Secondary Hyperlipoproteinaemias

For a review of secondary hyperlipoproteinaemias see reference [Durrington, 1995a].

 

Definition of secondary hyperlipoproteinaemias

Secondary hyperlipoproteinaemias are those caused by another primary disorder (see Table 3). When a disease that has dyslipidaemia as a complication occurs in an individual who has a primary hyperlipoproteinaemia, the two frequently synergise to produce marked hyperlipoproteinaemia.

Table 3. Common causes of secondary hyperlipoproteinaemia

This means that in societies in which polygenic hyperlipoproteinaemia is prevalent, secondary hyperlipoproteinaemia will have most impact. The best-known example of this is diabetes mellitus, which in Japan is only rarely complicated by CHD, whereas in the UK and the USA, CHD is the most common cause of premature death in patients with diabetes.

What is the phenotype?
The dominant dyslipidaemia in diabetes is hypertriglyceridaemia. This is more likely to be associated with hypercholesterolaemia and with decreased HDL-C in type 2 diabetes. Despite this, the risks of clinical atherosclerosis are increased in both types 1 and 2 diabetes. This may be because in both disorders the hypertriglyceridaemia results, not simply from an increase in VLDL, but also from an increase in IDL and a small, triglyceride-rich, cholesterol-depleted LDL particle. Since neither of these may contribute greatly to an increase in cholesterol, the term dyslipoproteinaemia is particularly apt for use in diabetes. Also, plasma fibrinogen levels, which are increased in both types of diabetes, relate to serum triglyceride levels.

Risk of CHD
Although lipoprotein abnormalities in type 1 diabetes may be less frequent than in type 2 diabetes, the risk of CHD in type 1 diabetes is more often compounded by the presence of proteinuria. In diabetes uncomplicated by proteinuria, the risk of CHD is about two to three times that of age-matched patients without diabetes. Proteinuria increases the risk by almost 40 times [Borch-Johnsen, 1987]. This may stem partly from hypertension and an exacerbation of the dyslipoproteinaemia, which accompany the development of proteinuria. The increase in risk is, however, greater than can be explained in this way, and may occur because the proteinuria reflects a generalised increase in the permeability of arterial endothelium, enhancing the entry of macromolecules into the subintima and thus accelerating atherogenesis.

Influence of insulin resistance syndrome
The increased blood glucose in diabetes mellitus results from insulin resistance, insulin deficiency, or both. Insulin resistance may be present in people without diabetes (usually obese) who are still able to secrete sufficient insulin to maintain control of blood sugar. In such people there is, however, often hypertriglyceridaemia with low HDL-C and hypercholesterolaemia, hypertension and increased risk of CHD. This syndrome is often referred to as the insulin resistance syndrome (syndrome X) or chronic cardiovascular risk syndrome. Clearly, it has features in common with familial combined hyperlipidaemia and also with diabetes. Indeed, some people with the condition ultimately develop diabetes [Reaven, 1993; Haffner, 1990], sometimes not until after they have already developed CHD. This may be part of the reason why glycaemic control in diabetes seems to have little impact in preventing its atheromatous complications.

Risk for women
Women with diabetes, particularly those with type 2 diabetes, tend to have a distribution of adipose tissue resembling that of obese men, with the adipose tissue being found mostly around the abdomen and waist, rather than the more female pattern that involves the buttocks and thighs, but leaves the waist relatively small. The relative protection from CHD that most women have (even those with familial hypercholesterolaemia), is largely lost by women with diabetes [Barrett-Connor, 1991], and it has been suggested that this may result from this androgenisation. Many women with a similar body habitus, but who have not yet developed diabetes, are insulin resistant, have hypertension, have dyslipidaemia and have an associated increased risk of CHD. There is an undoubted overlap here too with polycystic ovary syndrome.

