Familial Chylomicronemia Syndrome: A Clinical Guide For Endocrinologists.

OBJECTIVE: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder caused by mutations in lipoprotein lipase, resulting in accumulation of chylomicrons in plasma and hypertriglyceridemia. Elevated triglycerides cause several complications in patients, the most serious being episodes of acute pancreatitis. This review focuses on expert guidance and opinion from an experienced lipidologist and endocrinologist as well as a current review of the literature, as there are no specific guidelines on FCS. METHODS: Discussion of expert guidance and opinion review of current literature. RESULTS: To date, there is no pharmacologic treatment for affected patients, and management options primarily include adoption of an extremely restricted, very-low-fat diet, along with avoidance of certain medications and alcohol. Endocrinologists often diagnose and manage patients with metabolic disorders, including patients with high triglyceride levels, but rare diseases like FCS can be missed or poorly evaluated due to knowledge gaps about disease state. Given endocrinologists' role in the treatment of lipid disorders, it is important that they understand the clinical signs and symptoms of FCS to correctly diagnose patients. Patients with FCS can be identified based on a defined clinical criteria and a thorough review of medical history, after excluding differential diagnoses and secondary factors. Typical manifestations include hypertriglyceridemia characterized by lipemic serum, history of abdominal pain, and acute/recurrent pancreatitis. Secondary factors to be excluded are pregnancy, alcohol abuse, uncontrolled diabetes, and use of certain medications. CONCLUSION: FCS is a rare, inherited lipid disorder disease that often goes underdiagnosed and unmanaged. This review provides a summary of clinical characteristics of FCS that can be potentially used to screen patients in an endocrinologist's office and direct them to the appropriate standard of care. ABBREVIATIONS: apoB = apolipoprotein B; apoC-III = apolipoprotein CIII; ASO = antisense oligonucleotide; FCS = familial chylomicronemia syndrome; HTG = hypertriglyceridemia; LPL = lipoprotein lipase; LPLD = lipoprotein lipase deficiency.

The role of lipoprotein(a) in clotting reactions during lipoprotein apheresis--A case report.

In individuals with familial hypercholesterolemia (FH) who are unable to reach a target low-density lipoprotein level on a drug regimen, lipoprotein apheresis (LA) may be the treatment of choice. Severe reactions involving clotting during LA are not well described in the literature. We report a case of a 63-year-old woman with FH and markedly elevated lipoprotein(a) (Lp[a]) levels who experienced such a reaction while undergoing LA with a dextran-sulfate cellulose column on the Kaneka MA-01 Liposorber system. Owing to the clotting as well as a blood pressure drop to <100 mm Hg systolic, the procedure was stopped early. Before her second procedure, she was given an increased loading dose of unfractionated heparin. She did not develop clotting during this second procedure. A growing body of literature on the role of Lp(a) in atherothrombotic complications and hemostasis supports a possible mechanism by which clotting in the instrument could occur during apheresis. Our patient's initial pretreatment Lp(a) was 3.5 times greater than the mean Lp(a) levels in patients with FH. This theory is consistent with our case in that the patient's Lp(a) levels progressively declined with each procedure, and she had no subsequent clotting.

New treatments on the horizon for familial hypercholesterolemia.

Patients with familial hypercholesterolemia (FH) have higher baseline LDL cholesterol (LDLc) levels and are at high risk of developing premature cardiovascular disease. Disease is attributed to mutations in the LDLR gene, which encodes the LDL receptor protein and whose deficiency results in decreased uptake of apoB-containing cholesterol particles by the liver and elevated serum LDLc levels. Heterozygous FH is inherited in an autosomal-dominant pattern and has an incidence of 1:500 in the general population. These patients usually present with premature cardiovascular disease at 30-40 years of age and have baseline LDLc levels ranging from 190 to 230 mg/dl. Homozygous FH, however, is much rarer, occurring in one in a million births; those afflicted present with severe cardiovascular disease in childhood and have baseline LDLc levels greater than 300 mg/dl. Often FH patients do not reach their target LDLc levels on conventional therapies such as statins. Even with combination therapy, the percent of FH patients reaching target cholesterol levels is less than 30% and while apheresis is a therapeutic option for those with the most severe disease, many FH patients seek less invasive therapeutic strategies. New classes of cholesterol medications, aimed at either lowering LDLc levels or altering the progression of intra-arterial plaque, are currently in clinical development and may offer alternative or adjunctive therapies for this high-risk population.

