Dyslipidemia

The Management of Hypertension (Clinical Evaluation)

September 12, 2015 Cardiology, Diabetes, Infectious Diseases, Pharmacotherapy, Therapeutics No comments , , , , , , , ,

Frequently, the only sign of essential hypertension is elevated BP. The rest of the physical examination may be completely normal. However, a complete medical evaluation including a comprehensive medical history, physical examination, and laboratory and/or diagnostic test is recommended after diagnosis to identify secondary causes, identify other CV risk factors or comorbid conditions that may define prognosis and/or guide therapy, and assess for the presence of absence of hypertension-associated target-organ damage.

For the patients who have been diagnosed with hypertension, we should ask a few questions that are necessary to make a clinical evaluation for these patients. Here is an example of a patient with hypertension.

D.C. is a 44-year-old black man who presents to his primary care provider concerned about high BP. At an employee health screening last month he was told he has stage 1 hypertension. His medical history is significant for allergic rhinitis. His BP was 144/84 and 146/86 mm Hg last year during an employee health screening at work. D.C.’s father had hypertension and died of an MI at age 54. His mother had diabetes and hypertension and died of a stroke at age 68. D.C. smokes on pack per day of cigarettes and thinks his BP is high because of job-related stress. He does not engage in any regular exercise and does not restrict his diet in any way, although he knows he should lose weight.

Physical examination show he is 175 cm tall, weighs 108 kg (BMI, 35.2 kg/m2), BP is 148/88 mm Hg (left arm) and 146/86 mm Hg (right arm) while sitting, heart rate is 80 beats/minute. Six months ago, his BP values were 152/88 mm Hg and 150/84 mm Hg when he was seen by his primary-care provider for allergic rhinitis. Funduscopic examination reveals mild arterial narrowing and arteriovenous nicking, with no exudates or hemorrhages. The other physical examination findings are essentially normal.

D.C.’s fasting laboratory serum values are as follows:

Blood urea nitrogen, 24 mg/dL

Creatinine, 1.0 mg/dL

Glucose, 105 mg/dL (Fasting?)

Potassium, 4.4 mEq/L

Uric acid, 6.5 mg/dL

Total cholesterol, 196 mg/dL

Low-density lipoprotein cholesterol, 141 mg/dL

High-density lipoprotein cholesterol, 32 mg/dL

Triglycerides, 170 mg/dL

An electrocardiogram is normal except for left ventricular hypertrophy.

PS: Normal values are marked in green and abnormal values are marked in orange.


Clinical Presentation

Question 1 What is the clinical presentation D.C.?

All the information above could be the part of D.C.’s clinical presentation. Besides, we could classify the stage of D.C.’s hypertension as shown below.

D.C. has uncontrolled stage 1 hypertension. He has had elevated BP values, measured in clinical environments, and meets the diagnostic criteria for hypertension because two or more of his BP measurements are elevated on separate days. SBP values are consistently stage 1, whereas DBP values are all in the prehypertension range. The higher of the two classifications is used to classify hypertension.

Question 2 Why does D.C. have hypertension?

D.C. has essential hypertension; therefore, the exact cause is not known. He has several characteristics (e.g., family history of hypertension, obesity) that may have increased his chance of developing hypertension. Race and sex also influence the prevalence of hypertension Across all age groups, black have a higher prevalence of hypertension than do whites and Hispanics. Similar to other form of CV disease, hypertension is more server, more like to include hypertension-associated complications, and occurs at an earlier age in black patients.


Patient Evaluation and Risk Assessment

The presence of absence of hypertension-associated complications as well as other major CV risk factors (Table 14-5) must be assessed in D.C. Also, secondary cause of hypertension (Table 14-3), if suggested by history and clinical examination findings, should be identified and managed accordingly. The presence of concomitant medical conditions (e.g., diabetes) should be assessed, and lifestyle habits should be evaluated so that they can be used to guide therapy.

  • Hypertension-associated complications
  • Secondary causes of hypertension
  • Concomitant medical conditions

Question 3 Dose D.C. has secondary cause of hypertension?

The most common secondary causes of hypertension are list in Table 3-1. Patients with secondary hypertension might have signs or symptoms suggestive of the underlying disorders.

Table 3-1 Secondary Causes of Hypertension.

  • Patients with pheochromocytoma may have a history of paroxysmal headaches, sweating, tachycardia, and palpitations. Over half of these patients suffer from episodes of orthostatic hypotension.
  • In primary hyperaldosteronism symptoms related to hypokalemia usually include muscle cramps and muscle weakness.
  • Patients with Cushing’s syndrome may complain of weight gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscle weakness and have several classic physical features (e.g., moon face, buffalo hump, hirsutism).
  • Patient with coarctation of the aorta may have higher BP in the arms than in legs and diminished or even absent femoral pulses.
  • Patient with renal artery stenosis may have an abdominal systolic-diastolic bruit.

Also, routine laboratory tests may also help identify secondary hypertension. For example, Baseline hypokalemia may suggest mineralocorticoid-induced hypertension. Protein, red blood cells, and casts in the urine may indicate renovascular disease. Some laboratory tests are used specifically to diagnose secondary hypertension. These include plasma norepinephrine and urinary metanephrine for pheochromocytoma, plasma and urinary aldosterone concentrations for primary hyperaldosteronism, and plasma rennin activity, captopril stimulation test, renal vein renin, and renal artery angiography for renoascular disease.

Certain drugs and other products can result in drug-induced hypertension. For some patients, the addition of these agents can be the cause of elevated BP or can exacerbate underlying hypertension. Identify a temporal relationship between starting the suspected agent and developing elevated BP is most suggestive of drug-induced BP elevation.

Question 4 Which hypertension-associated complications are present in D.C.?

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A complete physical examination to evaluate hypertension-associated complications includes examination of the optic funds; auscultation for carotid, abdominal, and femoral bruits; palpation of the thyroid gland; heart and lung examination; abdominal examination for enlarged kidney, masses, and abnormal aortic pulsation; lower extremity palpation for edema and pulses; and neurologic assessment. Routine laboratory assessment after diagnosis should include the following: EKG; urinalysis; fasting glucose; hematocrit; serum potassium, creatinine, and calcium; and fasting lipid panel. Optional testing may include measurement of urinary albumin excretion or albumin-to-creatinine ratio, or additional tests specific for secondary causes if suspected.

