Hyperlipidemia (High Cholesterol):Terminology


Hyperlipidemia, also known as hyperlipoproteinemia or high cholesterol, is a disorder characterized by abnormally high concentrations of lipids (fats) in the blood that are correlated with the development of atherosclerosis, the underlying cause of coronary heart disease (CHD) and stroke. Hyperlipidemia is caused by abnormal lipid and lipoprotein metabolism.

Lipids are a group of naturally occurring fatty substances that are present in the blood and tissues of the body. They include cholesterol, cholesterol esters, triglycerides, and phospholipids. Lipids are essential dietary constituents because of their important functions.

LIPID FUNCTIONS

  • Provide energy required by the body
  • Serve as the major structural components of cell membranes
  • Aid in the efficient absorption of fat-soluble vitamins
  • Serve as insulating material beneath the skin and around certain organs (e.g. kidneys)
  • Serve as biosynthetic precursors (e.g., Cholesterol is a precursor for adrenal and gonadal steroid hormones and hepatic bile acids.)

Since lipids are insoluble in blood (plasma), they must be transported to and from the cells by special carriers called lipoproteins. Lipoproteins are spherical particles of high molecular weight. Each lipoprotein particle contains a non-polar core and a hydrophilic surface. The hydrophilic surface makes the lipoprotein soluble in plasma and acts as an interface between the plasma and lipid core. The core consists of hydrophobic lipids, triglycerides and cholesterol esters, surrounded by a hydrophilic surface coat of phospholipids, unesterified cholesterol, and specific proteins termed apolipoproteins or apoproteins. The apolipoproteins provide structural integrity to the lipoproteins and determine the lipoproteins’ metabolic fate by serving as binding sites for receptors and activating enzymes involved in lipid metabolism.

The six major classes of plasma lipoproteins are:

  • Chylomicrons : Particles of the lowest density that appear in the blood shortly after fat has been digested and absorbed from the small intestine. They transport dietary cholesterol and triglycerides to muscles (for energy), to fat tissue (for storage), and to breasts (for milk production).

  • Very low-density lipoproteins (VLDL) : Particles synthesized by the liver that transport triglycerides to muscles (for energy) and to fat tissue (for storage).

  • Intermediate density lipoproteins (IDL) : Particles formed as the triglyceride portion of the VLDLs are removed. IDLs are either converted to LDLs or directly taken up by the liver.

  • Low-density lipoproteins (LDL): Particles that are the primary plasma carriers of cholesterol. LDL is also known as the "bad cholesterol" because excess LDL cholesterol in the blood with other substances can form  plaques that can clog the arteries feeding the heart and brain. The formation of plaques in the arteries is a condition known as atherosclerosis in medical terminology. If a clot forms in the region of the plaque, blood flow to part of the heart muscle can become blocked which can lead to heart attack. If the clot cuts off blood flow to the brain, it can cause a stroke.

  • High-density lipoproteins (HDL): HDL is known as the "good cholesterol" because it mediates the removal of cellular cholesterol. HDL carries cholesterol away from body cells and tissues to the liver for excretion from the body. A high HDL level is associated with a lower risk for coronary heart disease (CHD).

  • Lipoprotein (a) (Lp(a)): Particle similar in composition to LDL but has an additional apoprotein, apo(a), covalently linked to apo B. Lp(a) is called the "deadly cholesterol" because it is 10 times more dangerous than low-density lipoprotein (LDL) and 15 times more potent than total cholesterol. Lp(a) levels are almost exclusively governed by race, ethnicity, and genetics, unlike other blood fats that are governed by age, gender, diet, and other environmental factors. A high level of Lp(a) is a risk factor for developing atherosclerosis prematurely. Patients at high risk for CHD should make major lifestyle changes (exercise routinely, avoid smoking, and monitor their weight, cholesterol, waist size, and calorie intake) to avoid the development of adverse lipid profiles that will magnify the deadly effects of elevated Lp(a) levels.