Randomized trial assessing the impact of a musculoskeletal intervention for pain before participating in a weight management program.

PURPOSE: Obesity increases the risk of developing physical disability and pain. Persons with a body mass index (BMI) of 30 kg/m or more have an increased risk for osteoarthritis compared with those with a BMI between 25 and 29 kg/m. The purpose of this study was to examine the effect of treatment directed at reducing musculoskeletal pain on weight loss in obese subjects prior to participation in a 6-month weight management (WM) program. METHODS: Subjects (BMI > or = 30 kg/m; n = 54, female = 41, male = 13) with musculoskeletal pain, as assessed by a visual analog scale score of more than 5, were randomized to a physician musculoskeletal evaluation with treatment and physical therapy prior to participation in a 6-month WM program (intervention) or direct entry into the WM program (control) between November 10, 2003, and January 20, 2005. RESULTS: Seventy-six percent of subjects completed the study (intervention, n = 18 [67%]; control, n = 23 [85%], P = .10). The intervention group demonstrated a significant decrease in visual analog scale score after musculoskeletal therapy (2.3 +/- 1.8, P < .0001). Despite a reduction in pain levels in the intervention group compared with the control group at the start of the WM program, there were no significant differences between the groups in percentage weight loss (P = .80), body fat composition (P = .20), or BMI (P = .06), all significantly improved in both groups. CONCLUSIONS: Musculoskeletal and physical therapy intervention directed at decreasing musculoskeletal pain in obese individuals prior to participation in a WM program reduces reported musculoskeletal pain for those participants completing the program but does not significantly improve weight loss over 6 months, compared with individuals with comparable musculoskeletal pain who enter directly into a WM program.

Dyslipidemia in South Asians living in a western community.

An increased prevalence of coronary heart disease (CHD) has been well documented in the South Asian population living worldwide. The prevalence of certain traditional CHD risk factors, like diabetes mellitus and tobacco use, have been on the rise in this ethnic group and likely contribute to the increase in CHD prevalence. Still, a disproportionate excess of CHD exists, and this may be linked to novel CHD risk factors. We have reviewed the prevalence of CHD in South Asians and its association to both traditional and novel CHD risk factors. We present a literature review of traditional and novel CHD risk factors, and incorporate the results of a cross-sectional study investigating the prevalence of these factors in a South Asian population residing in the United States with no prior diagnosis of CHD. The total cholesterol (TC) (mean ± standard deviation) was 193.72 ± 33.76 mg/dL, high-density lipoprotein (HDL) was 42.20 ± 12.11 mg/dL, and low-density lipoprotein (LDL) was 124.88 ± 27.22 mg/dL. The mean triglyceride level was 166.60 mg/dL. The prevalence of elevated TC (>200 mg/dL) was 41.3% and elevated LDL (>130 mg/dL) 40.7%. There was a significant difference between men and women in the prevalence of reduced HDL (<40 mg/dL) (67.3% vs. 49.4%), elevated triglycerides (>130 mg/dL) (56.4 vs. 30.4%), and small-dense LDL particles (53.6% vs. 27.8%). Considerably higher prevalence of novel CHD risk factors has been noted in the South Asian population. The CHD risk may increase significantly when these novel factors co-exist with traditional CHD risk factors.

Effect of a weight management program on the determinants and prevalence of metabolic syndrome.

OBJECTIVE: As prevalence of obesity and metabolic syndrome (met synd) rises, establishing effective, community-based treatments is imperative. Our investigation sought to evaluate and report the effect of a weight management program on the prevalence and determinants of met synd, and the effect of participation level. METHODS AND PROCEDURES: Between 10 July 2001 and 17 November 2005, 339 of 574 individuals enrolled in and completed our 6-month weight management program at the McConnell Heart Health Center in Columbus, Ohio. One hundred and sixty completers met our inclusion criteria for our retrospective analysis: (i) non diabetic, (ii) complete outcomes, (iii) no program participation in the previous 6 months. Met synd status was determined using AHA/NHLBI criteria. Blood pressure criterion was modified to a history of hypertension or current antihypertension medication use. Participation level was dichotomized as high participators (HP) and low participators (LP) using the number of center visits. RESULTS: The entire cohort showed significant reductions in BMI, waist circumference and met synd prevalence (51-39%). The met synd group had significant improvements in high-density lipoprotein (HDL), triglycerides, and glucose. Compared with LP, HP had a significant reduction in the prevalence of met synd and significantly greater improvement in the anthropometric, HDL and triglyceride determinants of met synd. DISCUSSION: This weight management program had a positive effect on determinants and prevalence of met synd. High participation levels were associated with significantly greater improvements in the anthropometric variables, HDL, triglycerides, met synd determinants, and reduction of met synd prevalence.