Question 5 What other forms of hypertension-associated complications is D.C. at risk for?

Hypertension adversely affects many organ systems, including the heart, brain, kidneys, peripheral circulation, and eyes (Table 14-5). Damage to these systems resulting from hypertension is termed hypertension-associated complications, target-organ damage, or CV disease. There are often misconceptions about the term CV disease and CAD. CV disease encompasses the broad scope of all forms of hypertension-associated complications. CAD is simply a subset of CV disease and refers specifically to disease related to the coronary vasculature, including ischemic heart disease and MI.

Hypertension can affect the heart either indirectly, by promoting atherosclerotic changes, or directly, via pressure-related effects. Hypertension can promote CV disease and increase the risk for ischemic events, such as angina and MI. Antihypertensive therapy has been shown to reduce the risk of these coronary events. Hypertension also promotes the development of LVH, which is a myocardial (cellular) change, not an arterial change. These two conditions often coexist, however. It is commonly believed that LVH is a compensatory mechanism of the heart in response to the increased resistance caused by elevated BP (more accurately, the afterload). Recall the definition of afterload, that is, wall tension=(pressure * radius)/(wall thickness). LVH is a strong and independent risk factor for CAD, left ventricular dysfunction, and arrhythmia. LVH does not indicate the presence of left ventricular dysfunction, but is a risk for progression to left ventricular dysfunction, which is considered a hypertension-associated complication. This may be caused by ischemia, excessive LVH, or pressure overload. Ultimately, left ventricular dysfunction results in a decrease ability to contract (systolic dysfunction).

Hypertension is one of the most frequent causes of cerebrovascular disease. Cerebrovascular signs can manifest as transient ischemic attacks, ischemic strokes, multiple cerebral infarcts, and hemorrhages. Residual functional deficits caused by stroke are among the most devastating forms of hypertension-associated complications. Clinical trials have demonstrated that antihypertensive therapy can significantly reduce the risk of both initial and recurrent stroke. A sudden, prolonged increase in BP also can cause hypertensive encephalopathy, which is classified as a hypertensive emergency.

The GFR is used to estimate kidney function, which declines with aging. This rate of decline is greatly accelerated by hypertension. Hypertension is associated with nephrosclerosis, which is caused by increased intraglomerular pressure. It is unknown whether a primary kidney lesion with ischemia causes systemic hypertension or whether systemic hypertension directly causes glomerular capillary damage by increasing intraglomerular pressure. Regardless, CKD, whether mild or severe, can progress to kidney failure (stage 5 CKD) and the need for dialysis. Studies have demonstrated that controlling hypertension is the most important strategy to slow the rate of kidney function decline, but it may not be entirely effective in slowing the progression of renal impairment in all patients.

In hypertension, stage 3 CKD or worse is considered a hypertension-associated complication (GFR values of <60 mL/min/1.73 m2). An estimated GFR of less than 60 mL/min/1.73 m2 corresponds approximately to a serum concentration of greater than 1.5 mg/dL in an average man and greater than 1.3 mg/dL in an average woman. This level of kidney compromise lowers an individual’s BP goal to less than 130/80 mm Hg according to multiple guidelines. The presence of persistent albuminuria (>300 mg albumin in a 24-hour urine collection or 200 mg albumin/g creatinine on a spot urine measurement) also indicates significant CKD, for which achieving the more aggressive BP goal is a strategy to minimize the rate of progression to kidney failure.

Peripheral arterial disease, a non coronary form of atherosclerotic vascular disease, is considered a hypertension-associated complication. It is equivalent in CV risk to CHD. Risk factor reduction, BP control, and anti platelet agent(s) are needed to decrease progression. Complications of peripheral arterial disease can include infection and necrosis, which in some cases require revascularization procedures or extremity amputation.

Hypertension causes retinopathies that can progress to blindness. Retinopathy is evaluated according to the Keith, Wagener, and Barker funduscopic classification system. Grade 1 is characterized by narrowing of the arterial diameter, indicating vasoconstriction. Arteriovenous nicking is the hallmark of grade 2, indicating atherosclerosis. Longstanding, untreated hypertension can cause cotton wool exudates and flame hemorrhages (grade 3). In severe cases, papilledema occurs, and this is classified as grade 4.

Question 6 Which major CV risk factors are present in D.C.?

As shown in Table 14-5, major CV risk factors include advanced age (>55 years for men, >65 years for women), cigarette smoking, diabetes mellitus, dyslipidemia, family history of premature atherosclerotic vascular disease (men <55 years or women <65 years) in primary relatives, hypertension, kidney disease (microablubuminuria or estimated GFR <60 mL/min/1.73 m2), obesity (BMI >=30 kg/m2), and physical inactivity.

PS: Estimated GFR calculated from online calculator for D.C. is 105 mL/min/1.73 m(online calculator: http://www.davita.com/gfr-calculator/).

So according to D.C.’s clinical presentation, he has major CV risk factors that are marked in orange, that is, 5 factors in total, including the essential hypertension.

Question 7 What is D.C.’s BP goal and how can Framingham risk scoring influence BP goal determination?

D.C. is a primary prevention patient because he does not yet have any hypertension-associated compilations (or compelling indications). He has multiple CV risk factors, so controlling his BP is of paramount importance to reduce the risk of developing hypertension-associated complications. The JNC-8 guidelines recommend the initial BP goal for hypertension patients with age of <60 years should be 140/90 mm Hg, which has grade A evidence (strong recommendation) for patients from 30 through 59 years of age, and grade E (expert opinion) for those from 18 through 29 years of age. So D.C.’s initial BP goal should be below 140/90 mm Hg.

