug options)††


Moderate risk: 2+ risk factors (10-year risk, <10%)

<130 mg/dl

≥130 mg/dl

≥160 mg/dl


Low risk: 0-1 risk factors

<130 mg/dl

≥160 mg/dl

≥190 mg/dl (160-189, LDL-lowering drug optional)


* CHD includes established coronary artery disease (history of myocardial infarction, unstable or stable angina, coronary revascularization, or evidence of clinically significant myocardial ischemia). CHD equivalents include diabetes and evidence of noncoronary atherosclerosis (peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, transient ischemic attacks or stroke.
† Very high risk favors the optional LDL-C goal of 70 mg/dl and in patients with high triglycerides and low HDL.
‡ In individual at high risk or moderately high risk with lifestyle-related risk factors (i.e., obesity, physical inactivity, elevated triglyceride, low HDL, metabolic syndrome), aggressive therapeutic lifestyle changes to modify these risk factors are advisable regardless of the LDL level.
** Risk factors include: age (men >45 years, and women >55 years), hypertension (BP >140/90 mm Hg or taking antihypertensive medication), smoking, low HDL (<40 mg/dl), and family history of premature CAD (CHD in male first-degree relative <55 years; CHD in female first-degree relative <65 years).
†† For moderately high-risk individuals, if the LDL is 100-129 mg/dl at baseline or on TLC, initiation of an LDL-lowering drug to achieve an LDL of <100 mg/dl is a therapeutic option.


The patient’s risk is estimated first by determining the number of risk factors. The first group comprises patients with none to one risk factor. Traditionally, this group has been assigned to a low-risk category (10-year risk of CHD, <10%), and the recommended LDL goal has been less than 160 mg/dl (Grade A). However, a very high LDL (>190 mg/dl) may warrant consideration of drug therapy to reduce long-term risk (Grade D). In addition, a single powerful risk factor (strong family history of premature CHD, heavy cigarette smoking, very low HDL, poorly controlled hypertension) favors the use of drugs to reduce the LDL (Grade D).

The second group of patients comprises those with two or more risk factors. The 10-year risk of a cardiac event is assessed by using the Framingham scoring, which takes into account the patient’s age, gender, HDL, blood pressure, smoking
status, and family history of premature ASCVD, and may be calculated by using tables or handheld and Internet-based online calculators (www.nhlbi.nih.gov/guidelines/cholesterol). Framingham scoring stratifies persons with multiple risk factors into those with a 10-year risk of CHD of more than 20%, 10% to 20%, or less than 10%. The LDL goal of patients with multiple (2+) risk factors and a 10-year risk of 10% to 20% has traditionally been less than 130 mg/dl [2], but an LDL goal of less than 100 mg/dl is a therapeutic option based on updated clinical guidelines [11], and drug therapy (in addition to therapeutic lifestyle changes) should be considered to achieve this goal (Grade A). Patients with multiple risk factors that confer a risk for a major cardiac event of more than 20% over a 10-year period are at highest risk and are treated as if they had established cardiovascular disease (Grade A).

A patient’s overall risk may be affected by other factors not included in major factors outlined earlier. Other risk factors that should be taken into consideration include obesity, sedentary lifestyle, and an atherogenic diet, which are excellent targets for clinical intervention (Grade C). Other emerging risk factors such as lipoprotein(a), proinflammatory markers, and impaired fasting glucose further guide the intensity of risk reduction in selected individuals (Grade A). Specifically, an elevated high-sensitivity C-reactive protein (hs-CRP) has been touted as a potentially useful marker for identifying individuals of higher risk who may benefit from more intensive lowering of LDL (Grade A). In addition, LDL subclasses may be measured through nuclear magnetic resonance (NMR) spectroscopy, and the detection of smaller, denser LDL particles may provide incremental information on cardiovascular risk [12]. Furthermore, the metabolic syndrome is a constellation of interrelated metabolic risk factors with underlying insulin resistance that imparts an especially high risk for the development of ASCVD and diabetes (Grade A) [11].

