Epidemiologic evidence supports the atherogenicity of VLDL, chylomicrons, and their remnants. They have been demonstrated in atherosclerotic plaques from humans. Impaired capacity of the VLDL of some individuals to accept cholesteryl esters from the LCAT reaction may also contribute to atherogenesis by impeding centripetal transport of cholesterol.
Very high levels of triglycerides in plasma are associated with a risk of acute pancreatitis, probably from the local release of FFA and lysolecithin from lipoprotein substrates in the pancreatic capillary bed. When these lipids exceed the binding capacity of albumin, they could lyse membranes of parenchymal cells, initiating a chemical pancreatitis. Many patients with lipemia have intermittent episodes of epigastric pain during which serum amylase does not reach levels commonly considered diagnostic for pancreatitis especially in patients who have had previous attacks. These episodes frequently evolve into classic pancreatitis suggesting that they represent incipient pancreatic inflammation. The progression of pancreatitis often can be prevented by rapid reduction of triglycerides, usually accomplished by restriction of all dietary fat for at least 72 hours or until symptoms disappear. In some cases, parenteral feeding, excluding fat emulsions, may be required for a few days.
When triglyceride levels in serum exceed 3000 to 4000 mg/dL (34.5-46 mmol/L), light scattering by these particles in the blood lends a whitish cast to the venous vascular bed of the retina, a sign known as lipemia retinalis (Figure 19–3). Markedly elevated levels of VLDL or chylomicrons may be associated with the appearance of eruptive cutaneous xanthomas (see Figure 19–3E). These lesions, filled with foam cells, appear as yellow morbilliform eruptions 2 to 5 mm in diameter, often with erythematous areolae. They usually occur in clusters on extensor surfaces such as the elbows, knees, and buttocks. They are transient and disappear within a few weeks after triglyceride levels are reduced.
Clinical manifestations of hyperlipidemias. A. Xanthelasma involving medial and lateral canthi. B. Severe xanthelasma and arcus corneae. C. Tuberous xanthomas. D. Large tuberous xanthoma of elbow. E. Eruptive xanthomas, singly and in rosettes. F. Xanthomas of extensor tendons of the hands. G. Xeroradiogram of Achilles tendon xanthoma. H. Xanthoma of Achilles tendon. (Normal Achilles tendons do not exceed 7 mm in diameter in the region between the calcaneus and the point at which the tendon fibers begin to radiate toward their origins.)
Effects of Hypertriglyceridemia on Laboratory Measurements
Light scattering from high levels of triglyceride-rich lipoproteins can cause erroneous results in most chemical determinations involving photometric measurements. Amylase activity in serum may be inhibited; therefore, lipemic specimens should be diluted for measurement of this enzyme. Because the lipoproteins are not permeable to ionic or polar molecules, their core regions constitute a second phase in plasma. When the volume of this phase becomes appreciable, electrolytes and other hydrophilic species are underestimated with respect to their true concentration in the aqueous phase. A practical rule for correcting these values is as follows: For each 1000 mg/dL (11.5 mmol/L) of triglyceride, the measured concentrations of all hydrophilic molecules and ions should be adjusted upward by 1%.
1. DEFICIENCY OF LIPOPROTEIN LIPASE ACTIVITY
The activity of LPL is dependent upon the integrity of the enzyme and its cofactor, Apo C-II. In addition, defects in Apo A-V, GPIHBP1, and LMF1 proteins can result in severe impairment of LPL activity. Because the clinical expressions of these defects are similar, they are considered together. On a typical North American diet, lipemia is usually severe (triglycerides of 2000-25,000 mg/dL) (23-287.5 mmol/L). Hepatomegaly and splenomegaly are frequently present. Foam cells laden with lipid are found in liver, spleen, and bone marrow. Splenic infarct has been described and may be a source of abdominal pain. Hypersplenism with anemia, granulocytopenia, and thrombocytopenia can occur. Recurrent epigastric pain and overt pancreatitis are frequently encountered. Eruptive xanthomas may be present. These disorders may be recognized in early infancy or may go unnoticed until an attack of acute pancreatitis occurs or lipemic serum is noted on blood sampling as late as middle age. Patients with these disorders are usually not obese and have normal carbohydrate metabolism unless pancreatitis impairs insulinogenic capacity. Estrogens intensify the lipemia by stimulating hepatic production of VLDL. Therefore, in pregnancy and lactation or during the administration of estrogenic steroids, the risk of pancreatitis increases.
