Hypertriglyceridemia

In medicine, hypertriglyceridemia (or "Hypertriglyceridaemia") denotes high (hyper-) blood levels (-emia) of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia (high cholesterol levels). It can also lead to pancreatitis in excessive concentrations. Very high triglyceride levels may also interfere with blood tests; hyponatremia may be reported spuriously (pseudohyponatremia).

Signs and symptoms

Modestly elevated triglyceride levels do not lead to any physical symptoms. Higher levels are associated with lipemia retinalis (white appearance of the retina), eruptive xanthomas (small lumps in the skin, sometimes itchy).

Causes
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Idiopathic (constitutional) Obesity High carbohydrate diet Diabetes mellitus and insulin resistance - it is one of the defined components of metabolic syndrome (along with central obesity, hypertension, and hyperglycemia) Excess alcohol intake Nephrotic syndrome Genetic predisposition Certain medications (e.g., isotretinoin) Hypothyroidism (underactive thyroid)

Treatment
Treatment of hypertriglyceridemia is by restriction of carbohydrates and fat in the diet, as well as with niacin, fibrates and statins (three classes of drugs). Increased fish oil intake may substantially lower an individual's triglycerides.[1][2][3] Clinical practice guidelines by the National Cholesterol Education Program (NCEP) suggests that pharmacotherapy be considered with a triglycerides level over 200 mg/dL.[4] The guidelines state "the sum of LDL + VLDL cholesterol (termed non-HDL cholesterol [total cholesterol HDL cholesterol]) as a secondary target of therapy in persons with high triglycerides (200 mg/dL). The goal for non-HDL cholesterol in persons with high serum triglycerides can be set at 30 mg/dL higher than that for LDL cholesterol (Table 9) on the premise that a VLDL cholesterol level 30 mg/dL is normal."[4]

NonHDL cholesterol contains the highly atherogenic, small, dense lipoproteins that are associated with a high incidence of cardiovascular disease (CVD). Studies subsequent to the NCEP report have shown that the nonHDL cholesterol level predicts CVD in people who have diabetes. It may be superior to LDL cholesterol in this regard, and should be used as the primary lipid target in persons with diabetes. [5]

Primary prevention
Omega-3 fatty acid supplementation in the form of fish oil has been found to be effective in decreasing levels of triglycerides and thus all cardiovascular events by 19% to 45%.[6] Gemfibrozil twice daily in asymptomatic men ages 4055 without heart disease was also found to be effective at reducing cardiac endpoints at 5 years (4.14% to 2.73%). This means that 54 people must take the treatment for five years to prevent one cardiac event (number needed to treat of 54).[7]

Secondary prevention
A randomized controlled trial of men with known heart disease and HDL cholesterol of 40 mg/dl or less , 600 mg of gemfibrozil twice daily reduced cardiac endpoints (non-fatal myocardial infarction or death from coronary causes) at 5 years from 21.7% to 17.3%. This means that 23 patients must be treated for five years to prevent one cardiac event (number needed to treat is 23).[8]

Familial hypertriglyceridemia

Familial hypertriglyceridemia is a common disorder passed down through families in which the level of triglycerides (a type of fat) in a person's blood are higher than normal. The condition is not associated with a significant increase in cholesterol levels. Causes Familial hypertriglyceridemia is caused by a genetic defect, which is passed on in an autosomal dominant fashion. This means that if you get a bad copy of the gene from just one of your parents, you will have the condition. Some people with this condition also have high levels of very low density lipoprotein (VLDL). The reason for the rise in triglycerides and VLDL is not understood.

Familial hypertriglyceridemia does not usually become noticeable until puberty or early adulthood. Obesity, hyperglycemia (high blood glucose levels), and high levels of insulin are frequently associated with this condition and make cause even higher triglyceride levels. Familial hypertriglyceridemia occurs in about 1 in 500 individuals in the United States. Risk factors are a family history of hypertriglyceridemia or a family history of heart disease before the age of 50. Symptoms You may not notice any symptoms. People with the condition may have coronary artery disease at an early age. Exams and Tests People with a family history of this condition should have blood tests to check very low density lipoprotein (VLDL) and triglyceride levels. Blood tests usually show a mild to moderate increase in triglycerides. A coronary risk profile may also be done. Treatment The goal of treatment is to control conditions that can raise triglyceride levels such as obesity, hypothyroidism, and diabetes. Your doctor may tell you not to drink alcohol. Because certain birth control pills can raise triglyceride levels, you should carefully discuss their use with your doctor. Treatment also involves avoiding excess calories and foods high in saturated fats and carbohydrates. If high triglyceride levels persist despite diet changes, medication may be needed. Nicotinic acid and gemfibrozil have been shown to lower triglyceride levels in people with this condition.