The framingham risk scoring system is available as an online calculator at NIH site of http://cvdrisk.nhlbi.nih.gov/calculator.asp. According to D.C.’s clinical presentation, he will has a CV risk of  14% in a next 10-year period of expectation before we intervention, which means in a population cohort such as D.C., 14 in 100 individuals will develop CV diseases after a period of 10-year, if we don’t treat these CV risk factors (if these risk factors worsen, the incidence of developing CV diseases would be higher). If we treat D.C.’s current hypertension target the BP goal, with other interventions that target D.C.’s rest risk factors like habit of smoking, etc., the incidence of developing CV diseases would be attenuated (In D.C.’s example, the incidence would decrease to 5%, that is 5 in 100 of individuals will develop CV diseases in a period of 10-year). Compare the results without/with interventions to D.C.

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The intervention above does not include the management of dyslipidemia. According to the latest AHA guideline, four types of patients need the intervention for dyslipidemia, including: 1.secondary prevention in individuals with clinical ASCVD; 2. primary prevention in individuals with primary elevations of LDL-C >=190 mg/dL; 3.primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL; and 4.primary prevention in individual without diabetes and with estimated 10-year ASCVD risk>=7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL. (References: http://www.tomhsiung.com/wordpress/2014/07/the-management-of-dyslipidemia/). So we need to calculate D.C.’s ASCVD risk from another tool developed by ACC/AHA (American College of Cardiology/American Heart Association), which is available as iOs apps. So the result of ASCVD risk of D.C. is 9.7% (>=7.5%) without any intervention, whereas ASCVD risk is 8.6% (still >=7.5%) with interventions of antihypertensive therapy and smoke cessation. Therefore, the dyslipidemia should be treated for D.C.

PS: ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin.

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The Management of Dyslipidemia

July 26, 2014 Cardiology, Diabetes, Pharmacotherapy, Pharmacy Education, Therapeutics No comments , , ,

Let's talk about ATP IV first, then we shall discuss how to detect, evaluate, and manage patients with lipid disorders.

This thread is based on the latest clinical guideline (Circulation. 2014:S1-S45) for therapy of dyslipidemia to reduce atherosclerotic cardiovascular risk in adults (>21 years of age) and the guideline is based on the Full Panel Report. Because RCT data were used to identify those most likely to benefit from cholesterol-lowering statin therapy, the recommendations will be of value to primary care clinicians as well as specialists concerned with ASCVD prevention.

These recommendations in the guideline are intended to provide a strong, evidence-based foundation for the treatment of cholesterol for the primary and secondary prevention of ASCVD in women and men. Of note, to manage the patients with dyslipidemia successfully and appropriately, besides the guideline clinicians should also know the detection, evaluation, and treatment of lipid disorders of these patients, with strategies for each specific individual.

Basically, the latest guideline or ATP IV is quite different from any previous guidelines such as ATP III. The latest ATP IV guideline only focus on the treatment of dyslipidemia to reduce risk of ASCVD, based on evidence-based medicine, RCTs.

PS: ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin.

In the figure on the left are new changes in ATP IV guideline. Here we shall keep in mind for those ones:

1.This guideline is based on a comprehensive set of data from RCTs from which 4 statin benefit groups were identify that focus efforts to reduce ASCVD event in secondary and primary prevention;

2.This guideline identifies high-intensity and moderate-intensity statin therapy for use in secondary and primary prevention;

3. The Expert Panel was unable to find RCT evidence to support continued use of specific LDL-C or non-HDL-C treatment target;(For secondary prevention the Expert Panel reviewed 19 RCTs to answer the question of specific LDL-C and non-HDL-C targets. No data were identified for treatment or titration to a specific LDL-C goal in adults with clinical ASCVD since no any RCTs compared 2 LDL-C treatment targets [<100 mg/dL or <70 mg/dL]. For primary prevention the Expert Panel reviewed 6 RCTs but did not find any RCTs that evaluated titration of all individuals in a treatment group to specific LDL-C targets <100 mg/dL or <70 mg/dL)

4.Nonstatin therapies, as compared with statin therapy, do not provide acceptable ASCVD risk-reduction benefits relative to their potential for adverse effects in the routine prevention of ASCVD. For safety of nonstatin please refer to the thread here http://forum.tomhsiung.com/pharmacotherapy/465-atp-4-guideline-for-dyslipidemia.html

There are more updates in ATP IV guideline. They are listed at left side.


The Management of Lipid Disorders

Detection

All adults older than age 20 year should have plasma levels of cholesterol, triglyceride, LDL-C, and HDL-C measured after a 12-hour overnight fast, at least once every five years. If the profile is obtained in the nonfasted state, only total cholesterol and HDL-C will be usable because LDL-C is usually a calculated value. If total cholesterol is >=200 mg/dL, or if HDL-C is <40 mg/dL, a followup fasting lipoprotein profile should be obtained.

Patient Evaluation

After a lipid abnormality is confirmed, we shall try efforts to define the category of the lipid disorder and to rule out any possible secondary causes of the hyperlipidemia. The Fredrickson classfication can be helpful in this regard.

Thereafter, major components of the evaluation are the history, physical examination, and laboratory investigations. A complete history and physical exam should assess:

(1) presence or absence of cardiovascular risk factors or definite cardiovascular disease in the individual; Major risk factors for ASCVD include: Age >=45 years (male) or>=55 years or premature menopause without estrogen replacement (female); High total choesterol; Low HDL-C; Hypertension, or use of antihypertensive therapy; Diabetes; Current smoking.

Additional factors contributing to ASCVD risk including: Family history of premature CHD (definite myocardial infarction or sudden death before 55 years of age in father or other male first-degree relative, or before 65 years of age in mother or other female first-degree relative); Primary LDL-C >=160 mg/dL or other evidence of genetic hyperlipidemias; High-sensitivity C-reactive protein >=2 mg/L, coronary artery calcium score >=300 Agatston units or >=75th percentile for age, sex, and ethnicity; Ankle-brachial index <0.9; or Elevated lifetime risk of ASCVD (see in following text).

(2) family history of premature cardiovascular disease or lipid disorders;

(3) presence or absence of secondary causes of lipid abnormalities, including concurrent medications (see http://forum.tomhsiung.com/physiology-and-pathophysiology/471-the-secondary-causes-of-dyslipidemia.html);

(4) presence or absence of xanthomas or abdominal pain, or history of pancreatitis, renal or liver disease, peripheral vascular disease, abdominal aortic aneurysm, or cerebral vascular disease (carotid bruits, stroke, or transient ischemic attack).