There is a preponderance of chylomicrons in serum. Many patients have a moderate increase in VLDL, however, and in pregnant women or those receiving estrogens, a pattern of mixed lipemia is usually present. Levels of LDL are decreased, reflecting catabolism of VLDL by pathways that do not involve the production of LDL.
A presumptive diagnosis of these disorders can be made by restricting oral intake of fat to 10 to 15 g/d. Triglycerides drop precipitously, usually reaching 200 to 600 mg/dL (2.3-6.9 mmol/L) within 3 to 4 days unless the patient has significant hepatic steatosis, in which case there may be continued excretion of VLDL. Confirmation of deficiency of LPL is obtained by measurement of the lipolytic activity of plasma 10 minutes after injection of heparin (0.2 mg/kg over 10 minutes) intravenously. Analysis of lipolysis is done with or without 0.5 mol/L sodium chloride, which inhibits LPL but does not suppress the activity of hepatic lipase. Abnormalities in LMF-1, GPIHBP, Apo A-V, and Apo C-II are identified by genotyping.
Treatment of chylomicronemia is primarily dietary. Plasmapheresis may be helpful in the initial management of acute or incipient pancreatitis. Intake of total fat should be limited in most adult patients to 15 g/d. Because the defect involves lipolysis, both saturated and unsaturated fats must be curtailed. The diet should contain at least 5 g of polyunsaturated fat as a source of essential fatty acids, and fat-soluble vitamins must be provided. Administration of 500 mg daily of marine omega-3 fatty acids is also recommended. Adherence to this diet invariably maintains triglycerides below 1000 mg/dL (11.2 mmol/L) in the absence of pregnancy, lactation, the administration of exogenous estrogens, or alcohol. Because this is below the level at which pancreatitis usually occurs, compliant patients are at low risk. Pregnant women with these disorders require particularly close monitoring. Antisense oligonucleotide knockdown strategy for Apo C-III, currently under active investigation, may prove to be useful in management of severe hypertriglyceridemia.
2. ENDOGENOUS AND MIXED LIPEMIAS
Etiology and Pathogenesis
Endogenous lipemia (elevated VLDL) and mixed lipemia probably both result from several genetically determined disorders. Because VLDL and chylomicrons are competing substrates in the intravascular lipolytic pathway, saturating levels of VLDL impede the removal of chylomicrons. Therefore, as the severity of endogenous lipemia increases, a pattern of mixed lipemia may supervene. In other cases, the pattern of mixed lipemia appears to be present continuously. Although specific pathophysiologic mechanisms remain obscure, certain familial patterns are known. In all forms, factors that increase the rate of secretion of VLDL aggravate the hypertriglyceridemia (ie, obesity with insulin resistance, appearance of fully developed type 2 diabetes mellitus, alcohol, and exogenous estrogens). Studies of VLDL turnover indicate that either increased production or impaired removal of VLDL may be operative in different individuals. A substantial number of patients with mixed lipemia have partial defects in catabolism of triglyceride-rich lipoproteins, often due to heterozygosity for mutations in LPL. Most patients with significant endogenous or mixed lipemia have centripetal obesity.
Clinical features of these forms of hypertriglyceridemia depend on their severity and include eruptive xanthomas, lipemia retinalis, recurrent epigastric pain, and acute pancreatitis.