The WOSCOPS trial [13] enrolled middle-aged men with hypercholesterolemia (mean total cholesterol, 272 mg/dl) and no history of myocardial infarction (MI) to treatment with pravastatin and found a significant reduction in death or nonfatal MI by 31% compared with placebo over a mean follow-up of 4.9 years. The ASCOT-LLA trial [14] evaluated treatment with atorvastatin in hypertensive patients with modest hypercholesterolemia (total cholesterol, <240 mg/dl) compared with placebo. After a median follow-up of 3.3 years, the trial was stopped prematurely because of a highly significant 36% reduction in fatal CHD and nonfatal MI, which became apparent in the first year of follow-up. The ALLHAT trial [15] was a similar study that evaluated the administration of pravastatin in the treatment of older, hypertensive, moderately hypercholesterolemic (mean total cholesterol, 244 mg/dl, and mean LDL, 148 mg/dl) patients with one additional risk factor compared with placebo with a mean follow-up of 4.8 years. The results of this trial showed that no statistically significant differences in mortality or CHD event rates existed, although this may have been due to the high rate of nonstudy statin in the usual-care group or the modest differential in total cholesterol and LDL between the pravastatin and usual-care group compared with prior statin trials. The AFCAPS/TeXCAPS trial [16] enrolled patients without CHD and with average serum cholesterol levels (mean total cholesterol, 221 mg/dl, and mean LDL, 150 mg/dl) and below-average HDL (mean HDL, 36 mg/dl) levels to lovastatin and demonstrated a reduction in the first acute major coronary event (MI, unstable angina, or sudden cardiac death) by 37% [16].

The JUPITER trial [17] enrolled 17,802 patients without known CHD with normal LDL levels (mean LDL 108 mg/dl) and elevated high-sensitivity C-reactive protein greater than 2.0 mg/l (median hs-CRP of 4.2 mg/l) to 20 mg of rosuvastatin or placebo. Patients were followed for a median of 1.9 years, and the
patients treated with rosuvastatin had statistically significant 44% decrease in the primary composite end point of cardiac death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization compared with placebo. This trial suggests a role for intensive lowering of LDL with statin therapy in apparently healthy men and women with an elevated hs-CRP and remains an area of ongoing research (Grade A).

Taken in aggregate, these landmark clinical trials [10, 13, 14, 15, 16] suggest that lipid-lowering therapy in intermediate- to high-risk patients without established ASCVD with moderate hypercholesterolemia is beneficial and is associated with lower adverse major cardiac event rates on follow-up (Grade A).


Secondary Prevention Trials

The highest-risk group includes those patients with established cardiovascular disease or a “CHD risk equivalent.” This group comprises patients with known coronary artery disease, other clinical forms of atherosclerotic vascular disease, including peripheral vascular disease, carotid artery disease, abdominal aortic aneurysm, and diabetes mellitus, and patients with multiple risk factors that confer a risk for a major cardiac event of more than 20% over a 10-year period. The identification of subclinical atherosclerotic disease such as high coronary calcification, significant carotid intimal medial thickness, or significant atherosclerotic burden on CT angiography likewise warrants aggressive and intensive lipid lowering.

