| Defects in the lipoprotein metabolism lead to disorders known as hyperlipidemias or, dyslipidemias. Table 17.3 gives the examples of dyslipidemias.
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| DYSLIPIDEMIA IS COMMON IN DIABETES MELLITUS |
Mr B was 67 years old and had type 2 diabetes and mild hypertension. When he visited the outpatient clinic, his cholesterol was 6.9 mmol/L (265 mg/dL), triacylglycerol (triglycerides) 1.9 mmol/L (173 mg/dL), and HDL 0.9 mmol/L (35 mg/dL). Fasting blood glucose was 8.5 mmol/L (153 mg/dL) and glycated hemoglobin 1c (HbA1c) 6%. He was treated with diet and a sulfonylurea derivative which potentiates glucose-stimulated insulin release and lowers blood glucose concentration. |
| Comment. Diabetes carries a 2-3 times increased risk of coronary heart disease. This patient's diabetes was well controlled but cholesterol level remained high, so that he required lipid-lowering drug treatment. Low HDL-cholesterol concentration is relatively common in type 2 diabetes. |
| The patient was prescribed a lipid lowering drug in addition to his treatment with a sulfonylurea derivative. Blood pressure responded to treatment with an angiotensin converting enzyme inhibitor (see Chapter 20). |
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| Note that in the western populations, approximately 30% of people have undesirably high plasma cholesterol concentration. The most frequent dyslipidemia (common hypercholesterolemia) is polygenic and is a result of combined genetic and environmental factors such as diet. Then there are rarer disorders with defined genetic background. The most important of these is the familial hypercholesterolemia, a monogenic disorder caused by a mutation in the gene coding for the apoB/E(LDL) receptor. It affects both fuel transport- and overflow pathways, and both remnants and LDL accumulate. The effect on LDL is the most visible. Patients with familial hypercholesterolemia have very high plasma cholesterol and LDL-cholesterol concentrations. There also is a prominent family history of early heart disease, consistent with the autosomal
dominant inheritance. In addition, some patients develop lipid deposits on hand and knee tendons, and particularly on the Achilles tendon: these are known as tendon xanthomas, and are diagnostic for the disorder. Familial hypercholesterolemia carries a high risk of cardiovascular disease.
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| Another disorder, similarly inherited dyslipidemia, is the familial combined hyperlipidemia characterized by an overproduction of apoB100 rather than the impairment of receptor-mediated clearance. There is an increased production of VLDL and consequently, increased generation of LDL: again, both the fuel transport- and the overflow pathway become overloaded. This dyslipidemia presents with variable plasma lipid patterns (either hypercholesterolemia or both hypercholesterolemia and hypertriglyceridemia). Familial combined hyperlipidemia is a relatively common cause of premature myocardial infarction (note: premature infarction is defined as one occurring in a man aged below 55 years or a woman below 65 years).
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| A dyslipidemia affecting primarily fuel transport pathway is the familial dysbetalipoproteinemia caused by a mutation in the apoE gene, yielding apoE isoform with low affinity for the apoB/E receptor (see Box). In this disease the remnants accumulate and there is an increase in both cholesterol and triglycerides in the plasma. Here the characteristic xanthomas occur in palms (palmar xanthoma). Familial dyslipidemia is also associated with early coronary disease.
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| FAMILIAL HYPERCHOLESTEROLEMIA IS A MONOGENIC LIPID DISORDER ASSOCIATED WITH HEART ATTACKS OCCURRING AT YOUNG AGE |
| A 32-year-old heavy smoker developed a sudden crushing chest pain. He was admitted to the casualty department. Myocardial infarction was confirmed by ECG changes and by high cardiac troponin concentration. On examination the patient had tendon xanthoma on hands and thickened Achilles tendons. There was a strong family history of coronary heart disease (his father had had a coronary bypass graft at the age of 40 and his paternal grandfather died of myorardial infarction in his early fifties). His cholesterol was 10.0 mmol/L (390 mg/dL), triglycerides 2 mmol/L (182 mg/dL) and HDL 1.0 mmol/L (38 mg/dL). |
| Comment. This patient has familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by a decreased number of LDL receptors. FH carries a very high risk of premature coronary disease, and heterozygotic individuals may suffer heart attacks as early as the 3rd or 4th decade of life. The frequency of FH homozygotes in western populations is approximately 1:500. |
| This patient was immediately treated with intravenous tissue plasminogen activator. Subsequently he underwent coronary artery bypass graft and was then treated with lipid-lowering drugs. His cholesterol concentration subsequently decreased to 4.8 mmol/L (185 mg/dL) and triglyceride (triacylglycerol) level to 1.7 mmol/L, with HDL-cholesterol increasing to 1.1 mmol/L (42 mg/dL). |
| Dyslipidemia affecting primarily the fuel transport pathway is also characteristic for the type 2 diabetes mellitus. There is the overload of the fuel transport pathway, due to increased VLDL synthesis and a consequent increase in the remnant concentration. Also, there is a decreased concentration
of HDL-cholesterol. The diabetic patients often have normal LDL-cholesterol because the overflow pathway remains quantitatively unaffected; however, it is possible that diabetic LDL are more atherogenic than the non-diabetic particles, because of changes in their size and density.
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| The instance where glucose intolerance or diabetes, low HDL-cholesterol, abdominal obesity, and hypertension occur together is known as the metabolic syndrome (actually, the presence of any three of these abnormalities is sufficient for diagnosis). The metabolic syndrome is associated with an increased risk of coronary disease.
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| A very rare dyslipidemia affecting exclusively the fuel transport pathway is caused by the deficiency of LPL. This overloads the 'front end' of the pathway; VLDL metabolism is defective and its accumulation leads to very high triacylglycerol (triglyceride) concentrations. Clinical signs include characteristic, rash-like skin xanthomas. The risk associated with LPL deficiency is primarily that of pancreatic inflammation (pancreatitis, see Chapter 9) caused by the large triacylglycerol load.
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