Lipids Are...

Lipids are blood fats.  Total cholesterol (TC) is carried in the blood by three proteins called lipoproteins: high density lipoproteins (HDL), low density lipoproteins (LDL), and very low density lipoproteins (VLDL).  The fourth major blood lipid is called triglyceride (TG) and this is carried by the VLDL.

            TC = LDL + HDL + 1/5 TG

Think of lipoproteins as various-sized circles.  The biggest and least dense is the VLDL.  LDL are medium-sized and more dense.  The smallest and most dense are HDL.  All three migrate from the blood stream through the artery wall into the lymph system and then return to the liver.  There they are broken down and/or returned to the blood stream for another trip through the arterial system.  The VLDL and the LDL are so big they tend to get trapped in the artery wall, leaving their cholesterol there.  These deposits attract scavenger (clean up) cells called macrophages, which try to eat the cholesterol, and in the process are damaged, along with the smooth muscle cells of the artery wall.  These muscle cells grow, produce excessive connective tissue and die due to lack of oxygen. 

At the same time, the smooth lining cells of the artery (endothelial cells) also become damaged, attracting platelets and macrophages which lead to small blood clots in the damaged area of the artery.  This progressive process leads to the formation of plaque which distorts the inside of the artery wall, causing it to bulge into the blood stream and partially obstruct the artery.  As the artery lumen becomes blocked, the flow of blood is affected and there is an even greater chance of a blood clot in the area.  In contrast to the damage caused by the LDL and VLDL, the HDL migrate easily through the vessel wall.  They pick up the cholesterol deposited there and return it to the liver where it can be excreted as is or be chopped up to make bile salts and then be excreted.

LDL and VLDL are the garbage (cholesterol) dumpers and the HDL is the garbage truck.  If there is more garbage dumped than the truck can hold, then the process of atherosclerosis (hardening of the arteries) is accelerated.  If the LDL and VLDL can be reduced and the HDL increased, then less garbage is dumped and the trucks can cart it away along with some old garbage which has been lying around for years.  As this process continues, enough garbage can be cleared away that the plaque will actually decrease and partial blockage of the artery wall can be reversed.

The higher the LDL, the greater the risk of heart attack. High triglycerides also increase the risk of heart disease and stroke.  On the other hand, HDL protects against heart disease and stroke; the higher the level, the lower the risk.  If triglycerides are above 1,000 mg/dl, there is an increased risk for pancreatitis. 

Lipoprotein (a) is another cholesterol-carrying lipoprotein which dumps cholesterol into the artery wall like LDL, increasing the risk of heart attack and stroke.  When Lipoprotein(a) is elevated, higher than 35, it is very important to lower LDL to less than 100.

Definitions

Homocysteine is an amino acid.  When the level is high, it injures the artery wall and increases the risk of blood clots. High homocysteine can be inherited or it can also be caused by reduced kidney function and by reduced absorption of vitamin B12 with low serum vitamin B12 levels. Rarely, high homocysteine can be caused by low serum folic acid levels.

Insulin is hormone secreted by the pancreas.  Its main function is to regulate carbohydrate, protein and fat metabolism.

Insulin resistance syndrome is an inherited resistance to the action of insulin which causes the pancreas to overproduce insulin.  Symptoms of this condition are high triglycerides, low HDL, obesity, high uric acid, Type II diabetes, high plasminogen activator inhibitor activity (PAI-Fx), and high blood pressure. 

Thrombophilia is a tendency to the occurrence of clotting which could result in a stroke.  Some of the hereditary factors influencing this are four major gene mutations (V Leiden, MTHFR, PTN, A1/A2 platelet glycoprotein), homocysteine, anticardiolipin antibodies, the lupus anticoagulant, protein C and protein S deficiency. 

Hypofibrinolysis is a reduced ability to dissolve blood clots.  Some factors influencing this are Lp(a), PAI-Fx, the 4G/4G polymorphism of the PAI-1 gene, and tissue plasminogen activator.

Causes

High TC, LDL and triglycerides and/or low HDL can be acquired, the result of other diseases, drugs, diet, and excessive alcohol.  Smoking lowers HDL.  High TC, LDL and triglycerides, and low HDL, can also be inherited.  It is important to identify all factors to set up the best possible treatment.

Common Causes of Acquired Lipid Disorders

Inherited lipid disorders in Americans are common in all races and both sexes:

high LDL:	1 in 250
low HDL:	1 in 250
high triglycerides:	1 in 200

The genetic traits appear in men, women and children.  The effects of these traits can occur in people who  follow a good diet, are thin, are non-smoking, don't drink, and do exercise. If there is a family history of heart disease, it is a good idea for all first degree relatives (parents, siblings, children) to have blood drawn for fasting (nothing to eat or drink for 12 hours) lipid profiles.