    Compared to LDL, Lp(a) preferentially deposits in the human atherosclerotic tissues. It binds with components in the blood to form plaques, promotes unwarranted clot formation within the arteries, and prevents their breakdown that obstructs normal blood flow.

    Besides function, lipoproteins also vary in composition, size and density. Their physicochemical characteristics are summarized in Table 1.

Table 1. Characteristics of Lipoproteins in Human Plasma

 

Lipo-
protein
Source Diameter
(nm) 
Density
(g/dl)
Mol. Wt.
(Daltons x106)
Lipid
Compo-
sition(%)
Apolipo-
proteins
Athero-
genicity
Chylom-
icrons

Intestine

75-1200

0.95

>400

88% TG

8% P

3% CE

1% C

AI,AII,

B48,CI,

CII,CIII,E

+

VLDL

Liver

30-80

0.96-1.006

10-80

56% TG

20% P

15% CE

8% C

1% FFA

B100,
CI,CII,
CIII,E

+

IDL

VLDL

25-35

1.006-1.019

5-10

29% TG

26% P

34% CE

9% C

1% FFA

B100,

CIII,E

+

LDL

VLDL, liver, intestines

18-25

1.019-1.063

2-3

13% TG

28% P

48% CE

10% C

1% FFA

B100

+++

HDL

Liver

5-12

1.063-1.210

1.7-3.6

13% TG

46% P

29% CE

6% C

6% FFA

A1, AII,
CI, CII,
CIII, E 

-

Lp(a)

Liver

25

1.05-1.1

2-3

13% TG

28% P

48% CE

10% C

1% FFA

B100,a

++++

* TG = Triglycerides, P = Phospholipids, CE = Cholesterol esters, C = Cholesterol, & FFA = Free fatty acids. Where composition does not add up to 100%, the remainder is mostly apolipoprotein.

As shown in Table 1, all of the lipoproteins except HDL increase one’s risk for atherosclerosis. Therefore it is important to monitor the levels of lipids in the blood (Table 2).

Table 2. Evaluation of Lipid Levels for People at High Risk for CHD

  Total
Cholesterol
(mg/dl)

Triglycerides
(mg/dl)
LDL
Cholesterol
(mg/dl)
  HDL
Cholesterol
(mg/dl)
Desirable levels

<200

<150

<130

>35

Borderline risk

200-239

150-200

130-159

30-35

High risk

>240

>200

>160

<30

Modestly elevated Lp(a) levels = 20-30 mg/dl (associated with a 2-3 fold higher risk of heart attack).

There is a 10-fold risk of heart attack when Lp(a) levels are > 50 mg/dl in people with high cholesterol levels.

Conversion Factors:

Cholesterol:
        mmol/L x 38.7 = mg/dL  mg/dL x 0.026 = mmol/L
Triglycerides:     mmol/L x 885.5 = mg/dL    mg/dL x 0.0113 = mmol/L
Phospholipids:   
g/L x 0.01 = mg/dL               mg/dL x 10 = g/L

There are 7 main classes of hyperlipoproteinemias, and they are dependent on the type(s) of lipids elevated in the blood.

Table 3. Classification of Hyperlipoproteinemias

Lipoprotein
Phenotype
Class Class Lipid
Abnormalities
Type I Familial
hyperchylo-
micronemia
Deficiency of lipoprotein
lipase (LPL)
Chylomicrons ,
TC , TG
Type IIa Familial hypercho-
lesterolemia
Deficiency of LDL (B/E) receptors LDL , TC ,
TG (N)
Type IIb Familial Combined Hyper-
lipidemia.
High Apo B synthesis and defective Apo E. LDL , VLDL ,
TC , TG
Type III Familial dys-beta-
lipoproteinemia
Abnormal IDL metabolism IDL , TC , TG
Type IV Familial hypertri-
glyceridemia
Abnormal VLDL metabolism VLDL , TC ,
TG
Type V Familial mixed hypertri-
glyceridemia
Abnormal metabolism
of VLDL and chylomicrons
Chylomicrons ,
VLDL ,
TC ,TG

-

Familial hyper Lp(a) Excess Lp(a) Lp(a)

              LPL is an enzyme involved in lipid metabolism.