Outlook (Prognosis) Persons with this condition have an increased risk of coronary artery disease and pancreatitis. Losing weight and keeping diabetes under control helps improve the outcome. Possible Complications
y y

Pancreatitis Coronary artery disease

Prevention Screening family members for high triglycerides may detect the disease early.

High-density lipoprotein
High-density lipoprotein (HDL) is one of the five major groups of lipoproteins (chylomicrons, VLDL, IDL, LDL, HDL) that enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream. In healthy individuals, about thirty percent of blood cholesterol is carried by HDL.[1] It is hypothesized that HDL can remove cholesterol from atheroma within arteries and transport it back to the liver for excretion or re-utilization, which is the main reason why HDL-bound cholesterol is sometimes called "good cholesterol", or HDL-C. A high level of HDL-C seems to protect against cardiovascular diseases, and low HDL cholesterol levels (less than 40 mg/dL or about 1mmol/L) increase the risk for heart disease. Cholesterol contained in HDL particles is considered beneficial for the cardiovascular health, in contrast to "bad" LDL cholesterol.

Structure and function

HDL is the smallest of the lipoprotein particles. They are the densest because they contain the highest proportion of protein. Their most abundant apolipoproteins are apo A-I and apo A-II.[2] The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles. They are capable of picking up cholesterol, carried internally, from cells by interaction with the ATP-binding cassette transporter A1 (ABCA1). A plasma enzyme called lecithin-cholesterol acyltransferase (LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of the lipoprotein particle, eventually making the newly synthesized HDL spherical. They increase in size as they circulate through the bloodstream and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins, for example by the interaction with the ABCG1 transporter and the phospholipid transport protein (PLTP). HDL transports cholesterol mostly to the liver or steroidogenic organs such as adrenals, ovary, and testes by direct and indirect pathways. HDL is removed by HDL receptors such as scavenger receptor BI (SR-BI), which mediate the selective uptake of cholesterol from HDL. In humans, probably the most relevant pathway is the indirect one, which is mediated by cholesteryl ester transfer protein (CETP). This protein exchanges triglycerides of VLDL against cholesteryl esters of HDL.

As the result, VLDLs are processed to LDL, which are removed from the circulation by the LDL receptor pathway. The triglycerides are not stable in HDL, but degraded by hepatic lipase so that finally small HDL particles are left, which restart the uptake of cholesterol from cells. The cholesterol delivered to the liver is excreted into the bile and, hence, intestine either directly or indirectly after conversion into bile acids. Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis of steroid hormones.

Several steps in the metabolism of HDL can contribute to the transport of cholesterol from lipid-laden macrophages of atherosclerotic arteries, termed foam cells, to the liver for secretion into the bile. This pathway has been termed reverse cholesterol transport and is considered as the classical protective function of HDL toward atherosclerosis. However, HDL carries many lipid and protein species, several of which have very low concentrations but are biologically very active. For example, HDL and their protein and lipid constituents help to inhibit oxidation, inflammation, activation of the endothelium, coagulation, and platelet aggregation. All these properties may contribute to the ability of HDL to protect from atherosclerosis, and it is not yet known what are the most important.

Recommended range

The American Heart Association, NIH and NCEP provides a set of guidelines for fasting HDL levels and risk for heart disease. Level mg/dL <40 for men, <50 for women 4059 >60 Level mmol/L <1.03 1.031.55 >1.55 Interpretation Low HDL cholesterol, heightened risk for heart disease Medium HDL level High HDL level, optimal condition considered protective against heart disease

Measuring HDL
Reference ranges for blood tests, comparing HDL cholesterol (in orange at right) to other blood constituents. Many laboratories used a two-step method: Chemical precipitation of lipoproteins containing apoprotein B, then calculating HDL as cholesterol remaining in the supernate, but there are also direct methods. Labs use the routine dextran sulfate-Mg2+ precipitation method with ultracentrifugation/dextran sulfate-Mg2+ precipitation as reference method. HPLC can be used. Subfractions (HDL-2C, HDL-3C) can be measured and have clinical significance.

Memory
A link has been shown between level of HDL and onset of dementia. Those with high HDL were less likely to have dementia.[13] Low HDL-C in late-middle age has also been associated with memory loss.

Raising HDL
Diet and lifestyle
Certain changes in lifestyle can have a positive impact on raising HDL levels:
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Aerobic exercise Weight loss Smoking cessation Removing trans fatty acids from the diet

One drink of alcohol a day or less yields higher HDL-B levels, more so in women than men. HDL transports cholesterol to the liver and cholesterol is known to have a protective effect on the cell membrane. It is likely that this reflects the liver's need for more cholesterol to protect itself from the alcohol. Adding soluble fiber to diet Using supplements such as omega 3 fish oil or flax oil Increasing intake of cis-unsaturated fats and cholesterol, decreasing intake of trans-fats. Avoiding supplements that contain omega 6 fish oil (omega 6 reduces cholesterol but does not discriminate between good and bad cholesterol) as well as limiting foods high in omega 6 (tilapia, most vegetable oils, nuts)

y y y y

A very-low-carbohydrate diet involving ketogenesis may have similar response to taking niacin as described above (lowered LDL and increased HDL) through beta-hydroxybutyrate coupling the Niacin receptor 1.