(5) baseline lab value such as fasting lipid profile, liver function, renal function, and creatine kinase;

(6) history of previous statin intolerance or muscle disorders;

(7) whether the individual had comorbidities, possible concurrent medications and DDIs.

To evaluate the potential risk for ASCVD, ATP IV guideline suggest using the new Pooled Cohort Risk Assessment Equations developed by the Risk Assessment Work Group to estimate the 10-year ASCVD risk (defined as first-occurrence nonfatal and fatal MI and nonfatal and fatal stroke) or the lifetime ASCVD risk (more detail see Pharmacy Profession Forum at http://forum.tomhsiung.com/pharmacotherapy/467-how-to-estimate-the-risk-of-ascvd-the-latest-equations.html). The predicted 10-year ASCVD risk is defined as first-occurrence nonfatal and fatal MI and nonfatal and fatal stroke.

Estimates of 10-year risk for ASCVD are based on data from multiple community-based populations and are applicable to African-American and non-Hispanic white men and women 40 through 79 years of age. For other ethnic groups, we recommend use of the equations for non-Hispanic whites, though these estimates may underestimate the risk for persons from some race/ethnic groups, especially American Indians, some Asian Americans (e.g., of south Asian ancestry), and some Hispanics (e.g., Puerto Ricans), and may overestimate the risk for others, including some Asian Americans (e.g., of east Asian ancestry) and some Hispanics (e.g., Mexican Americans)Estimates of lifetime risk for ASCVD are provided for adults 20 through 59 years of age and are shown as the lifetime risk for ASCVD for a 50-year old without ASCVD who has the risk factor values entered into the spreadsheet. The estimates of lifetime risk are most directly applicable to non-Hispanic whites. We recommend the use of these values for other race/ethnic groups, though as mentioned above, these estimates may represent under- and overestimates for persons of various ethnic groups. Because the primary use of these lifetime risk estimates is to facilitate the very important discussion regarding risk reduction through lifestyle change, the imprecision introduced is small enough to justify proceeding with lifestyle change counseling informed by these results.

Note that 10-year risk estimation is only calculated for the 40 to 79 year range. Life-time risk estimation is only calculated for the 20 to 59 year range.

Also there is iPad app of this new tool, completely free – https://itunes.apple.com/us/app/ascvd-risk-estimator/id808875968?mt=8.

General Approach

Therapeutic lifestyle change (TLC) should be implemented in all patients prior to considering drug therapy. Many persons should be given a three-month trial (two visits spaced 6 Weeks apart) of TLC unless patients are at very high risk.

PS: Very high risk for ASCVD is defined as the presence of established CVD plus one or more of:
1. multiple major risk factors (especially diabetes)
2. severe and poorly controlled risk factors (especially continued cigarette smoking)
3. multiple risk factors of the metabolic syndrome (especially high triglycerides >=200 mg/dL plus non-HDL-C>=130 mg/dL with low HDL-C [<40 mg/dL])
and/or
4. on the basis of PROVE IT, patients with acute coronary syndromes.

However, this criteria is derived from ATP III guideline. The ATP IV guideline has changed largely and according to a clinical pharmacy specialist/BCPS/Cardiology, whose name is Brent Reed, the very high risk category is no longer valid in the new guidelines (Clinical Practice Guideline of ATP IV).

If drug therapy to further reduce lipid profile is necessary, before initiation of drug therapy the patient shall be evaluation, not only the potential risk for ASCVD, but also ASCVD risk-reduction benefits, adverse effects, DDIs, and patient preferences (e.g., comorbidities, age >75 years, etc.)

In the latest ATP IV guideline, generally, four groups of patients would definitely benefit from statin therapy (ASCVD risk reduction clearly outweighs the risk of adverse events based on a strong body of evidence). They are 1.secondary prevention in individuals with clinical ASCVD; 2. primary prevention in individuals with primary elevations of LDL-C >=190 mg/dL; 3.primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL; and 4.primary prevention in individual without diabetes and with estimated 10-year ASCVD risk>=7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL. Patient with heart failure or hemodialysis are excluded and no suggestion would be made to these two cohorts.

PS: clinical ASCVD is defined by the inclusion criteria for the secondary-prevention statin RCTs, which include acute coronary syndromes, a history of Mi, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin.

Also, moderate evidence supports the use of statin for primary prevention in individuals with 5% to <7.5% 10-year ASCVD risk, 40 to 75 years of age with LDL-C 70 to 189 mg/dL. Selected individuals with <5% 10-year ASCVD risk, or <40 or >75 years of age may also benefit from statin therapy, but in these circumstances clinicians shall consider the potential ASCVD risk reduction benefits, adverse effects, DDIs, and patient preferences.

Nonpharmacologic Therapy

It must be emphasized that lifestyle modification (i.e., heart-healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) remains a crucial component of health promotion and ASCVD risk reduction, both prior to and in concert with the use of cholesterol-lowering drug therapies. Individualized diet counseling that provides acceptable substitutions for unhealthy foods and ongoing reinforcement by a registered dietitian are necessary for maximal effect.

Generally, lifestyle modification includes stopping excessive dietary intake of cholesterol and saturated fatty acids, weight control, increasing physical activity, increasing intake of soluble fiber, intake of fish oil supplementation, fat substitutes, and plant sterols & stanols.

Excessive dietary intake of cholesterol and saturated fatty acids leads to decreased hepatic clearance of LDL and deposition of LDL and oxidized LDL in peripheral tissues. Compared with polyunsaturated and saturated fat, intake of cholesterol has been found to have a greater effect on the concentration of LDL. Note that changes in blood lipid levels may change before three months, but may require a longer period time too. If all of the recommended dietary changes from NCEP are made, the estimated reduction, on average, in LDL-C would range from 20-30%.

Thus, ideally, lifestyle modification shall reduced intake of saturated fats and cholesterol. Weight control plus increased physical activity reduces risk beyond LDL-C and non-HDL lowering, but also can raises HDL.