Optimal management of lipids in diabetes and metabolic syndrome.

Patients with diabetes or metabolic syndrome frequently have higher triglycerides, lower high-density lipoprotein (HDL) cholesterol, and more particles containing apolipoprotein B (ApoB); this combination contributes significantly to their cardiovascular risk. Optimal management of dyslipidemia and increased atherosclerotic risk requires a fundamental understanding of diabetic dyslipidemia, the clinical evidence for different interventional strategies, and the potential benefit of achieving therapeutic targets. For this review, we considered guidelines, recent reviews, and clinical trial results. The features of dyslipidemia in type 2 diabetes and the metabolic syndrome are linked metabolically and are related to central adiposity and insulin resistance. Levels of ApoB and HDL cholesterol are particularly important markers of risk. Guidelines broadly agree that low-density lipoprotein (LDL) cholesterol should be reduced below population average levels. Additional or secondary strategies in patients with diabetes or the metabolic syndrome are to decrease non-HDL cholesterol, ApoB and/or LDL particle concentration, to increase HDL cholesterol, and to reduce triglycerides. Lifestyle changes and statins are the bedrock of treatment, although second-line treatment using fibrates or niacin will likely benefit many patients with residual risk. Ezetimibe, too, has a favorable effect on lipid profile and inflammatory biomarkers of risk. Dyslipidemia in type 2 diabetes and metabolic syndrome has a distinct profile, suggesting the need for a tailored therapy that targets the key features of lowered HDL cholesterol and raised triglycerides, in addition to the primary antiatherogenic strategy of lowering ApoB-containing lipoproteins, such as LDL. With the prominent failure of some recent intervention trials, new therapeutic strategies-particularly safe and effective means to raise HDL-are needed to manage dyslipidemia in this high-risk population.

A systematic approach to improve lipids in coronary artery disease patients participating in a cardiac rehabilitation program.

PURPOSE: To determine the effectiveness of an intervention, directed toward the primary care physician (PCP), to improve the number of patients treated to low-density lipoprotein cholesterol (LDL-C) goal in a cardiac rehabilitation (CR) population. METHODS: A pre-post intervention cohort comparison using data collected from participants in a CR program with LDL-C > or =100 mg/dL at entry. The control cohort participated in CR between 1/00 and 10/02, 41.5% (n = 178) had an entry LDL-C > or =100 mg/dL. The intervention cohort participated in CR between 10/03 and 1/05, 26.4% (n = 67) had an entry LDL-C > or =100 mg/dL. The intervention group had identical treatment as the control group as well as the following: each participant with an LDL-C > or =100 mg/dL in the intervention cohort had an entry letter sent to his or her cardiologist and PCP from the programs Cardiology Medical Director, detailing the lipid goals and therapeutic options. In addition, monthly faxes on progress toward lipid goals were sent to the PCP. RESULTS: The control cohort was less likely to achieve LDL-C goal compared with the intervention cohort (43% vs 67%, respectively; P = .001). A patient was also less likely to have a lipid medication change during CR in the control group compared with the intervention group (29% vs 42%, respectively; P = .05). CONCLUSION: Use of systematic reminders directed at the PCP during CR can substantially increase the percentage of patients achieving nationally recognized LDL-C goals.

Effect of a community-based weight management program on weight loss and cardiovascular disease risk factors.

OBJECTIVE: The purpose of our retrospective database analysis was to describe and evaluate the outcomes of a weight loss intervention in a community medical wellness center. RESEARCH METHODS AND PROCEDURES: Four hundred eighteen overweight and obese adults entered the program between 2001 and 2004. Forty-seven percent completed the 6-month program designed using standards and recommendations established by the NIH, the American Dietetic Association, and the American Academy of Sports Medicine. Data analysis was limited to 198 participants (142 women, 56 men) completing the program. RESULTS: Individuals completing the 6-month program averaged a weight loss of 7.3% in men and 4.7% in women. Fasting lipids and blood glucose improved in both genders regardless of age. Outcomes including BMI and lipids improved in women regardless of menopausal status or hormone replacement therapy. There was a significant correlation between percentage weight loss and number of weekly counseling sessions attended and number of visits to the wellness center for exercise. DISCUSSION: Participants who complete a structured community-based weight management program can achieve significant weight loss and improvement in cardiovascular risk factors regardless of age, gender, or menopausal status. Our analysis suggests that national treatment guidelines/recommendations for weight management can be effectively implemented in a community medical wellness center. The relatively high drop-out rate associated with this program suggests the need to identify strategies and techniques to enhance adherence and completion of programs.

