Hyperlipidemia

What is hyperlipidemia?

• Lipoprotein lipase is located in the endothelium of adipose and muscle capillaries, this enzyme is responsible for the release of free fatty acids from both VLDLs and chylomicrons. It is inhibited by Apo CIII and activated by Apo CII. Lipoprotein lipase is responsible for the breakdown of triglycerides to free fatty acids. The process does not require insulin, unlike the uptake of free fatty acids into muscle or adipose tissue. MTP is involved in Apo B assembly. LCAT esterifies free cholesterol into hydrophobic cholesterol esters that move into the center of HDL particles. Cubulin is the Apo AI receptor responsible for renal clearance of HDL.

• Although most hepatic receptors for triglyceride-rich lipoproteins will recognize Apo E, allowing clearance though the liver, Apo B100 is required for LDL binding to its receptor in the liver. Mutations within the gene for this lipoprotein can cause a form of familial hypercholesterolemia. Most VLDL and IDL also contain Apo E, as well as Apo B100. It is only LDL that is dependent on Apo B100 for hepatic uptake secondary to its lack of Apo E.
• Epidemiological and clinical studies provide evidence that HDL-C levels are linked to rates of coronary events. The cardioprotective effects of HDL-C have been attributed to its role in reverse cholesterol transport. The cardioprotective effects of HDL-C have been attributed to its effect on endothelial cells and its antioxidant activity. Low HDL-C is caused by cigarette smoking, very high carbohydrate intake, and the use of certain drugs (e.g., progestational agents, anabolic steroids). Low HDL-C is one of five major CHD risk factors. HDL-C level is a component of the Framingham scoring system, the method used to estimate 10-year CHD risk and to determine the intensity of lipid lowering therapy. While the new guidelines do emphasize the importance of HDL in the management of hyperlipidemia, they have not set specific targets at this time because we do not yet have appropriate data from a large randomized controlled trial.

Case I: A 35-year-old African American male presents to your office for follow up on his free cholesterol screening that he received at the mall this past weekend. He is a nonsmoker who takes no medication and reports that he has been relatively healthy for his entire life except for occasional flares of gout. He has a grandfather who had an MI at 60. He exercises with a trainer four times per week and appears to be in good physical shape.

Total Cholesterol	151
Triglycerides	130
HDL-C	25
LDL-C	100

Based on current studies, which therapy would most benefit your patient at this time?

Answer: With a statin you can expect to raise the HDL-C by 5-15%.

Based on the current guidelines, this patient’s LDL is at/below goal. The most obvious abnormality in his profile is the markedly low HDL. Initiating therapeutic lifestyle changes that incorporate weight loss and increased physical activity would be the first step taken to raise HDL; however, this particular patient is already exercising on a regular basis. His goal HDL is 50, which may be unobtainable. Normally, trying to raise HDL via drug therapy, niacin and statins are usually excellent choices. In this particular patient, however, niacin would not be the best choice, as it tends to exacerbate gout.

Case II: A 31-year-old man seeks medical advice after his older brother survives a myocardial infarction. He has no medical history, does not smoke or drink alcohol. His BP is 130/85. He has corneal arcus and an Achilles tendon xanthoma. His lipid profile shows total cholesterol of 300 mg/dL with an LDL-C of 240 mg/dL and an HDL of 40 mg/dL. Which phenotypical lipid disorder is this patient expressing?

Answer: Type II hyperlipidemia or familial hypercholesterolemia is due to defects in LDL uptake into the liver secondary to problems with the LDL receptor. Heterozygotes have a prevalence of 1:500 and manifest coronary disease by the 4th decade. Xanthomas, a positive family history, and elevated LDL make the diagnosis.

Case III: A 45-year-old man is seeking treatment for his elevated cholesterol found at a free health fair. He is asymptomatic and has no physical signs of hypercholesterolemia such as corneal arcus or xanthomas. His fasting cholesterol profile shows a total cholesterol of 220 mg/dL, triglycerides 400 mg/dL, LDL 100 mg/dL and HDL 40 mg/dL. A postprandial triglyceride level is 1000 mg/dL. You suspect that he has familial hypertriglyceridemia (Type IV hyperlipoproteinemia). The metabolic defect responsible for his condition is?