Increased intake of soluble fiber can result in useful adjunctive reductions in total and LDL cholesterol. However, increased fiber intake has little or no effect on HDL-C or triglyceride concentrations. It is unclear whether the reduction in CHD risk associated with large amount of cold water, oily fish is the same with commercially prepared fish oil products. Note that fish oil supplementation has fairly large effect in reducing triglycerides and VLDL-C but it either has no effect on total and LDL-C or may cause elevations in these fractions.

Fat substitutes is similar in composition to triglycerides, but is not hydrolyzed in the gastrointestinal tract by pancreatic lipase, and, consequently, is not taken up by the intestinal mucosa. However, the absorption of lipophilic drugs or vitamins (A, D, E, and K) would be kept in the tract and excreted in the feces.

Plant sterols and stanols have demonstrated LDL-lowering effect in recent studies. The two are efficaciously comparable.

Pharmacotherapy Therapy

Nonstatin therapies, as compared with statin therapy, do not provide acceptable ASCVD risk-reduction benefits relative to their potential for adverse effects in the routine prevention of ASCVD. For patients with clinical ASCVD and within age of 75 years, high-intensity statin therapy should be initiated if they are not on statin therapy, or the intensity shall be increased in those receiving a low- or moderate-intensity statin therapy unless they have a history of intolerance to high-intensity statin therapy or other characteristics that could influence safety. If high-intensity statin therapy would otherwise be used, either when high-intensity statin therapy is contraindicated or when characteristics predisposing to statin-associated adverse effects are present, moderate-intensity statin should be used as the second option, if tolerated.

Dosage of Statin TherapyPatients with clinical ASCVD

For patients with clinical ASCVD and >75 years of age, RCTs data of high-intensity versus moderate-intensity statin therapy is few. However, there was no clear evidence of an additional reduction in ASCVD events from high-intensity statin therapy. In contrast, individuals >75 years of age did experience a reduction in ASCVD events in  moderate-intensity statin therapy, as compared with control. Thus, moderate-intensity statin therapy should be considered for individual >75 years of age with clinical ASCVD.

Although atorvastatin 40 mg reduces LDL-C by approximately >=50%, this dose was used in only 1 RCT if the participant was unable to tolerate atorvastatin 80 mg/dL. Whether an individual receiving atorvastatin 40 mg should be uptitrated to atorvastatin 80 mg shall be based on the potential for adverse effects, DDIs, and patient preferences.

Patients with LDL-C >=190 mg/dL

For patient >=21 years of age without clinical ASCVD but with LDL-C >=190 mg/dL (primary), severe elevation of LDL-C have a high lifetime risk for ASCVD events. Thus, at age 21, these individuals should receive statin therapy if they have not already been diagnosed and treated before. Patients with primary elevations of LDL-C >=190 mg/dL require even more substantial reductions in their LDL-C levels and intensive management of other risk factors to reduce their ASCVD event rates. Therefore, it is reasonable to use high-intensity statin therapy to achieve at least 50% reduction. It is recognized that maximal statin therapy might not be adequate to lower LDL-C sufficiently to reduce ASCVD event risk in individuals with primary severe elevations of LDL-C. In addition to a maximally tolerated dose of statin, nonstatin cholesterol level medications are often needed to lower LDL-C to acceptable levels in these individuals. It is also important that secondary causes, if it were exist, can contribute to the degree and severity of LDL-C >=190 mg/dL. Therefore these secondary causes should be corrected if possible.

Patients with diabetes and LDL-C is between 70 and 189 mg/dL

A high level of evidence supports the use of moderate-intensity statin therapy in persons with diabetes who are 40 to 75 years of age. The only trial of high-intensity statin therapy in primary prevention was performed in a population without diabetes. However, a high level of evidence existed for event reduction with statin therapy in individuals with a >=7.5% estimated 10-year ASCVD risk who did not have diabetes to recommend high-intensity statin therapy preferentially for individuals with diabetes and a >=7.5% estimated 10-year ASCVD risk. This consideration for those with diabetes who are 40 to 75 years of age recognizes that these individuals are at substantially increased lifetime risk for ASCVD events and death. Moreover, individuals with diabetes experience greater morbidity and worse survival after the onset of clinical ASCVD. For patients with diabetes but the 10-year ASCVD risk <7.5% moderate-intensity is recommended.

In patients with diabetes who are <40 years of age or >75 years of age, or whose LDL-C is <70 mg/dL, statin therapy should be individualized on the basis of considerations of ASCVD risk-reduction benefits, the potential for adverse effects and drug-drug interactions, and patient preferences.

Patients without diabetes and with LDL-C between 70 and 189 mg/dL

In individuals 40 to 75 years of age with LDL-C 70 to 189 mg/dL who do not have clinical ASCVD or diabetes, initiation of statin therapy based on estimated 10-year ASCVD risk is recommended, regardless of sex, race, or ethnicity. A high level of evidence for an ASCVD restriction benefit from initiation of moderate- or high-intensity statin therapy in individuals 40 to 75 years of age with >=7.5% estimated 10-year ASCVD risk was found. The reduction in ASCVD risk clearly outweighs the potential for adverse effects. Thus, it is recommended that individuals 40 to 75 years of age, who are not already candidates for statin therapy on the basis of the presence of clinical ASCVD, diabetes, or LDL-C >=190 mg/dL, receive statin therapy if they have a >=7.5% estimated 10-year risk for ASCVD and LDL-C 70 to 189 mg/dL.

For patients in this group (age 40-75) with estimated risk of 5-7.5%, although a similar level of evidence of a reduction in ASCVD events from moderate- and high-intensity statin therapy is present, the potential for adverse effects may outweigh the potential for ASCVD risk-reduction benefit when high-intensity statin therapy is used. Thus, it is recommended that moderate-intensity statin therapy should be used in this cohort since ASCVD risk-reduction benefit from moderate-intensity statin therapy clearly exceeds the potential for adverse effects.

For patients in this group (age 40-75) with estimated risk of <5%, patients 21 to 39 years of age, patients >75 years of age, or patients with LDL-C <70 mg/dL, the decision to initiate statin therapy and the starting dosage should based on ASCVD risk-reduction benefits, adverse effects, DDIs, and patient preferences.