• Obesity is a potent cause of dyslipidaemia and has more impact in people with glucose intolerance.
• In its own right, obesity predominantly causes hypertriglyceridaemia (usually type IV), but it can exacerbate all forms of primary dyslipidaemia.
• It frequently, therefore, accompanies hypercholesterolaemia as well as hypertriglyceridaemia. The exception appears to be familial hypercholesterolaemia, which is not associated with obesity.
• Alcoholic beverages, particularly wine and beer, are energy rich and may be a cause of obesity, and alcohol itself also causes hypertriglyceridaemia.
• Weight loss is generally associated with decreases in serum cholesterol and triglyceride levels. Anorexia nervosa is paradoxical in that it may be associated with quite marked elevations of serum cholesterol.

• In hypothyroidism, serum LDL-C and, less frequently, serum triglyceride levels are raised, while HDL levels tend to be increased.
• There is decreased receptor-mediated LDL catabolism and lipoprotein lipase activity may be decreased.
• Hypothyroidism should always be considered in the diagnosis of dyslipidaemia, and it is particularly important to exclude it when marked dyslipidaemia occurs in women and in patients with diabetes.

• Renal disease is becoming an important cause of secondary dyslipidaemia in clinical practice, because improvements in long-term renal management are now exposing CHD as the major cause of premature death in many renal disorders.
• In the nephrotic syndrome, the major lipoprotein disorder is a rise in serum LDL-C.
• In chronic renal failure, hypertriglyceridaemia is produced by an increase in both VLDL and LDL triglycerides.
• Haemodialysis, chronic ambulatory peritoneal dialysis and high-energy diets exacerbate the dyslipidaemia.
• Following renal transplantation, many of the lipoprotein abnormalities resolve if good renal function is established, but corticosteroid therapy, weight gain, antihypertensive therapy and, perhaps, cyclosporin treatment mean that even then, dyslipidaemia persists in approximately 25% of patients.
• Lp(a) is markedly elevated in renal disease, even after transplantation.

• Beta-blockers without intrinsic sympathomimetic activity raise triglycerides and lower HDL-C.
• Thiazide diuretics tend to increase both cholesterol and triglycerides. These effects may be relatively small in people whose serum lipids are not elevated at the outset, but in patients with hypertriglyceridaemia or with diabetes they may be substantial.
• Oestrogens tend to raise serum triglycerides, but will often lower LDL-C after the menopause. They also raise serum HDL.
• Androgens have the opposite effect, decreasing triglycerides, raising LDL-C and lowering HDL. Androgens may contribute to premature cardiac death in athletes unwise enough to use them in training.
• Glucocorticoids increase serum LDL-C and triglycerides and often HDL-C.
• Retinoic acid derivatives used in the management of skin disorders cause hypertriglyceridaemia.
• Phenytoin and phenobarbitone raise serum HDL-C.

• Cholestatic liver diseases, such as primary biliary cirrhosis, produce hypercholesterolaemia.
• This is not caused by an increase in apo B-containing LDL, but by an abnormal lipoprotein, designated lipoprotein X (LpX), produced largely as the result of reflux of biliary phospholipids into the circulation.
• Xanthelasmata are common in biliary obstruction, and other xanthomata occasionally develop. In the later phase of chronic biliary obstruction, when secondary biliary cirrhosis and hepatocellular disease set in, hepatic lipid biosynthesis plummets and the dyslipidaemia of biliary obstruction resolves.
• Hepatocellular diseases may themselves be associated with moderate hypertriglyceridaemia, probably because of impaired hepatic lipoprotein clearance. HDL concentrations are markedly decreased and LCAT activity is low.
• Some authorities believe that this defect in cholesterol esterification contributes to the complications of liver failure.

• Hyperuricaemia is present in as many as 50% of men with hypertriglyceridaemia.
• Hyperuricaemia may lead to gout, particularly if such patients are receiving diuretic therapy.
• The association of hypertriglyceridaemia and hyperuricaemia appears to be more common than can be entirely explained by the coincidence of common aetiological factors, such as obesity and high alcohol consumption. Yet they are not causally related, because lowering one specifically does not usually decrease the other. They must, therefore, have some unknown antecedent in common.