Drugs
Pharmacological therapy to increase the level of HDL cholesterol includes use of fibrates and niacin. Fibrates, however, have shown that they have no effect on overall deaths from all causes, despite their effects on lipids.[21] Niacin (B3), increases HDL by selectively inhibiting hepatic Diacylglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74[22] otherwise known as Niacin receptor 2 and HM74A / GPR109A,[20] Niacin receptor 1. Pharmacologic (1- to 3-gram) doses increase HDL levels by 1030%, making it the most powerful agent to increase HDL-cholesterol. A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events.[26] However, niacin products sold as "no-flush", i.e. not having side-effects such as "niacin flush", do not contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as "sustained-release" may contain free nicotinic acid, but "some brands are hepatotoxic"; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation. Both fibrates and niacin increase artery toxic homocysteine, an effect that can be counteracted by also consuming a multivitamin with relatively high amounts of the B-vitamins. Pharmacologic (1- to 3-gram) doses increase HDL levels by 1030%, making it the most powerful agent to increase HDL-cholesterol. A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events. However, niacin products sold as "no-flush", i.e. not having side-effects such as "niacin flush", do not contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as "sustained-release" may contain free nicotinic acid, but "some brands are hepatotoxic"; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation. In contrast, while the use of statins is effective against high levels of LDL cholesterol, it has little or no effect in raising HDL cholesterol.

DIABETIC CATARACT
While diabetes induced cataracts is common in older people, those with diabetes are more susceptible to experiencing problems at a younger age. People who have diabetes are at a higher risk of losing clear vision due to the faster progression of the disease. Diabetes induced cataracts clouds the lens of the eyes blocking light, which results in bleared vision. Left untreated diabetes induced cataracts can seriously limit a diabetics vision, allowing a person to only see light and dark images. Mild diabetes induced cataracts, at times, can be treated with prescription eyeglasses. If diabetes induced cataracts is left undiagnosed over time the cataracts can impair a persons lifestyle. People who suffer from cataracts often find themselves having to give up driving. Vision has become cloudy and it is near impossible for them to distinguish road sign or streetlights. Diabetics, like other people with cataracts reach a point when they are even unable to distinguish a pedestrian crossing the street. Those who do suffer from cataracts and who have avoided getting treatment find that their entire lifestyle is turned upside down. Before they know it, their independence is lost and they are, know longer able to live alone. As for the question of how to deal with diabetes induced cataracts, there are very limited options. Natural supplements have been proven to help or there is the surgically option. Yet if the diabetes is too far out of control, and the blood sugar is too high, the surgical option no longer applies. Blood sugar levels play an important roll between the diabetic and their eyesight. The lower the blood sugar is maintained the greater the chance of keeping the formation of cataracts at bay. One-way to deal with cataracts for the diabetic is to have your eyes checked regularly, keep blood sugar under control, and do not ignore any symptom that might be considered a warning sign of eye problems developing. Diabetic should have their eyes checked once a year, this way if diabetes induced cataracts has started treatment can get started immediately. It is surprising to know that many medications that a diabetic or anyone else takes can have drastic effects on ones eyes, medications for heart disease and depression

can have adverse effects on ones eyes, causing everything from glaucoma to retinopathy, to cataracts to eventual blindness. Knowing this you may fear taking medications and fear having a surgical procedure. Diabetic cataract: rare, usually bilateral, opacity shaped like a snowflake, affecting the anterior and posterior cortices of young diabetics; sometimes it can be reversed when the blood glucose is brought under control, but in most cases it progresses rapidly to a mature cataract.

Cardiovascular Autonomic Neuropathy Due to Diabetes Mellitus:

CAN is a common form of diabetic autonomic neuropathy and causes abnormalities in heart rate control as well as central and peripheral vascular dynamics. The clinical manifestations of CAN include exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension, painless myocardial ischemia, and increased risk of mortality. CAN contributes to morbidity, mortality, and reduced quality of life for persons with diabetes THE AUTONOMIC NERVOUS system modulates the electrical and contractile activity of the myocardium via the interplay of sympathetic and parasympathetic activity. An imbalance of autonomic control is implicated in the pathophysiology of arrhythmogenesis. Cardiovascular autonomic neuropathy (CAN), a common form of autonomic dysfunction found in patients with diabetes mellitus, causes abnormalities in heart rate control, as well as defects in central and peripheral vascular dynamics. Individuals with parasympathetic dysfunction have a high resting heart rate most likely because of vagal neuropathy that results in unopposed increased sympathetic outflow. Persons with a combined parasympathetic/sympathetic dysfunction have slower heart rates. With advanced nerve dysfunction, heart rate is fixed. Thus, it is apparent that the determination of heart rate itself is not a reliable diagnostic sign of CAN. Reduction in variability of heart rate is the earliest indicator of CAN. Clinical manifestations of CAN include exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension (OH), asymptomatic ischemia, painless myocardial infarction (MI), and increased risk of mortality Exercise intolerance In diabetic individuals with CAN, exercise tolerance is limited as a result of impaired parasympathetic/sympathetic responses that would normally enhance cardiac output and result in directing peripheral blood flow to skeletal muscles.