Combination Therapy

No evidence support the routine use of nonstatin drugs combined with statin therapy to further reduce ASCVD events. However, high-risk patients who have a less than-anticipated response to statins, who are unable to tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant, may be added a nonstatin cholesterol level therapy. High-risk patients include those with ASCVD, those with LDL-C >=190 mg/dL, and those with diabetes 40-75 years of age. Due to that the potential benefits and safety are not clear in combination therapy, ASCVD risk-reduction benefits, adverse effects, DDIs, and patient preferences should be considered.

Monitor

Once pharmacotherapy for dyslipidemia initiates, clinicians should monitor the efficacy, safety, adherence of the choosen regimen. To monitor the efficacy, the evidence is less clear with regard to the most appropriate tests for determining whether an anticipated therapeutic response to statin therapy has occurred on the maximally tolerated dose. However, it is reasonable to use following as indicators of anticipated therapeutic response for the monitor of statin therapy. The percent LDL-C reduction may not only indicate adherence, but also may reflect biological variability in the response to statin therapy.

1.High-intensity statin therapy generally results in an average LDL-C reduction of >=50% from the untreated baseline.

2.Moderate intensity statin therapy generally results in an average LDL-C reduction of 30% to <50% from the untreated baseline.

3.If the baseline levels of LDL-C of the patients are unknown and already on a statin, an LDL-C of <100 mg/dL was observed in most individuals receiving high-intensity statin therapy in RCTs.

The most important issue in statin safety is to manage the muscle symptoms. The recommendation is list in the table below.

Statin Safety RecommendationsSome recommendation shall be emphasized here.

Routine measurement of creatine kinase is not recommended. To monitor it when patients have symptoms and signs of muscle problems.

If the 2 consecutive values of LDL-C are <40 mg/dL, clinicians shall consider decreasing the statin dose. This recommendation was based on the approach taken in 2 RCTs. However, no data were identified that suggest an excess of adverse events occurred when LDL-C levels were below this level.

The frequency of monitor should be every 3 to 12 months as clinical indicated, with the first re-check 4 to 12 Weeks after initiation of statin therapy.


Updates

Feb 11 2016

Major cardiovascular risk factors

  • Advanced age (>55 years for men, >65 years for women)
  • Cigarette smoking (no information available)
  • Diabetes mellitus
  • Dyslipidemia (no information available)
  • Familiy history of premature atherosclerotic vascular disease (men <55 years or women <65 years) in primary relatives
  • Hypertension
  • Kidney disease (microalbuminuria or estimate GFR <60 mL/min/1.73 m2)
  • Obesity (BMI >=30 kg/m2)
  • Physical inactivity (no information available)

Additional cardiovascular rsik factors

  • Family history of premature CHD (definite myocardial infarction or sudden death before 55 years of age in father or other male first-degree relative, or before 65 years of age in mother or other female first-degree relative)
  • Primary LDL-C >=160 mg/dL or other evidence of genetic hyperlipidemias
  • High-sensitivity C-reactive protein >=2 mg/L, coronary artery calcium score >=300 Agatston units or >=75th percentile for age, sex, and ethnicity
  • Ankle-brachial index <0.9
  • Elevated lifetime risk of ASCVD

The Etiology of Primary Dyslipidemia

May 12, 2014 Cardiology, Cytogenetics, Physiology and Pathophysiology No comments , ,

Generally primary dyslipidemia are due to mutations of various genes. Thus these disorders of lipid are inheritable and have a obvious family history, which is important in dignosing the primary dyslipidemia. Primary disorders of lipid consist of disorders of elevated apoB-containing lipoproteins, disorders of low apoB-containing lipoproteins level, disorders of low HDL-C level, and disorders of high HDL-C level.


Primary Disorders of Elevated ApoB-Containing Lipoproteins

ApoB-containing lipoproteins include chylomicrons (apoB-48), VLDL (apoB-100), IDL (apoB-100), and LDL (apoB-100). To understand dyslipidemia, we here list the component of each lipoprotein.

Chylomicron consists of 3% of cholesterol, 90% of triglyceride, 6% of phospholipid, and 1% of protein.

VLDL consists of 22% of cholesterol, 55% of triglyceride, 15% of phospholipid, and 8% of protein.

IDL consists of roughly similar amounts of cholesterol and triglyceride.

LDL consists of 50% of cholesterol, 5% of triglyceride, 25% of phospholipid, and 20% of protein.

HDL consists of 20% of cholesterol, 5% of triglyceride, 25% of phospholipid, and 50% of protein.


Lipid disorders associated with elevated LDL-C and normal triglycerides

1. Familial Hypercholesterolemia (FH). FH is an autosomal codominant disorder characterized by elevated plasma levels of LDL-C and normal triglycerides, tendon xanthomas, and premature coronary atherosclerosis.

FH is caused by a large number (>1000) mutations in the LDL receptor gene, which can be divided into homozygous FH and heterozygous FH. The estimated incidence of homozygous FH is 1/1,000,000, and heterozygous FH of 1/500. The elevated levels of LDL-C in FH are due to an increase in the production of LDL from IDL (since a portion of IDL is normally cleared by LDLR endocytosis on the liver) and a delayed removal of LDL from the blood also by LDLR on the liver.

Fredrickson Classification of HyperlipoproteinemiasPS: 40%-60% of IDL is removed by the liver via LDLR with cofactor ApoE. Approximately 70% of circulating LDL is cleared by LDLR in the liver (also with cofactor ApoE). For more information about the metabolism of lipoproteins please refer http://forum.tomhsiung.com/physiology-and-pathophysiology/402-the-pathway-of-lipids.html

Individuals with two mutated LDL receptor alleles (homozygous) have much higher LDL-C levels than those with one mutant allele (heterozygous). Among homozygous FH individuals, patients can be classified into one of two groups based on the amount of LDL receptor activity measured in their skin fibroblasts: those patients with <2% of normal LDL receptor activity are called receptor negative and those patients with 2-25% normal LDL receptor activity are called receptor defective. In patients with homozygous FH total cholesterol levels are usually >500 mg/dL and can be higher than 1000 mg/dL.

Heterozygous FH is one of the most common single-gene disorders (occuring in approximately 1 in 500). The elevated level of LDL-C usually is 200-400 mg/dL and the triglyceride is normal.