The 4S trial [8] was the first trial to demonstrate a reduction in total mortality (30% relative risk reduction) in middle-aged patients with high cholesterol (mean total cholesterol, 272 mg/dl, and mean LDL, 190 mg/dl) with established CHD treated with simvastatin compared with placebo, in addition to reducing major coronary events and coronary revascularization, over an average of 5.4 years. The CARE [10] trial extended these findings and to patients with established CHD and “average” cholesterol levels (mean total cholesterol, 209 mg/dl, and mean LDL, 139 mg/dl) and demonstrated a 24% relative risk reduction in the primary end points (mortality and major cardiac event rates and stroke). The LIPID trial [9] was the largest trial of secondary prevention and similarly demonstrated a 24% reduction in CHD mortality, as well as total mortality and fatal and nonfatal MI. The Heart Protection Study [18] demonstrated a reduction in all-cause mortality with treatment with simvastatin in a wide range of highrisk patients (coronary artery disease, occlusive arterial disease, or diabetes), irrespective of their baseline LDL level. Importantly, a significant reduction was noted in nonfatal MI, stroke, and coronary and noncoronary revascularization, and the risk reductions were similar and significant, even in patients with a “low” baseline LDL level (<116 mg/dl), suggesting that lower is better. In summary, these large, randomized clinical trials clearly demonstrated that lipid-lowering therapy with statins in patients with established ASCVD resulted in a highly significant reduction in mortality and cardiac events over a wide range of LDL values (Grade A).


How Low Should You Go?

The Heart Protection Study [18] and the PROVE IT trial [19] showed incremental 22% and 16% reductions in risk for adverse cardiac events with LDL levels reduced to less than 100 mg/dl. The Treat To New Targets (TNT) trial [20] demonstrated a 22% relative and a 2.2% absolute risk reduction of more major cardiac events (including death from CHD, nonfatal MI, resuscitation after a cardiac arrest, and fatal or nonfatal stroke) in the group receiving high-dose atorvastatin compared with the low-dose group. The mean LDL in the high-dose group was 77 mg/dl compared with 101 mg/dl in the low-dose group. Overall, these data suggest
that no clear-cut identifiable threshold exists for LDL level for risk reduction and that “lower is better.” Based on these recent trials demonstrating reduced cardiovascular event rates with lower LDL levels, the current recommendation for optimal LDL is less than 70 mg/dl in patients at very high risk (Grade A) [11]. The factors that place a patient at very high risk include established ASCVD and CHD equivalents, multiple major risk factors, and severe and poorly controlled risk factors (i.e., smoking). No major safety issues have been identified thus far with reducing LDL to the range of 50 to 70 mg/dl [21]. The current evidence from the major clinical trials to date favors LDL lowering primarily with a statin as the initial therapeutic strategy (Grade A).


Treatment Options


Dietary Modification

Lifestyle and dietary modifications remain crucial, and reduced intake of saturated fat and cholesterol, increased physical activity, and weight control for all patients are recommended. All patients should be advised to adopt therapeutic lifestyle changes including reduced intake of saturated fats (<7% of total calories) and cholesterol (<200 mg/d), increased intake of soluble fiber (10-25 g/d), weight reduction, and increased physical activity (Grade A). Dietary modification should be a mainstay of any LDL-lowering strategy; however, the average LDL reduction from diet alone is in the range of 5% to 10% [22], and compliance with a strict diet remains problematic in routine clinical practice.


Statins (3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors)

Statins reduce serum LDL levels through intracellular inhibition of the rate-limiting step in cholesterol production, which reduces cholesterol biosynthesis in the liver and upregulates LDL-C receptors to increase clearance of LDL-C from the blood. The statins reduce the LDL by 18% to 55%, increase HDL by 5% to 15%, and reduce TAG by 7% to 30% (Table 7.3). At the current available doses, rosuvastatin and atorvastatin are the most potent statins, followed in order of LDL-reducing potency by simvastatin, lovastatin, pravastatin, and fluvastatin. Each doubling of a statin dose achieves an approximately 6% additional reduction in serum LDL (the “rule of 6s”). A large meta-analysis involving 14 randomized, placebo-controlled trials involving 90,056 patients showed that lowering LDL cholesterol levels by 39 mg/dl (1 mmol/l) with statin therapy significantly reduces the 5-year risk of major coronary events, coronary revascularization, and stroke by 21% [23]. This benefit emerged early, was sustained, and was related mainly to the individual’s absolute risk and to the absolute reduction in LDL cholesterol levels achieved.

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Aug 2, 2016 | Posted by in ENDOCRINOLOGY | Comments Off on Lipid Disorders

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