Endogenous lipemia is frequently an element in a constellation of metabolic abnormalities termed the metabolic syndrome. Insulin resistance, usually associated with central obesity, is a core feature of this syndrome. Patients may or may not have hyperglycemia. Low levels of HDL cholesterol largely reflect increased transfer of CE into circulating VLDL and, therefore, are not a primary component of the syndrome. Hypertension and hyperuricemia are frequently present.
The first element of treatment is severe restriction of total fat intake. The objective of long-term dietary management is reduction to ideal body weight. Because alcohol causes significant augmentation of VLDL production, abstinence is important. If weight loss is achieved, the triglycerides almost always show a marked response, often approaching normal values. When the fall in triglycerides is not satisfactory, a fibrate or nicotinic acid (in the absence of insulin resistance), singly or in combination, usually produces further reductions. When insulin resistance is present, metformin may be a useful adjunct.
3. FAMILIAL COMBINED HYPERLIPIDEMIA
This inherited disorder, which is the most common form of hyperlipidemia, occurs in 1% to 2% of the population. The underlying process involves overproduction of VLDL. Some affected individuals have increased levels of both VLDL and LDL (combined hyperlipidemia); some have predominantly increased levels of either VLDL or LDL. The level of Apo B-100 is increased. Patterns in the serum of an individual may change with time. It is known that the offspring of an individual having any one of the three phenotypic patterns can have one of the other patterns. Affected children often have hyperlipidemia. If the child is obese, hypertriglyceridemia is likely present, whereas a child of normal weight may have only an elevated LDL.
Neither tendinous nor cutaneous xanthomas other than xanthelasma occur. This disorder appears to be inherited as a Mendelian dominant trait involving alternative loci. Modifying genes have been published, but major loci have not been identified. Factors that increase the severity of hypertriglyceridemia in other disorders aggravate the lipemia in this syndrome as well.
The risk of coronary disease is significantly increased, and patients should be treated aggressively with diet and drugs. Because LDL levels often increase with fibrate therapy in these patients and because resins increase triglycerides, the recommended treatment is an HMG-CoA reductase inhibitor. The addition of niacin or fenofibrate may be required if triglycerides remain elevated. Fenofibrate may be used cautiously with rosuvastatin.
4. FAMILIAL DYSBETALIPOPROTEINEMIA (TYPE III HYPERLIPOPROTEINEMIA)
Etiology and Pathogenesis
A permissive genetic constitution for this disease (homozygosity for Apo E-2) occurs in about 2% of the U.S. population but the expression of hyperlipidemia apparently requires environmental and possibly additional genetic determinants. The molecular basis is the presence of isoforms of Apo E that are poor ligands for high-affinity receptors. In its fully expressed form, the lipoprotein pattern is dominated by the accumulation of remnants of VLDL and chylomicrons. Levels of LDL are decreased, reflecting interruption of the transformation of VLDL remnants to LDL. The primary defect is impaired hepatic uptake of remnants of triglyceride-rich lipoproteins. The remnant particles are enriched in cholesteryl esters such that the level of cholesterol in serum is often as high as that of triglycerides. Absence of the E-3 and E-4 alleles in genomic DNA confirms the diagnosis. Additional ligand defective mutations of Apo E are now known to result in dysbetalipoproteinemia. Some of these cause hyperlipidemia in the heterozygous state, a disorder termed dominant dysbetalipoproteinemia.
Hyperlipidemia and clinical signs are not usually evident before age 20. In younger patients with hyperlipidemia, hypothyroidism or obesity is likely to be present. Adults frequently have tuberous or tuberoeruptive xanthomas (see Figure 19–3C). Both tend to occur on extensor surfaces, especially elbows and knees. Tuberoeruptive xanthomas are pink or yellowish skin nodules 3 to 8 mm in diameter that often become confluent. Tuberous xanthomas—shiny reddish or orange nodules up to 3 cm or more in diameter—are usually moveable and nontender. Another type, planar xanthomas of the palmar creases, strongly suggests dysbetalipoproteinemia. The skin creases assume an orange color from deposition of carotenoids. They occasionally are raised above the level of adjacent skin and are not tender. (Planar xanthomas are also seen in cholestasis.)