2. Familial defective ApoB-100 (FDB)

FDB is a dominantly inherited disorder that clinically resembles heterozygous FH. This disease is rare in most populations except individuals of German descent, where the frequency can be as high as 1 in 1000. FDB is also characterized by elevated plasma LDL-C levels with normal triglycerides, tendon xanthomas, and an increased incidence of premature ASCVD (atherosclerotic cardiovascular disease).

FDB is caused by mutations in the LDL receptor-binding domain of apoB-100, most commonly due to a substitution of glutamine for arginine at position 3500 (Arg3500Glu). As a consequence of the mutation in apoB-100, LDL binds the LDL receptor with reduced affinity, and LDL is removed from the circulation at a reduced rate (both IDL and LDL, similar like FH).

Clinically, patients with FDB tend to have lower plasma levels of LDL-C than FH heterozygotes.

3. Autosomal dominant hypercholesterolemia due to mutations in PCSK9 (ADH-PCSK9 or ADH3)

ADH3 is a rare autosomal dominant disorder caused by gain-of-function mutations in proprotein converstase subtilisin/kexin type 9 (PCSK9). PCSK9 is a secreted protein that binds to the LDL receptor, resulting in its degradation. Normally, after LDL binds to the LDL receptor it is internalized along with the receptor. In the low pH of the endosome, LDL dissociates from the receptor and the receptor returns to the cell surface. The LDL is delivered to the lysosome. When PCSK9 binds the receptor, the complex is internalized and the receptor is redirected to the lysosome rather than to the cell surface.

The mutations causing enhanced activity of PCSK9 results in reduced number of hepatic LDL receptors and the hypercholesterolemia. Loss-of-function mutations in PCSK9 cause low LDL-C levels.

4. Autosomal recessive hypercholesterolemia (ARH)

ARH is a rare disorder due to mutations in a protein (LDLRAP) involved in LDL receptor-mediated endocytosis in the liver, which is characterized by hypercholesterolemia, tendon xanthomas, and premature coronary artery disease. In the absence of LDLRAP, LDL binds to the LDL receptor but the lipoprotein-receptor complex fails to be internalized.

The levels of plasma LDL-C tend to be intermediate between the levels present in FH homozygotes and FH heterozygotes. LDL receptor function in cultured fibroblasts is normal or only modestly reduced in ARH, whereas LDL receptor function in lymphocytes and the liver is negligible.

5. Sitosterolemia

Sitosterolemia is another rare autosomal recesive disease that can result in severe hypercholesterolemia, tendon xanthomas, and premature ASCVD. Misshapen red blood cells and megathrombocytes are visible on blood smear. Episodes of hemolysis are a distinctive clinical feature of this disease compared to other genetic forms of hypercholesterolemia.

Sitosterolemia is caused by mutations in either of two members of the ATP-binding cassette (ABC) half transporter family, ABCG5 and ABCG8. These genes are expressed in enterocytes and hepatocytes. The proteins heterodimerize to form a functional complex that pumps plant sterols such as sitosterol and campesterol, and animal sterols, predominantly cholesterol, into the gut lumen and into the bile. In normal individuals, <5% of dietary plant sterols are absorbed by the proximal small intestine and delivered to the liver. Absorbed plant sterols are preferentially secreted into the bile and are maintained at very low levels.

In sitosterolemia, the intestinal absorption of sterols is increased and biliary excretion of the sterols is reduced, resulting in increased plasma and tissue levels of both plant sterols and cholesterol. Incorporation of plant sterols into cell membranes results in misshapen red blood cells and megathrombocytes that are visible on blood semear.

6. Polygenic hypercholesterolemia

This condition is characterized by hypercholesterolemia due to elevated LDL-C with a normal plasma level of triglyceride in the absence of secondary causes of hypercholesterolemia.

Plasma LDL-C levels are generally not as elevated as they are in FH and FDB.

7. Elevated plasma levels of lipoprotein(a)

Unlike the other major classes of lipoproteins, that have a normal distribution in the population, plasma levels of Lp(a) have a highly skewed distribution with levels varying over 1000-fold range. Levels are strongly influenced by genetic factors, with individuals of African and South Asian descent having higher levels than those of European descent.


Lipid Disorders Associated with Elevated Triglycerides

1. Familial chylomicronemia syndrome

Genetic deficiency or inactivity of either LPL or ApoC-II (cofactor of LPL) results in impaired lipolysis and profound elevations in plasma chylomicrons. These patients can also have elevated plasma levels of VLDL, but chylomicronemia predominates. The fasting plasma is turbid, and if left at 4℃ for a few hours, the chylomicrons float to the top and form a creamy supernatant. In these disorders, fasting triglyceride levels are almost invariably>1000 mg/dL. Fasting cholesterol levels are also elevated but to a lesser degree.

LPL deficiency has autosomal recessive inheritance and has a frequency of approximately 1 in 1 million in the population. ApoC-II deficiency is also recessive in inheritance pattern and is even less common than LPL deficiency. Multiple different mutations in the LPL and apo-C-II genes cause these diseases. Obligate LPL heterozygotes have normal or mild-to-moderate elevations in plasma triglyceride levels, whereas individuals heterozygous for mutation in apoC-II do not have hypertriglyceridemia.

For unknown reasons, some patients with persistent and pronounced chylomicronemia never develop pancreatitis, eruptive xanthomas, or hepatosplenomegaly.

2. ApoA-V deficiency

ApoA-V circulates at much lower concentrations than the other major apolipoproteins. Individuals harboring mutations in both ApoA-V alleles can present as adults with chylomicronemia. The exact mechanism of action of ApoA-V is not known, but it appears to be required for the association of VLDL and chylomicrons with LPL.

3. GPIHBP1 deficiency

After LPL is synthesized in adipocytes, myocytes or other cells, it is transported across the vascular endothelium and is attached to a protein on the endothelial surface of capillaries called GPIHBP1. Homozygosity for mutations that interfere with GPIHBP1 synthesis or folding  cause severe hypertriglyceridemia

The frequency of chylomicronemia due to mutations in GPIHBP1 has not been established but appears to be very rare.