Reduced ejection fraction, systolic dysfunction, and decreased diastolic filling, potentially as a result of CAN, also limit exercise tolerance. For diabetic persons likely to have CAN, it has been suggested that cardiac stress testing should be performed before beginning an exercise program. When discussing exercise instructions and goals with patients with CAN, healthcare providers need to emphasize that the use of heart rate is an inappropriate gauge of exercise intensity because maximal heart rate is depressed in persons with CAN. Recently it has been shown that percentage of heart rate reserve, an accurate predictor of percentage of VO2 reserve, can be used to prescribe and monitor exercise intensity in diabetic individuals with CAN Intraoperative cardiovascular lability There is a 2- to 3-fold increase in cardiovascular morbidity and mortality intraoperatively for patients with diabetes. Studies have demonstrated that the induction of anesthesia causes a greater degree of decline in heart rate and blood pressure in diabetic patients compared with nondiabetic individuals and that hemodynamic stability, in the intraoperative period, depends on the severity of autonomic dysfunction. Patients with severe autonomic dysfunction have a high risk of blood pressure instability, and intraoperative blood pressure support is needed more often in those with greater impairment. Intraoperative hypothermia, which may decrease drug metabolism and affect wound healing, and impaired hypoxic-induced ventilatory drive have also been shown to be associated with the presence of CAN. Orthostatic hypotension A change from lying to standing normally results in activation of a baroreceptorinitiated, centrally mediated sympathetic reflex, resulting in an increase in peripheral vascular resistance and cardiac acceleration. OH is characterized by a defect in this reflex arc, resulting in signs and symptoms such as weakness, faintness, dizziness, visual impairment, and syncope. Although the absolute fall in blood pressure is arbitrary, OH is usually defined as a fall in blood pressure [i.e. >2030 mm Hg for systolic or >10 mm Hg for diastolic in response to postural change, from supine to standing. Painless myocardial ischemia Inability to detect ischemic pain can impair the recognition of myocardial ischemia or MI. The mechanisms of painless myocardial ischemia are, however, complex and not fully understood. Altered pain thresholds, subthreshold ischemia not

sufficient to induce pain, and dysfunction of the afferent cardiac autonomic nerve fibers have all been suggested as possible mechanisms Increased risk of mortality Impaired autonomic control of heart rate is linked to increased risk of mortality. Reduced parasympathetic function or increased sympathetic activity may provide the propensity for lethal arrhythmias

Treatment Interventions to Ameliorate Cardiovascular Autonomic Dysfunction via Pharmacological Agents

Glycemic control For persons with type 2 diabetes, intensive insulin therapy showed a small tendency for improved autonomic function, whereas deterioration was noted in the conventionally treated group Antioxidants During chronic hyperglycemia, the metabolism of glucose also results in the generation of free radicals. Although free radicals of superoxide and hydrogen peroxide are essential for normal cell function, excessive accumulation of free radicals is detrimental and has a direct neurotoxic effect. -Lipoic acid, an antioxidant that reduces free radical formation, appears to slow progression of CAN. For persons with type 2 diabetes, the improvement in CAN was seen after 4 months of treatment with an oral dosage of 800 mg/d . Angiotensin converting enzyme (ACE) inhibitors Microvascular insufficiency has also been proposed as a potential component in the pathogenesis of diabetic neuropathy. Results of animal studies have suggested that impaired ganglion blood flow in diabetes could be responsible for neurodegenerative changes in autonomic postganglionic cell bodies Angiotensin type 1 blockers Angiotensin type 1 (AT1) receptor mediates all potentially deleterious effects of angiotensin II. AT1 antagonists block the AT1 receptor, thus blocking the harmful effects of angiotensin II.

Aldosterone blockers Aldosterone has been shown to affect the autonomic nervous system with sympathetic activation and parasympathetic inhibition and impair the baroreflex response. Other dysfunctions associated with aldosterone include the blockage of myocardial uptake of norepinephrine in animal models and decreased arterial and venous compliance, leading to vascular organ damage. Spironolactone, an aldosterone-receptor blocker, has been used to reduce the morbidity and mortality for patients with severe heart failure