Hypercholesterolemia, and

Small amounts of trans-unsamrated fatty acids are found in ruminant fat (eg, butter fat has 2-7%), where they arise from the action of microorganisms in the rumen, but the main source in the human diet is from partially hydrogenated vegetable oils (eg, margarine). Trans fatty acids compete with essential fatty acids and may exacerbate essential fatty acid deficiency. Moreover, they are strucmrally similar to samrated fatty acids (Chapter 14) and have comparable effects in the promotion of hypercholesterolemia and atherosclerosis (Chapter 26). 

GR is a 68-year-old African-American male who presents to the emergency department with dizziness and loss of speech that began 1 hour ago. His past medical history is significant for hypertension, diabetes mellitus, hypercholesterolemia, and benign prostatic hypertrophy (BPH). Social history is significant for smoking 1 pack per day for the last 38 years. Current medications include metoprolol 50 mg twice daily, insulin NPH 20 units twice daily, and simvastatin 20 mg daily. 

Patients receiving LT4 therapy who are not maintained in a euthyroid state are at risk for long-term adverse sequelae. In general, overtreatment and a suppressed TSH is more common than undertreatment27 with an elevated TSH. Patients with long-term overtreatment may be at higher risk for atrial fibrillation and other cardiovascular morbidities, depression, and post-menopausal osteoporosis. Patients who are undertreated are at higher risk for hypercholesterolemia and other cardiovascular problems, depression, and obstetric complications. 

Fig. 11.1. Atherogenesis is a persistent inflammatory response that occurs in response to conditions that cause endothelial damage (e.g., hypercholesterolemia and oxLDL). After endothelial cells are activated, they elaborate cytokines, chemokines, and other mediators that recruit mononuclear cells (monocytes and T lymphocytes) to extravasate into the vessel wall where they are activated and release additional proinflammatory factors. Macrophages are able to take up oxLDL via scavenger receptors causing them to differentiate into foam cells and form a fatty streak that progresses to an atheroma with a necrotic lipid core and a fibrous cap. Chemokines can lead to weakening of the fibrous cap and eventual plaque rupture leading to thrombosis and occlusion of the involved vessel.

Hyperlipemia may manifest itself by an increased concentration of lipids, or certain groups thereof. For example, hypercholesterolemia and hypertriglyceri-demia may be mentioned in this connection. Since practically all the blood plasma lipids make part of lipoproteins, hyperlipemias may be reduced to one of the hyper-lipoproteinemia forms which differ in the varied ratios of plasma lipoproteins of different groups. 

Erotein whether or not cholesterol was added to the diets C3) ince the publication of this experiment over 45 years ago, there has been a recent resurgence of interest in the area of protein effects on plasma lipids and atherosclerosis. This paper summarizes some of the data generated in our laboratory over the last several years and discusses their significance in relation to hypercholesterolemia and atherosclerosis in other species including humans. 

The standard diet used in our experiments is a semipurified, cholesterol-free preparation that is composed of 25% protein, 40% sucrose, 13% coconut oil, 1% corn oil, 15% cellulose, 5% mineral mix, and 1% vitamin mix. This diet has been shown to induce an endogenous hypercholesterolemia and lead to atherosclerosis in rabbits and monkeys (4, 5). The specific question addressed by our series of investigations is whether the type of dietary protein, when all other dietary components are constant, can influence the development of hyperlipoproteinemia and atherosclerosis. More specifically, we have examined the effects of the individual amino acids, lysine and arginine, and their ratios in the diet on plasma and hepatic lipids as well as the development of arterial plaques. 

Sorensen, K. E., Celermajer, D. S., Georgakopoulos, D., Hatcher, G., Betteridge, D. J., and Deanfield, J. E., Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J. Clin. Invest. 93, 50-55 (1994). 

Currently, there is stUl a gap for the potential of gene therapy to be fulfilled. Gene therapy clinical trials have been conducted for diseases such as severe combined immunodeficiency disease (SCID, bubble baby syndrome), sickle cell anemia, cystic fibrosis, familial hypercholesterolemia, and Gaucher disease. 

Mnshrooms are important in the ecosystem because they are able to biodegrade the substrate and therefore use the wastes of agricultural production [1]. Mushrooms have also been reported as therapeutic foods, useful in preventing diseases such as hypertension, hypercholesterolemia, and cancer. These functional characteristics are mainly due to their chemical composition [2]. Heavy metal concentrations in mushroom are considerably higher than those in agricultural crop plants, vegetables and fmit. This suggests that mushrooms possess a very effective mechanism that enables them readily to take up some heavy metals from the ecosystem. 

Atypical dysbetalipoproteinemia, associated with the APOE-313 phenotype rather than the classic APOE-212 phenotype, is characterized by severe hypercholesterolemia and hypertriglyceridemia, xanthomatosis, premature vascular disease, and a preponderance of 3-VLDL. Subjects with atypical dysbetalipoproteinemia are homozygous for an amino acid substitution in APOE at residue 158 (495). In AD, APOE-4 carriers show lower levels of APOE in the CSF compared to controls (496). 