 

High Risk Indicators: 

• prior heart attack or angina, angioplasty, stent, or bypass

  Or 2 or more of the following:

• heart attack before age 55 in first degree relative
• high LDL
• male
• smoke more than 10 cigarettes per day
• high blood pressure
• low HDL
• diabetes
• peripheral vascular disease
• severe obesity:  greater than 30% over ideal body weight (IBW)

Ratio of Total Cholesterol to HDL:

Triglycerides:

 

Assessment of the Risks of Heart Attack and Stroke

The risks of heart attack or angina (symptomatic reduction of blood flow to the heart) in people with high total and LDL cholesterol, high triglycerides or low HDL-cholesterol,  if not treated are as follows:

• 40% by age 40 years
• 50% by age 50 years     
• 65% by age 60 years
• up to 80% by age 70 years
  

Relationship Between Blood Fats and the Risk of Heart Disease

	Total Cholesterol							LDL Cholesterol							Triglycerides		HDL Cholesterol
	Men			Women				Men				Women			M	W	Men			Women
Age	A	B	C		A	B	C		A	B	C	A	B	C	C	C	C	B	A	C	B	A
0-4	137	151	171		139	156	172		-	-	-	-	-	-	84	96	-	-	-	-	-	-
5-9	143	159	175		146	163	179		80	90	103	88	98	115	85	90	42	49	70	38	47	67
10-14	140	155	173		144	158	174		81	94	109	81	94	110	102	114	40	46	71	40	45	64
15-19	132	146	165		140	155	172		80	93	109	78	93	111	120	114	34	39	59	38	43	68
20-24	146	165	186		149	170	190		85	101	118	82	102	118	165	141	32	38	57	37	44	72
25-29	159	178	202		155	173	193		96	116	138	90	108	126	199	142	32	37	58	39	47	74
30-34	167	190	213		158	176	196		107	124	144	91	109	128	213	146	32	38	59	40	46	73
35-39	176	197	223		164	183	205		110	131	154	96	116	139	251	160	31	36	58	38	44	74
40-44	182	203	228		171	192	215		115	135	157	104	122	146	248	170	31	36	60	39	48	79
45-49	188	210	234		178	201	226		120	141	163	105	127	150	253	184	33	38	60	41	47	82
50-54	187	210	235		192	215	240		118	143	162	111	134	160	250	192	31	36	58	41	50	84
55-59	189	212	235		200	223	248		123	145	168	120	145	168	235	203	31	38	64	41	50	85
60-64	188	210	235		202	226	252		121	143	165	126	149	168	235	201	34	41	69	44	51	87
65-69	190	210	233		205	226	252		125	146	170	125	151	184	208	203	33	39	74	38	49	85
70+E	182	205	229		199	224	251		119	142	164	127	147	170	212	203	33	40	70	38	48	82

Total Cholesterol and LDL:

• Best to have values in column A
• Good in column B
• Increased risk of coronary heart disease in column C
• >C has substantially increased risk of coronary heart disease and atherosclerosis

Triglycerides:

• Reasonable to have values in column C
• >C has increased risk for heart disease and pancreatitis

 HDL-C:

• Best to have values in column A
• <C and B has an increased risk for coronary heart disease

Targets:

In order to determine your risk of heart attack, stroke, and thrombosis, we measure most of these variables with the following targets: 

• TC (total cholesterol) :  less than 200 mg/dl
• LDL
  • less than 130 mg/dl with no previous coronary heart disease
  • less than 100 mg/dl with previous coronary heart disease or if one of the following is  present:
    • Lp(a) greater than or equal to 35 mg/dl, homocysteine greater than 13.1
    • diabetes mellitus
    • hypertension           
    • cigarette smoking
• HDL:  greater than 35 mg/dl
• Triglyceride:  less than 250 mg/dl
• Lp(a): less than 35 mg/dl
• Homocysteine: less than 13.1 umol/L
• Methylmalonic Acid:  less than 250 nmol/l
• Anticardiolipin Antibodies*: IgG  less than 22 units and IgM less than 10 units.
• The Lupus Anticoagulant* (this is measured only rarely):  Negative

*These are antibodies which can increase the risk of blood clots in the arteries and  veins.

Treatment

Lipid-Lowering Drugs

1. The statin drugs block the synthesis of most cholesterol within the liver cells.  The liver cells  then have to synthesize more receptors to pull LDL out of the blood.  These are the most  potent single LDL cholesterol-lowering drugs, and are often used alone, or in combination  with the bile acid binding resins, or rarely, with nicotinic acid.  This class drug has little  effect on triglycerides, and little if any increase in HDL.