Answer: Increased hepatic production of VLDL. Decreased LDL receptors cause Type II hyperlipidemia or familial hypercholesterolemia. Abnormal Apo B100 causes a phenotype indistinguishable from familial hypercholesterolemia. Decreased LPL activity causes familial hyperchylomicronemia. Abnormal Apo E is the metabolic defect in Type III hyperlipoproteinemia.

• Although familial combined hyperlipidemia has been defined in the laboratory as a total cholesterol greater than the 90th percentile and/or a plasma triglyceride level greater than the 90th percentile, both adjusted for age and gender, these cutpoints could miss up to 25% of affected patients. Apolipoprotein B markers can be added to total cholesterol or triglyceride levels to better predict familial combined hyperlipidemia. Apo B levels greater than 1200 mg/dL greatly increase the likelihood of familial combined hyperlipidemia in patients with elevated triglycerides (>1.5 mmol/L) or total cholesterol (>6 mmol/L).

Case IV: A 42-year-old female consults you for advise on staying healthy. She exercises daily and has never had any symptoms of heart disease. She has never smoked. Her father died of a massive myocardial infarction at the age of 44. She has been treated for hypertension over the last five years with an angiotensin converting enzyme inhibitor (ACE) and says that her BP is usually 140/88. Her total serum cholesterol is 220 mg/dl and her HDL-C is 30.

You order a complete fasting lipid profile and the results come back as follows:

Total Cholesterol	230 mg/dl
Triglycerides	455 mg/dl
HDL-C	34 mg/dl

Calculate the patient’s LDL-C?

Answer: You are unable to calculate it given the current information because the formula for the calculation of LDL-C:LDL-C = Total Cholesterol – HDL-C – (Triglycerides/5)

P.S. ATP III guidelines suggest for individuals who have 2+ risk factors that their LDL-C goal is <130 mg/dl. Her LDL-C goal is supposed to be <130 mg/dl.

Let’s just say her LDL-C is 165 mg/dl. Can we recommend her  a treatment based on the data provided? Nope because the ATP III guidelines state that the treatment to achieve the LDL-C goals in patients with 2+ risk factors should not only be based on the LDL-C levels but should also be further modified by the Framingham 10-year CHD Risk Calculation for these individuals.

Treatment Guide:

I.	Raises HDL-C, lowers both LDL-C and triglycerides. No large randomized control trials have been reported for its use in isolated low HDL-C patients	Niacin
II-	Can raise HDL-C by 10-20%, modestly lower LDL-C and substantially lower triglycerides. Absolutely contraindicated in patients with severe renal or hepatic disease	Fibrates
III-	Apo-I Milano administreted weekly to 123 patients via IV infusion post ACS demonstrated a 1.06% decrease in atheroma volume as evaluated by intravascular ultrasound at five weeks.	Exogenous HDL Mimetic
IV-	Recommended by ATP III and the treatment of choice by raising HDL especially in patients with the metabolic syndrome.	Increased physical activity.
V-	Effectively lower LDL-C while mildly increasing HDL and decreasing triglycerides minimally. They are contraindicated in patients with active liver disease.	Statins

Case V:

A 34-year-old obese male with a history of hypertension presents to your office for his first visit. He has a strong family history of CAD and currently has cut back to smoking two cigarettes a day. He is currently on no lipid lowering medications:

Total Cholesterol	200 mg/dl
Triglycerides	205 mg/dl
HDL-C	40 mg/dl
LDL-C	119 mg/dl

Answer: You initiate TLC(Therapeutic Lifestyle Changes), together with close follow up, are the initial steps in the treatment of moderate risk patients.

The patients returns for follow/up four months later and states that he has been watching his diet and that he now exercises three times per week. His laboratory work is listed below:

Total Cholesterol	195 mg/dl
Triglycerides	200 mg/dl
HDL-C	42 mg/dl
LDL-C	113 mg/dl

See, this time TLC didn’t help. We need to treat him with low dose statin. Based on the updated ATP III guidelines, this patient is considered to be in the moderate risk category (2+ risk factors and a 10-year risk of 10-20%). The new guidelines state that his LDL-C should be below 130 mg/dl and they give you the therapeutic option to lower it to treat the LDL-C to <100 mg/dl when the initial untreated measurements are between 100 and 129 mg/dl.