Cardiac rehabilitation is associated with an improvement in C-reactive protein levels in both men and women with cardiovascular disease.

PURPOSE: Inflammation is involved in the development of atherosclerotic plaque. The most studied indicator of inflammation in coronary heart diseases (CHD) is C-reactive protein (CRP) which has prognostic significance in those with CHD. The purpose of this study is to evaluate the effect of participation in cardiac rehabilitation (CR) on this marker of vascular inflammation, CRP. METHODS: We analyzed CRP levels in 172 patients with CHD who participated in a CR program. RESULTS: Men and women in CR demonstrated significant improvement in body mass index (-0.35, P = .002), exercise capacity (METs 1.8, P < .0001), HDL-C (1.8, P = .003), and CRP (-3.1, P = .003). The improvement in CRP was not significantly different based on age or the presence of metabolic syndrome. CONCLUSION: Participation in CR was associated with a marked improvement of cardiac risk factors and appears to independently decrease the level of CRP regardless of gender, age, or presence of metabolic syndrome.

Clinical profile and outcomes of diabetic and nondiabetic patients in cardiac rehabilitation.

BACKGROUND: Patients with diabetes mellitus have increased risk of cardiovascular disease; however, there are limited data addressing cardiac rehabilitation in these patients. This study assessed the effectiveness of participation in cardiac rehabilitation on clinical outcomes after myocardial infarction and/or revascularization procedures in diabetic and nondiabetic patients. METHODS: Analysis on 1505 patients completing a minimum of 7 weeks of a 12-week cardiac rehabilitation program included fasting lipid profile and glucose, body mass index, and metabolic equivalent time in patients with diabetes (n = 292) and without diabetes (n = 1213). RESULTS: There were significant improvements in total cholesterol, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in each group after cardiac rehabilitation. Diabetic women and nondiabetic men had the greatest improvement in HDL-C, with an improvement of 4.9% in diabetic women (P = .02) and an improvement of 4.1% in nondiabetic men (P < or = .0001). On completion of cardiac rehabilitation, both diabetic and nondiabetic patients were at National Cholesterol Education Program Adult Treatment Panel III goals in total cholesterol, LDL-C, HDL-C, and triglycerides at a higher rate. However, patients with diabetes did not reach National Cholesterol Education Program goals for HDL-C, total cholesterol, and triglycerides as effectively as nondiabetic patients. Exercise capacity improved by 28.1% in diabetic patients after cardiac rehabilitation (P < .0001). Improvement in outcomes in the patients with diabetes occurred without significant change in body mass index. CONCLUSIONS: These results suggest that participation in a comprehensive cardiac rehabilitation program integrates care of patients with chronic conditions such as diabetes to achieve comparable cardiac risk factor reduction as achieved with nondiabetic patients.

Independent effect of cardiac rehabilitation on lipids in coronary artery disease.

PURPOSE: We evaluate the effects cardiac rehabilitation (CR) participation independent of using lipid-altering agents (LAAs) on low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, total cholesterol, and triglyceride. Measurements included absolute and relative change in lipids and increases in percent of patients achieving goals. METHODS: Analysis of 766 patients who participated in CR between 2000 and 2003 was performed. On enrollment to CR, all were being treated with an LAA defined as HIviG-CoA reductase inhibitors, bile acid sequestrant, fibrate, and niacin, hormone replacement therapy. Preenrollment and postenrollment lipids were obtained. Analysis was performed on 2 cohorts, participants enrolled on an LAA with no change in medication (n = 13) and participants enrolled on an LAA with a change in medications (n = 153). RESULTS: At completion of CR, 74.9% of patients on LAA at enrollment with no medication adjustments during the program were at Adult Treatment Panel III goal for low-density lipoprotein cholesterol compared with 68.5% at entry (P = .01), all other lipid parameters also significantly improved. Sixty-three percent who started CR on an LAA and had dose adjustment or an additional LAA added achieved low-density lipoprotein cholesterol goal compared with 43.1% at entry (P < .0001). CONCLUSION: Participation in CR significantly potentiates the lipid-improving effects of pharmacological therapy and independently contributed to the percent of patients achieving all lipid levels at Adult Treatment Panel III goal.