2. Bile acid binding resins force the excretion of bile acids from the gut thus lowering cholesterol.  These drugs primarily lower LDL, may slightly elevate HDL, and occasionally elevate triglyceride levels.

3. Nicotinic acid blocks the synthesis of cholesterol and cholesterol precursors in the liver, and  also reduces the synthesis of triglycerides in the liver.  This drug reduces LDL, increases HDL, and reduces triglyceride levels. It is rarely used alone to lower LDL, and is often  used along with bile acids and/or Lovastatin.

4. Gemfibrozil and Fenofibrate reduce the synthesis of triglyceride in the liver and also increases  the catabolism (chopping up) of triglycerides in the periphery.

5. Fish oils increase the catabolism of triglycerides in the periphery, may slightly reduce synthesis  of cholesterol in the liver.  The fish oils are useful in lowering triglyceride levels, may  elevate HDL, and may slightly lower LDL.

Interventions to lower triglyceride levels:

1. Triglyceride greater than 1,000 mg/dl: 

Dangerous; high risk of pancreatitis, venous and arterial blood clots, acute heart attack and stroke.  Requires immediate intervention with:

• fat-free diet (less than 5% of calories as fat)
• alcohol-free diet
• medications:
  • Lopid 1.5 g/day or Fenofibrate 200-300 mg/day
  • omega-3 fatty acids (8-12g/day)
  • control of secondary factors (alcohol, estrogen replacement therapy, corticosteroids)

2. Triglyceride 750-1,000 mg/dl: 

Dangerous; requires immediate intervention with

• low fat diet (less than 20% of calories as fat)
• alcohol-free diet
• medications:
  • Lopid 1.2 g/day or Fenofibrate 200-300 mg/day
  • omega-3 fatty acids (4-8 g/day)
• control of secondary factors  

3. Triglyceride 500-750 mg/dl: 

Requires intervention with

• low fat diet (less than 25% of calories)
• alcohol-free diet
• medications
  • Lopid 1.2 g/day or Fenofibrate 200-300 mg/day
  • omega-3 fatty acids (4-6g/day)
• control of secondary factors

4. Triglyceride 250-500 mg/dl: 

Requires intervention with

• diet and, if values do not fall below 250 mg/dl on diet alone
• medications: 
  • Lopid 1.2 g/day or Fenofibrate 200-300 mg/day
  • Lipitor 10-40 mg/day, or Zocor 10-40 mg/day if LDL is greater than 130 mg/dl
  • omega-3 fatty acids (2-4 g/day)
• control of secondary factors

General Comment:

Weight loss, avoidance of alcohol, and tight control of diabetes (fasting blood sugar less than 130, Hemoglobin AIC less than 7.1) are very important in control of high plasma triglycerides.

Interventions to raise HDL cholesterol levels

Lifestyle changes:

• stop smoking
• weight loss
• tight control of diabetes (fasting blood glucose less than 130 mg/dl, Hemoglobin AIC less than 7.1%)
• increased aerobic exercise (usually requires 5 sessions/week, 30 minutes/session).

Medications:

• Gemfibrozil 1.2 g/day
• micronized Fenofibrate 200 mg/day
• NiaSpan 1.5 g/day.

If that doesn't work:

• vigorous lowering of LDL cholesterol with statin drugs will improve the ratio of total cholesterol/HDL and reduce coronary heart disease events.

Treatment for Homocysteine Levels

• folic acid (by prescription) the usual dose is 5 mg a day
• B ₆ (pyridoxine) usual dose of 100 mg a day
• B ₁₂  usual dose is 1000 micrograms per day (if methylmalonic acid is less than 250)
• Have blood drawn after one month on the vitamins to be sure serum vitamin B₁₂ and folic acid levels are normal.

Treatment for Methylmalonic Acid Levels

• B₁₂  dose of 1000 micrograms per day
• measurement of serum vitamin B₁₂ and folic acid after 1 month on therapy to be sure that serum vitamin B₁₂ levels are normal
• in those patients whose serum B ₁₂ levels stay low even on the oral vitamin, monthly injections of the vitamin may be necessary        

Treatment for Insulin Resistance

• Metformin in doses of 500 or 850 mg three times a day

This is a very exciting time in the diagnosis and treatment of lipid disorders.  Sophisticated diagnosis followed by diet and drug therapy (as needed) can not only normalize blood lipid levels, but put them in the range of reversing atherosclerosis.

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Jewish Hospital Cholesterol Center, Charles J. Glueck MD, Director, James E. Lang MD, Associate Director, LeAnn Coberly MD Assistant Medical Director. Jewish Hospital Cholesterol Center, 3200 Burnet Ave, Cincinnati, Ohio 45229. 

E-mail: glueckch@healthall.com
or cglueck@fuse.net
Fax: 513-585-7950