Pro tip: -hs-CRP- (high-sensitivity CRP): Elevated hs-CRP levels have been demonstrated to be effective in predicting the development of hypertension and a good predictor of incident type 2 diabetes and add prognostic values on vascular risk at all levels of the metabolic syndrome. hs-CRP levels can effectively be lowered with “statin” therapy. hs-CRP continues to evolve as a major risk de facto marker for CHD. In addition, it has emerged as a predictor of disease progression in many of the comorbidities associated with CHD: hypertension, type 2 diabetes mellitus. It has been demonstrated that hs-CRP can be reduced with statins and other antinflammatory agents.

Hyperlipidemia and Risks

• CD40 ligand is a proinflammatory mediator that plays a crucial role in the pathogenesis of the acute coronary syndrome and has been shown to be elevated in patients with unstable coronary syndromes. In the MIRACL patient population, soluble CD40 ligand (sCD40L) was measured at baseline and at 16 weeks. Patients with an elevated sCD40L >90th centile compared to patients with a sCD40L <90th centile had an odds ratio of 1.86 for a recurrent event. Treatment with atorvastatin abolished this increased risk, it appears that only a high level of sCD40L is associated with increased cardiovascular risk. Even in the >90th centile patient group, event rates with atorvastatin treatment were similar to the <90th centile group. In addition, in the patient group with sCD40L <90th centile, treatment with atorvastatin was not associated with any decrease in event rate. This may allow selection of high-risk patients in whom early intensive statin therapy would decrease event rates.
• Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family that act as transcription factors involved in the regulation of several metabolic pathways that may influence cardiovascular risk. PPARs have three types. PPAR-alpha was the first discovered and controls target genes such as HMG-CoA-synthetase, Apo A1 and Apo-CIII. It is also the target for the fibric acid derivatives, gemfibrozil and fenofibrate. It was shown in PPAR-alpha deficient mice that the agonist of PPAR-alpha did not lower triglyceride levels. PPAR-gamma regulates the expression of acyl-CoA-synthetase, lipoprotein lipase and fatty acid binding protein. It is the target for the thiazolidione class of antidiabetic drugs. Its over-expression can drive the differentiation of fibroblasts to an adipocyte-like phenotype. Another activator of PPAR-gamma is oxidized linoleic acid, a component of oxidized LDL. This is one potential mechanism for the deleterious effects of oxidized LDL on plaque stability. With the changing of a fibroblast to an adipocyte-like phenotype, the “fibrous” cap is more susceptible to rupture.

Those information provided was for my healthcare colleagues and now, dumbing it down for the rest of you:

Wud, wud, wud? Hyperlipidemia is an elevation of lipids in the bloodstream, cholesterol, cholesterol esters, estersphospholipids and triglycerides.

Causes? Primary and secondary, primary causes: heredity and taking certain medications, however the greatest risk factor is a poor diet, with a fat intake >49% of total calories, saturated fat intake >10% of total calories and cholesterol intake >300 mg/day. Secondary causes may be a clue to the presence of an underlying systemic disorder. A convenient way to recognize secondary causes is to think of the four Ds(diet, drugs, disorders of metabolism, diseases). For example, hypothyroidism is the most common secondary cause of hyperlipidemia, also pregnancy, alcohol, estrogens, steroids.

Symptoms? No symptoms. Regular cholesterol screening with blood tests should be part of your life.

Treatment? As I mentioned above, TLC – Therapeutic Lifestyle Changes. Dietary and lifestyle modification, followed by drug therapy(which I gave details above above), if necessary.

Preventation: Exercise 3 times/week and watch your fat intake.

Have a great week. Happy early Thanksgiving!

Would you mind checking out this website and donate to the Haiti Cholera Children in Emergency Fund to support Save the Children’s response to the deadly cholera outbreak in Haiti? Thanks in advance.

https://secure.savethechildren.org/site/c.8rKLIXMGIpI4E/b.6238941/k.E6AE/Support_the_Haiti_Cholera_Children_in_Emergency_Fund/apps/ka/sd/donor.asp?c=8rKLIXMGIpI4E&b=6238941&en=cvINK3PLLbLWJdNOIaLSIfM5IvL5KcPWKmKZKgMZLnJUIfPaG