Evaluation and prevention of diabetic neuropathy.

Diabetic neuropathy is a debilitating disorder that occurs in nearly 50 percent of patients with diabetes. It is a late finding in type 1 diabetes but can be an early finding in type 2 diabetes. The primary types of diabetic neuropathy are sensorimotor and autonomic. Patients may present with only one type of diabetic neuropathy or may develop combinations of neuropathies (e.g., distal symmetric polyneuropathy and autonomic neuropathy). Distal symmetric polyneuropathy is the most common form of diabetic neuropathy. Diabetic neuropathy also can cause motor deficits, silent cardiac ischemia, orthostatic hypotension, vasomotor instability, hyperhidrosis, gastroparesis, bladder dysfunction, and sexual dysfunction. Strict glycemic control and good daily foot care are key to preventing complications of diabetic neuropathy.

Cardiovascular disease risk of type 2 diabetes mellitus and metabolic syndrome: focus on aggressive management of dyslipidemia.

Type 2 diabetes mellitus and the closely related metabolic syndrome markedly increase the risk of cardiovascular disease a major contributor is the dyslipidemia. Recent studies and new national guidelines suggest these very high risk patients with cardiovascular disease achieve optional low density lipoprotein cholesterol (LDL-C) level of less than 70 mg/dl. In addition there may be no threshold to begin therapeutic lifestyle change and pharmacologic therapy to reduce LDL-C by 30-40%. Although randomized controlled trials with statins indicate that LDL reduction clearly reduces cardiovascular risk in these patients, the typical dyslipidemia of type 2 diabetes mellitus is also characterized by low high density lipoprotein cholesterol (HDL-C) levels, increased triglyceride-rich lipoproteins and small dense LDL, as well as increased postprandial lipemia. The later lipoproteins increase non-HDL-C levels. In order to address these abnormalities it may be necessary to utilize combined approaches with a fibrate or nicotinic acid, or other agents with statins to help reduce risk beyond statins. In addition, supervised, therapeutic life-style change is often underutilized therapy in patients with established coronary artery disease. This review will focus on maximizing the treatment of dyslipidemia in type 2 diabetes and the metabolic syndrome and discuss the evidence based studies and new developments in the management in these very high risk patients.

Therapeutic approaches to dyslipidemia in diabetes mellitus and metabolic syndrome.

Type 2 diabetes mellitus and the closely related metabolic syndrome are associated with significant risk for cardiovascular disease. Recent evidence suggests that both conditions are increasing in epidemic proportions. Dyslipidemia is characterized by increased triglyceride-rich lipoproteins; low high-density lipoprotein cholesterol; small, dense low-density lipoprotein particles; increased postprandial lipemia; and abnormal apolipoprotein A1 and B metabolism. All these lipoprotein disturbances accelerate atherosclerosis in these patients. It is likely that many patients will need combinations of lipid-modifying therapy to achieve American Diabetes Association (ADA), Adult Treatment Panel III, and American Heart Association (AHA)/American College of Cardiology (ACC) guidelines to help prevent cardiovascular disease and death.

Acute psychological stress reduces plasma triglyceride clearance.

Acute stress elevates blood lipids, with the largest increases among men and postmenopausal women. The mechanisms for the effect are unknown, but may be due to altered lipid metabolism. This study investigated if acute stress induces transient reductions in triglyceride clearance in middle-aged men and women, and determined if gender and menopause affect triglyceride metabolism. Of the 35 women, half were premenopausal, and half were naturally postmenopausal; men (n = 35) were age matched. Clearance of an intravenously administered fat emulsion was assessed twice: once during a nonstress session, and again during a stress-testing session. During the stress session, a battery of behavioral stressors (serial subtraction, speech, mirror tracing, and Stroop) were performed for 40 min. The clearance rate of exogenous fat was significantly diminished during the stress, relative to the nonstress session. Women had more efficient clearance, relative to men, but there were no effects of menopausal status. The diminished ability to clear an intravenous fat emulsion during stress suggests one mechanism for stress-induced elevations in lipids.