Some patients have impaired glucose tolerance, which is usually associated with higher levels of blood lipids. Obesity is commonly present and tends to aggravate the lipemia. Patients with the genetic constitution for dysbetalipoproteinemia often develop severe hyperlipidemia if they are hypothyroid. Atherosclerosis of the coronary and peripheral vessels occurs with increased frequency, and the prevalence of disease of the iliac and femoral vessels is especially high.
Management includes a weight reduction diet providing a reduced intake of cholesterol, fat, and alcohol. When the hyperlipidemia does not respond satisfactorily to diet, a fibrate or niacin in low doses (if the patient does not have insulin resistance) is usually effective. These agents can be used together in resistant cases. Some patients respond to the more potent reductase inhibitors alone, and the addition of niacin normalizes the lipid levels in most.
In patients with diabetes, levels of VLDL in plasma are frequently elevated. The severe lipemia associated with absence or marked insufficiency of insulin is attributable to decreased transcription of the LPL gene. The administration of insulin usually restores triglyceride levels to normal within a few days. However, if massive fatty liver is present, weeks may be required for the VLDL to return to normal while the liver secretes its triglycerides. Conversion of massive amounts of VLDL to LDL as the impedance of VLDL catabolism is relieved leads to marked accumulation of LDL that may persist for weeks, leading to a spurious diagnosis of primary hypercholesterolemia.
The moderately elevated VLDL seen in type 2 diabetes under average control probably reflects chiefly an increased flux of FFA to liver that stimulates production of triglycerides and their secretion in VLDL. In addition to VLDL, LDL levels are also somewhat increased in diabetic individuals under poor control, probably accounting in part for their increased risk of CHD. Some have much higher levels of VLDL, suggesting that an additional genetic factor predisposing to lipemia is present. Still another cause of lipemic diabetes is the compromised insulinogenic capacity that can result from acute pancreatitis. The deficiency may be severe enough to require exogenous insulin, often only in small doses. In diabetic individuals who develop nephrosis, the secondary lipemia of nephrosis compounds their hypertriglyceridemia. In the presence of hyperglycemia, lipoproteins become glycosylated, leading to their uptake by macrophages.
Lipemia may be very severe, with elevated levels of both VLDL and chylomicrons when control is poor. Lipemic patients usually have ketoacidosis when they are insulin-deficient, but lipemia can occur in its absence. Patients with type 1 diabetes who have been chronically undertreated with insulin may have mobilized most of the triglyceride from peripheral adipose tissue, so that they no longer have sufficient substrate for significant ketogenesis. These emaciated individuals may have severe lipemia and striking hepatomegaly.
In type 1 diabetes, the rigid control of blood glucose levels, which can be attained with continuous subcutaneous insulin infusion, is associated with sustained normalization of levels of both LDL and VLDL. The lipemia of type 2 diabetes usually responds well to control of the underlying disorder. In obese insulin-resistant individuals, weight loss is essential. Diets containing slowly absorbed carbohydrates are well tolerated, allowing a decrease in the burden of chylomicron triglycerides in plasma (see Chapter 17).
Uremia is associated with modest isolated increases in VLDL. The most important underlying mechanisms are probably insulin resistance and impairment of catabolism of VLDL. Many uremic patients are also nephrotic. The additional effects of nephrosis on lipoprotein metabolism may produce a combined hyperlipidemia. Patients who have had renal transplants may be receiving glucocorticoids, which induce elevation of LDL.
3. HUMAN IMMUNODEFICIENCY VIRUS INFECTION
HIV infection per se is associated with hypertriglyceridemia (see Chapter 25). A syndrome of partial lipodystrophy and insulin resistance, often with marked lipemia, occurs with multidrug treatment that includes certain inhibitors of viral proteases. Acute pancreatitis can ensue. Limited clinical experience suggests that fibric acid derivatives are of some value. Alcohol must be avoided.