4. Hepatic lipase deficiency

HL is a member of the same gene family as LPL and hydrolyzes triglycerides and phospholipids in remnant lipoproteins and HDLs. HL deficiency is a very rare autosomal recessive disorder characterized by elevated plasma levels of cholesterol and triglycerides (mixed hyperlipidemia) due to the accumulation of circulating lipoprotein remnants (both IDL & chylomicrons remnants;supporting reference: Removal of chylomicron remnants in transgenic mice overexpressing normal and membrane-anchored hepatic lipase at http://www.ncbi.nlm.nih.gov/pubmed/15520453) and either a normal or elevated plasma level of HDL-C (HL hydrolyze TG and phopholipids of large HDL).

PS: HL hydrolyzes both TG and PL principally on remnant lipoproteins and HDL, and may facilitate the uptake of apoB-containing lipoproteins through interaction with HSPG (heparan sulfate proteoglycan).

5. Familial dysbetalipoproteinemia (FDBL)

Familial dysbetalipoproteinemia is characterized by a mixed hyperlipidemia due to the accumulation of remnant lipoprotein particles. ApoE is present in multiple copies on chylomicron and VLDL remnants and mediates their removal via hepatic lipoprotein receptors. The APOE gene ispolymorphic in sequence, resulting in the expression of the three common isoforms: apoE3, which is the most common; and apoE2 and apoE4, which both differ from apoE3 by a single amino acid.

ApoE4 is not associated with FDBL. ApoE2 has a lower affinity for the LDL receptor; therefore, chylomicron and VLDL remnants containing apoE2 are removed from plasma at a slower rate. Individuals who are homozygous for the E2 allele comprise the most common subset of patients with FDBL. Approximately 0.5% of the general population are apoE2/E2 homozygotes, but only a small minority of these individuals develop FDBL. In most cases, an additional, identifiable factor precipitates the development of hyperlipoproteinemia. The most common precipitating factors are high-fat diet, diabetes mellitus, obesity, hypothyroidism, renal disease, HIV infection, estrogen deficiency, alcohol use, or certain drugs.

Other mutations in apoE can cause a dominant form of FDBL where the hyperlipidemia is fully manifest in the heterozygous state, but these mutations are rare.

6. Familial hypertriglyceridemia (FHTG)

FHTG is a relatively common autosomal dominant diorder of unknown etiology (~1 in 500). FHTG is characterized by moderately elevated plasma triglycerides accompanied by more modest elevations in cholesterol. Some patients with FHTG have a more severe form of hyperlipidemia in which both VLDLs and chylomicrons are elevated (Type V hyperlipidemia), since VLDL and chylomicron compete for the same lipolytic pathway.

The major class of lipoproteins elevated in this disorders is VLDL, thus, patients with this disorder are often referred to as as having Type IV hyperlipoproteinemia. The elevated plasma levles of VLDL are due to increased production of VLDL, impaired catabolism of VLDL, or a combination of these mechanisms.

Increased intake of simple carbohydrates, obesity, insulin resistance, alcohol use, and estrogen treatment, all of which increase VLDL synthesis, can exacerbate this syndrome.

For unknown reasons, some patients with persistent and pronounced chylomicronemia never develop pancreatitis, eruptive xanthomas, or hepatosplenomegaly

FHTG appears not to be associated with increased risk of ASCVD in many families.

7. Familial combined hyperlipidemia (FCHL)

FCHL is generally characterized by moderate elevations in plasma levels of triglycerides (VLDL) and cholesterol (LDL) and reduced plasma levels of HDL-C. However, the disease typically has one of three possible phenotypes: (1). elevated plasma levels of LDL-C; (2). elevated plasma levels of triglycerides due to elevation in VLDL; or (3). elevated plasma levels of both LDL-C and triglyceride. And the lipoprotein profile can switch among these three phenotypes in the same individual over time and may depend on factors such as diet, exercise, and weight, etc.

Til today, the molecular etiology of FCHL remains poorly understood, and it is likely that defects in several different genes can cause the phenotype of FCHL.


Inherited Causes of Low Levels of HDL-C

1. Gene deletion in the ApoAV-AI-CIII-AIV locus and coding mutations in ApoA-I

Complete genetic deficiency of apoA-I due to deletion of the apoA-I gene result in the virtual absence of HDL from the plasma.

The genes encoding apoA-I, apoC-III, apoA-IV, and apoA-V are clustered together on chromsome 11, and some patients with no apoA-I have genomic deletions that include other genes in the cluster.

Missense and nonsense mutations in the apoA-I gene have been identified in some patients with low plasma level of HDL-C. ApoA-I is required for LCAT activity. With low levels and/or activity of mutant ApoA-I, LCAT activation is impaired, which precludes the normal esterifying of free cholesterol in the HDL and as a result the HDL is rapidly catabolismed from circulation.

2. Tangier disease (ABCA1 deficiency)

Tangier disease is a very rare autosomal codominant form of extremely low plasma HDL-C caused by mutations in the gene encoding ABCA1, a cellular transporter that facilitates efflux of unesterified cholesterol and phospholipids from cells to apoA-I, which form nascent HDL. Without ABCA1, the apoA-I secreted from the liver and intestine are poorly lipidated and as a result these apoA-I is immediately cleared from the circulation.

3. LCAT deficiency

LCAT deficiency is a very rare autosomal recessive disorder which is caused by mutations in LCAT, an enzyme synthesized in the liver and secreted into the plasma. In LCAT deficiency, the proportion of free cholesterol in circulating lipoproteins is greatly increased. Lack of normal cholesterol esterification impairs formation of mature HDL particles, resulting in the rapid catabolism of circulating apoA-I. Two genetic forms of LCAT deficiency have been described in humans: 1. complete deficiency or so-called classic LCAT deficiency, and 2. partial deficiency or fish-eye disease.

4. Primary hypoalphalipoproteinemia

Primary hypoalphalipoproteinemia is defined as a plasma HDL-C level below the tenth percentile in the setting of relatively normal cholesterol and triglyceride levels, with no apparent secondary causes of low plasma HDL-C and no clinical signs of LCAT deficiency or Tangier disease.

The metabolic etiology of this disease appears to be primarily accelerated catabolism of HDL and its apolipoproteins.