LDL receptor deficiency leads to extreme hypercholesterolemia and its sequelae by two mechanisms. -Failure to take up cholesterol bound to LDL particles leads to accumulation and consequent elevation of blood LDL cholesterol. 

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

HMG-CoA Reductase Inhibitors Statins inhibit HMG-CoA reductase, the enzyme synthesizing mevalonic acid (a key step in cholesterol biosynthesis). These drugs are indicated to treat hypercholesterolemia and to reduce LDL cholesterol. 

Simvastatin is indicated in patients with coronary heart disease and hypercholesteremia, for the reduction of elevated total and LDL cholesterol in patients with primary hypercholesterolemia (type Ila and Ilb hyperlipoproteinemia), combined hypercholesterolemia and hypertriglyceridemia. 

Is an indigenous drug obtained from gum guggul used for treatment of hyperlipidemia, hypercholesterolemia and hypertriglyceridemia. 

In combination with a resin or reductase inhibitor, niacin normalizes LDL in most patients with heterozygous familial hypercholesterolemia and other forms of hypercholesterolemia. These combinations are also indicated in some cases of nephrosis. In severe mixed lipemia that is incompletely responsive to diet, niacin often produces marked reduction of triglycerides, an effect enhanced by marine omega-3 fatty acids. It is useful in patients with combined hyperlipidemia and in those with dysbetalipoproteinemia. It is clearly the most effective agent for increasing HDL and the only agent that may reduce Lp(a). 

For treatment of heterozygous familial hypercholesterolemia, most patients require 2-6 g of niacin daily more than this should not be given. For other types of hypercholesterolemia and for hypertriglyceridemia, 1.5-3.5 g daily is often sufficient. Crystalline niacin should be given in divided doses with meals, starting with 100 mg two or three times daily and increasing gradually. 

This combination is highly synergistic in treating primary hypercholesterolemia and has some use in the treatment of patients with homozygous familial hypercholesterolemia who have some receptor function. 

Patients with HL deficiency present with hypercholesterolemia and hypertriglyceridemia, and accumulate VLDL remnants, triglyceride-rich LDL, and HDL [84]. These remnants mainly derive from a reduced catabolism of apoB-containing lipoproteins [82]. The disorder appears to be inherited in an autosomal recessive trait and is associated with an increased risk for coronary artery disease [8]. 

The initial steps in BA synthesis are characterised by the introduction of a hy-droxylic group in the la position, or in position 27, followed by another in the la position into the cholesterol nucleus. Both synthetic pathways (the neutral and the acidic pathways) possess a distinct microsomal 7-oxysterol hydroxylase, which is regulated by different genes. The most recently described disorder of BA synthesis is cholesterol 7a-hydroxylase deficiency, in which their decreased production through the classical pathway is partially balanced by activation of the alternative pathway. Cholesterol levels increase in the liver, with a consequent low-density lipoprotein hypercholesterolemia, and cholesterol gallstones may result, although there is no liver disease. In contrast, a defect in the conversion of 27-hydroxy-cholesterol to la,27-dihydroxy-cholesterol due to deficiency of the oxysterol 7a-hydroxylase specific for the alternate pathway, causes severe neonatal liver disease [8]. 

Production of LDL from VLDL in the plasma With these modifications, the VLDL is converted in the plasma to LDL. An intermediate-sized particle, the intermediate-density lipoprotein (IDL) or VLDL remnant, is observed during this transition. IDLs can also be taken up by cells through receptor-mediated endocytosis that uses apo E as the ligand. [Note Apolipoprotein E is normally present in three isoforms, E2, E3, and E4. Apo E2 binds poorly to receptors, and patients who are homozygotic for apo E2 are deficient in the clearance of chylomicron remants and IDLs. The individuals have familial type III hyperlipoproteinemia (familial dysbetalipoproteinemia, or broad beta disease), with hypercholesterolemia and premature atherosclerosis. Not yet understood is the fact that the E4 isoform confers increased susceptibility to late-onset Alzheimer disease.]... 

After binding, the LDL-receptor complex is internalized by endocytosis. [Note A deficiency of functional LDL receptors causes a significant elevation in plasma LDL and, therefore, of plasma cholesterol. Patients with such deficiencies have type II hyperlipidemia (familial hypercholesterolemia) and premature atherosclerosis. The thyroid hormone, T3, has a positive effect on the binding of LDL to its receptor. Consequently, hypothyroidism is a common cause of hypercholesterolemia.]... 

A 29-year-old woman, a smoker with a history of renal insufficiency, obesity, hypertension, hypercholesterolemia, and cardiac dysrhythmias, underwent termination... 

---