In endogenous Cushing syndrome and with corticosteroid treatment, insulin resistance is present, and levels of LDL are increased. It appears that the hyperlipidemia is primarily due to increased secretion of VLDL, which is then catabolized to LDL. More severe lipemia ensues when steroidogenic diabetes appears, reducing catabolism of triglyceride-rich lipoproteins via the LPL pathway.
When estrogens are administered to normal women, triglyceride levels may increase by as much as 15%, reflecting increased production of VLDL. Paradoxically, estrogens increase the efficiency of catabolism of triglyceride-rich lipoproteins. Whereas estrogens tend to induce insulin resistance, it is not clear that this is an important mechanism, because certain nortestosterone derivatives decrease plasma triglycerides despite the induction of appreciable insulin resistance.
Certain individuals, usually those with preexisting mild lipemia, develop marked hypertriglyceridemia when receiving estrogens even in relatively small doses. Thus, triglycerides should be monitored during estrogen therapy. Contraceptive combinations with predominantly progestational effects produce less hypertriglyceridemia than purely estrogenic compounds. Transdermal delivery of estrogen probably results in lesser increases in VLDL secretion because it avoids the hepatic first-pass effect.
Ingestion of appreciable amounts of alcohol does not necessarily result in significantly elevated levels of triglycerides, but many alcoholics are lipemic. Alcohol profoundly increases triglycerides in patients with primary or secondary hyperlipemias. In Zieve syndrome, the alcohol-induced lipemia is associated with hemolytic anemia and hyperbilirubinemia. Because LCAT originates in liver, severe hepatic parenchymal dysfunction may lead to deficiency in the activity of this enzyme. A resultant accumulation of unesterified cholesterol in erythrocyte membranes may account for the hemolysis seen in Zieve syndrome.
Alcohol is converted to acetate, exerting a sparing effect on the oxidation of fatty acids that are then incorporated into triglycerides. This results in hepatomegaly due to fatty infiltration and in marked enhancement of secretion of VLDL. In many individuals, there is sufficient adaptive increase in the removal capacity for triglycerides so that plasma levels are normal.
7. NONALCOHOLIC FATTY LIVER DISEASE AND NONALCOHOLIC STEATOHEPATITIS
These conditions are characterized by hepatic steatosis and abnormalities of liver enzymes in the absence of alcohol ingestion. The cause is not yet understood, but it is likely that misdirection of fatty acids from oxidative pathways to hepatic triglyceride synthesis is involved. Five to ten percent of patients with nonalcoholic fatty liver disease (NAFLD) progress to more severe liver disease, including cirrhosis, end-stage liver disease, and hepatocellular carcinoma. In NAFLD, spontaneous improvement can occur. About 80% of patients with NAFLD or nonalcoholic steatohepatitis (NASH) have features of the metabolic syndrome, including abdominal obesity, hypertension, insulin resistance/glucose intolerance, and hypertriglyceridemia. They are at increased risk for atherosclerosis. Weight reduction with exercise and diet in overweight or obese patients is a central element in treatment. Bariatric surgery has proven effective in a large percentage of morbidly obese patients with NASH. Studies to date reveal only marginal benefit attributable to metformin. Treatment of coexisting dyslipidemia, diabetes, and hypertension is important. Statins, fenofibrate, and marine omega-3 fatty acids do not appear to increase the risk of further hepatic injury in most patients. Mixed tocopherols are beneficial.
The hyperlipidemia of nephrosis is biphasic. Before serum albumin levels fall below 2 g/dL, LDL increases selectively. The synthesis and secretion of VLDL appear to be coupled to that of albumin. The increased flux of VLDL from liver increases production of LDL. As albumin falls below 1 to 2 g/dL, lipemia ensues. Impaired hydrolysis of triglycerides by LPL is due to lack of albumin as an FFA receptor. FFA bind to lipoproteins when albumin levels are low, impairing their ability to undergo lipolysis.