The hyperlipoproteinemias are characterized by various physical symptoms such as corneal arcus, xanthomas (yellowish, swollen nodule or plaque in the skin due to fat deposition), and xanthelasma (yellowish fat deposits around the eyes).

Some of the risk factors for developing hyperlipoproteinemia are:

  • Obesity
  • Diabetes
  • Hyperthyroidism
  • Nephrotic disorder
  • Liver disease
  • Hypertension
  • Family history of high cholesterol or heart disease
  • Diet high in fat and cholesterol
  • Cigarette smoking
  • Sedentary lifestyle
  • Increasing age

Treatment

After proper diagnosis of hyperlipoproteinemia and before medicinal intervention, lifestyle changes and risk factor reduction is warranted. This includes diet modification, weight loss, exercise, smoking cessation, and control of underlying disorders such as diabetes and hypertension. Such changes can lead to significant reductions in plasma lipoproteins. If dietary and lifestyle changes fail, hypolipoproteinemic (cholesterol-reducing) drugs are advised. The types of drugs used to lower blood lipids and block atherogenesis are:

  1. Cholesterol biosynthesis inhibitors (e.g. Lovastatin)
  2. Fibrates (e.g. Clofibrate )
  3. Bile acid sequesterants (e.g. Cholestyramine)
  4. Cholesterol absorption inhibitors
  5. LDL oxidation inhibitors (e.g. Probucol)
  6. Hypolipidemic drugs with multiple mechanisms (e.g. Nicotininc acid and Gugulipid)

Cholesterol biosynthesis inhibitors (e.g. Lovastatin)

Cholesterol biosynthesis inhibitors reduce cholesterol biosynthesis by increasing the uptake of plasma LDL particles via the LDL receptor. The most important group of cholesterol biosynthesis inhibitors is hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors. These compounds are derived by fermentation, and they all contain a dihydroxycarboxylate moiety. Clinically, HMG-CoA reductase inhibitors are effective in lowering (20-40%) total plasma cholesterol levels and inducing small but significant increases in HDL cholesterol levels.

Many synthetic inhibitors have been prepared to serve as alternate therapies to the fermentation derived inhibitors. The synthetic compounds possess the dihydroxycarboxylate moiety or a related system, but they have a different lipophilic anchoring group. Lovastatin, Pravastatin, and Simvastatin are some popular synthetic HMG-CoA inhibitors. They have been found to reduce serum cholesterol levels by 30-40%, LDL by 35-45%, triglycerides are reduced moderately, and HDL is elevated slightly. Although these drugs are well tolerated, side effects do occur. Some of these side effects include infrequent and mild dyspepsia (indigestion) and transient elevation of hepatocellular enzymes and creatine kinase (in some cases). There is a rare occurrence of symptomatic myopathy in less than 0.1% people during monotherapy (single drug use), but it is dose-dependent and more common in patients simultaneously receiving cyclosporine, nicotinic acid, gemfibrozil, or erythromycin. Consequently, the development of myopathy warrants cessation of drug therapy. Cholesterol synthesis inhibitors are contraindicated in patients with cholestasis or impaired hepatic function.

Fibrates (e.g. Clofibrate )

Fibrates primarily lower triglycerides. It is believed that the major benefit of fibrates is the elevation of HDL cholesterol. (Elevation of HDL cholesterol is beneficial because it is associated with reverse cholesterol transport, a system believed to carry cholesterol away from the lesion sites and back to the liver. Elevated levels of HDL cholesterol may indicate that reverse cholesterol transport has been accelerated.)