Because coronary disease is prevalent in patients with longstanding nephrotic syndrome, treatment of the hyperlipidemia is indicated, although few studies of the effect of treatment have been reported. The hyperlipidemia is resistant to diet. Fibrates may precipitate myopathy even in small doses. Bile acid–binding resins, niacin, and reductase inhibitors may be useful.
9. GLYCOGEN STORAGE DISEASE
In type I glycogenosis, insulin secretion is decreased, leading to increased flux of FFA to liver and increased secretion of VLDL. The low levels of insulin in plasma are the probable cause of reduced activity of LPL. The fatty liver in these patients tends to progress to cirrhosis.
Frequent small feedings, including during the night, help maintain blood glucose levels and ameliorate the lipemia. Other forms of hepatic glycogen storage disease may be associated with elevated levels of VLDL and LDL in serum.
10. HYPOPITUITARISM AND ACROMEGALY
Part of the hyperlipidemia of hypopituitarism is attributable to secondary hypothyroidism, but hypertriglyceridemia may persist after thyroxine replacement. Deficiency of growth hormone is associated with elevated levels of both LDL and VLDL. Decreased insulin levels may be the major underlying defect; however, deficiency of growth hormone may impair the disposal of FFA by oxidation and ketogenesis in the liver, favoring synthesis of triglycerides. Mild hypertriglyceridemia is often associated with acromegaly, probably resulting from insulin resistance. Although growth hormone acutely stimulates lipolysis in adipose tissue, FFA levels are normal in acromegaly.
Whereas significant hypothyroidism produces elevated levels of LDL in nearly all individuals, only a few develop hypertriglyceridemia. The increase in LDL results in part from decreased conversion of cholesterol to bile acids and downregulation of LDL receptors. Lipemia, when present, is usually mild, although serum triglycerides in excess of 3000 mg/dL (34.5 mmol/L) can occur in myxedema reflecting decreased activity of hepatic lipase. Increased content of cholesteryl esters and Apo E in the triglyceride-rich lipoproteins suggests accumulation of remnant particles. Hypothyroidism often causes expression of hyperlipidemia in individuals with dysbetalipoproteinemia.
12. IMMUNOGLOBULIN-LIPOPROTEIN COMPLEX DISORDERS
Both polyclonal and monoclonal hypergammaglobulinemias may cause hypertriglyceridemia. IgG, IgM, and IgA have each been involved. Monoclonal antibodies associated with myeloma, macroglobulinemia, lymphomas, and lymphocytic leukemias have been implicated. Lupus erythematosus and other autoimmune disorders have been associated with the polyclonal type. Binding of heparin by immunoglobulin, with resulting inhibition of LPL, can cause severe mixed lipemia. More commonly, the triglyceride-rich lipoproteins have an abnormally high density, probably as a result of bound immunoglobulin, although some may be remnant-like particles. These complexes usually have gamma mobility on electrophoresis.
Xanthomatosis associated with immunoglobulin complex disease includes tuberous and eruptive xanthomas, xanthelasma, and planar xanthomas of large areas of skin. The latter are otherwise seen only in patients with cholestasis. Deposits of lipid-rich hyaline material can occur in the lamina propria of the intestine, causing malabsorption and protein-losing enteropathy. Circulating immunoglobulin-lipoprotein complexes can fix complement, leading to hypocomplementemia. In such patients, administration of whole blood or plasma can cause anaphylaxis. Hence, washed red cells or albumin are recommended when blood volume replacement is required.
Treatment is directed at the underlying disorder. The critical temperature of cryoprecipitation of some of these complexes is close to body temperature. Therefore, if plasmapheresis is indicated to remove offending immunoglobulins, it should be done at a temperature above the critical temperature measured in serum.