Some common fibrates include clofibrate, beclobrate, bezafibrate, ciprofibrate, fenofibrate, and gemfibrozil. The fibrates vary in potency and therefore dosage. They are usually well tolerated. Side effects include GI discomfort, headaches, insomnia, rashes and pruritis (itching), reversible myopathy, and increased hepatocellular enzymes. Fibrates, especially clofibrate, have the potential to increase biliary lithogenicity that may in turn increase the long-term risk of cholelithiasis (formation of stones in the gallbladder). As a result, periodic monitoring of liver function is necessary. Impaired renal function is a contraindication for all fibrates. Also, caution should be taken if one is taking anticoagulants with fibrates because fibrates may potentiate the action of the anticoagulants. If one is taking anticoagulants and fibrates, the dosage of the anticoagulants should be reduced up to 50% and then adjusted as necessary thereafter.

Bile acid sequestrants (e.g. Cholestyramine)

Bile acids, organic acids in the bile, mostly occur as bile salts (e.g. sodium glycocholate and sodium taurocholate), and they are secreted by the liver into the intestine where they assist in the dissolution and absorption of lipids (fats). Untreated, approximately 95% of the bile acids that are secreted are reabsorbed and returned to the liver. The loss is replaced by de novo biosynthesis from cholesterol. Treated, the recirculation process (i.e. bile acids are reabsorbed and returned to the liver) is interrupted. This causes a greater loss of bile acids from the body. In order to replace this loss, biosynthesis of bile acids from cholesterol increases. This leads to partial depletion of the hepatic cholesterol pool. Uptake via the LDL receptor results in lower LDL levels. The following flow chart summarizes the effects of bile acid sequestrants in vivo.

Cholestyramine is the most commonly used bile acid sequestrant. It, like other bile acid sequestrants, is a high molecular weight, cationic, ion exchange resin that binds anionic bile acids therefore preventing their reabsorption. Perhaps the major issue with these agents is their palatability problem, and great measures have been taken to remedy it. Because LDL receptor activity is increased, cholesterol levels are normally reduced by 20-30%. In contrast, triglycerides and HDL cholesterol levels may increase.

The major side effects of bile acid sequestrants are constipation, exacerbation of pre-existing hemorrhoids, and GI discomfort. They also interfere with the absorption of both folic acid and other fat-soluble vitamins. As a result, folate supplements should be taken during drug therapy with bile acid sequestrants.

Cholesterol absorption inhibitors

Cholesterol absorption inhibitors, as their name implies, blocks the absorption of intestinal cholesterol. This results in an increase in the uptake of LDL from the plasma. These agents not only block elevated serum cholesterol levels induced by diet but they also bring about a net drain of the system. 

LDL oxidation inhibitors (e.g. Probucol)

LDL oxidation is believed to increase atherosclerosis through high serum LDL levels inducing LDL particles to migrate into subendothelial space. In this environment, LDL oxidation can occur. The process by which LDL particles are oxidized begins with lipid peroxidation followed by fragmentation to short-chain aldehydes. At the same time, lecithin is converted to lysolecithin, a selective chemotactic agent for monocytes that becomes a macrophage and ingests oxidized LDL. The new macrophage, formerly lysolecithin, becomes engorged with cholesteryl esters from taking up so much oxidized LDL that it changes into a foam cell. Groups of foam cells form a fatty streak, the earliest indication of atherosclerosis.

Probucol, a bis-phenol, is one of the most common LDL oxidation inhibitors. It has potent antioxidant properties and has been shown to directly inhibit LDL oxidation. Probucol reduces cholesterol by causing decreases in both LDL (5-15%) and HDL (upto 25%). Probucol accumulates in the core of lipoprotein particles, altering their structure in a manner that enhances uptake by the cells that is independent of LDL receptors. Although the reduction of HDL is not desirable, no evidence indicates increased progression of atherosclerosis following probucol use. Side effects of probucol include abdominal pain, diarrhoea, and dyspepsia or nausea. It should not be used if the patient has ventricular arrhythmias. Thus, regular ECG monitoring is advised.

Hypolipidemic drugs with multiple mechanisms (e.g. Nicotinic acid and Gugulipid)

The treatment of hyperlipidemia include a) Nicotinic acid and b) Gugulipid (a drug developed by the Central Drug Research Institute (CDRI) in Lucknow , India.

a) Nicotinic Acid

Nicotinic acid reduces lipolysis in adipose tissues. In addition, it causes

  • direct inhibition of the synthesis and secretion of apo B containing particles by the liver,
  • a reduction in the synthesis of lipoprotein (a) (Lp(a)) (38%),
  • changes in the metabolism of HDL particles.,
  • reductions in triglycerides and cholesterol (20-40%),
  • reductions in VLDL and LDL production (20-35%)
  • elevation of HDL (10-20%)

Due to the many attributes of nicotinic acid (niacin), it is a useful therapeutic agent. However, experience in its use is necessary because numerous acute and chronic side effects can occur. The following side effects have been described for nicotinic acid:

  • Severe flushing and itching after each dose in the first 7-14 days of therapy
  • GI discomfort
  • Dry skin
  • Hyperuricemia (presence of a high concentration of uric acid in the blood)
  • Cholestatsis and impaired liver function

In order to minimize the side effects, therapy is started with low doses. Flushing is characteristic of niacin use, and it can be significantly reduced by premedicating the patient with a low dose of aspirin. Niacin is contraindicated in people with active liver disease, history of peptic ulcer, hyperuricemia and Type II diabetes.

b) Gugulipid

The CDRI (Central Drug Research Institute, Lucknow , India) conducted studies on a standardized, ethyl acetate extract containing guggulsterones Z and E. Gugulipid was evaluated in a large, multicentric, clinical trial (12 weeks) to confirm the efficacy of gugulipid in 245 patients with primary hyperlipidemia in Bombay, Bangalore, Delhi, Jaipur, Lucknow, Nagpur, and Varanasi. A Significant lowering of serum cholesterol and triglycerides was observed in 80% of the patients.

In a double blind, crossover study the effects of gugulipid therapy and clofibrate therapy were compared in 125 and 108 patients, respectively. The hypolipidemic effects observed on cholesterol and triglyceride levels were similar for both therapies. HDL cholesterol levels were significantly elevated in 60% of the gugulipid patients. In contrast, significant elevations were not observed in the clofibrate patients. Significant reductions were also observed in the levels of LDL, ratio of LDL/HDL, and TC/HDL. The hypolipidemic effect provided by gugulipid was evident within 4-8 weeks of therapy, and it persisted throughout the treatment. After withdrawal of gugulipid, a sustained lowering of lipids continued for an average time of 20 weeks.

Gugulipid therapy was successful in treating fifty patients with non-insulin-dependent diabetes mellitus (NIDDM) who controlled their diabetes using oral antidiabetic drugs. The patients were given a washout/diet control period for 8 weeks before receiving gugulipid. Fasting blood glucose levels were maintained below 110 mg/dL and glycosylated hemoglobin (GHbA1C) was maintained between 4-8%. Significant reductions were observed in the levels of serum cholesterol, serum triglycerides, and HDL. LDL levels fell, and a significant reduction of the atherosclerosis risk ratio TC/HDL was also observed. The glycemic status of the patients did not become worse, and gugulipid was also shown to be effective in controlling secondary hyperlipidemia in diabetes.

Unlike many other drug therapies, gugulipid has no significant or major side effects. Except rare, minor gastrointestinal disturbances, such as fullness and dyspepsia, no other side effects have been reported. In addition, it has no teratogenic, fetotoxic, or carcinogenic effects.

"These statements have not been evaluated by the Food and Drug Administration.
This product is not intended to diagnose, cure, or prevent any disease"

 

 

Copyright © Sabinsa Corporation. All Rights Reserved