Causes of Hyperlipidemia

3. Causes of Hyperlipidemia

Hyperlipidemia may be the result of lipid abnormalities secondary to a number of other conditions (Table 3). Conditions resulting in secondary hyperlipidemia include hypothyroidism, pancreatitis, cholestasis, hyperadrenocorticism, diabetes mellitus, nephrotic syndrome, obesity, and the feeding of very high fat diets. These conditions should be investigated and eliminated as potential causes of the hyperlipidemia before primary hyperlipidemia is considered.

Hypothyroidism

Hypothyroidism is the most common endocrine disease in dogs and often causes serum hyperlipidemia. In a survey of 2007 dogs with reported recurrent hyperlipidemia, 413 (21%) were diagnosed with hypothyroidism. Dogs with fasting hyperlipidemia were 3.2 times more likely to have hypothyroidism than dogs that did not have hyperlipidemia (Schenck, 2004).

Increases in both serum cholesterol and triglyceride concentrations have been associated with canine hypothyroidism (Rogers et al., 1975b; Boretti et al., 2003). In one study of 50 dogs with hypothyroidism, 88% exhibited hypertriglyceridemia and 78% had hypercholesterolemia (Dixon et al., 1999). Congenital hypothyroidism resulted in hypercholesterolemia in 4 out of 5 Giant Schnauzers (Greco et al., 1991). Cholesterol elevations are usually moderate (Jaggy et al., 1994), and with adequate treatment of hypothyroidism, both cholesterol and triglyceride concentrations return to normal (Rogers et al., 1975b; Cortese et al., 1997). In dogs with hypercholesterolemia and hypertriglyceridemia associated with hypothyroidism, there are increases in VLDL, LDL and HDL1 (Mahley et al., 1974b; Rogers et al., 1975b), and the lipoprotein electrophoresis pattern should return to normal with thyroid replacement therapy. Cholesterol accumulation is seen in VLDL, and these cholesterol-rich particles may stimulate cholesteryl ester synthesis within tissue macrophages (Mahley et al., 1980).

In humans with hypothyroidism, mRNA for LDL receptors is decreased resulting in decreased cholesterol and chylomicron clearance (Kovanen, 1987). Lipoprotein lipase activity may be increased (Hansson et al., 1983), diminished (Pykalisto et al., 1976) or unaltered (Franco et al., 2003), and there is decreased excretion of cholesterol into bile (Gebhard et al., 1992). Cholesterol synthesis is also decreased, but the decrease in clearance is greater than the decrease in synthesis, leading to a net increase in cholesterol concentration (Field et al., 1986).

Pancreatitis

Pancreatitis usually results in hyperlipidemia with an increase in both serum cholesterol and triglyceride concentrations, but the lipoprotein electrophoresis pattern remains normal until 48 to 72 hours post-induction of pancreatitis (Whitney et al., 1987). Free fatty acids and β-migrating lipoproteins (VLDL and LDL) increase (Rogers et al., 1975b; Whitney et al., 1987; Chikamune et al., 1998), and there is a consistent decrease in α1-migrating lipoprotein (HDL2) (Bass et al., 1976; Whitney et al., 1987). Changes in α2-migrating lipoproteins (HDL1) are inconsistent, and may be increased or decreased (Whitney et al., 1987). In addition, there may be other differences in the lipoprotein electrophoresis pattern depending on whether the pancreatitis is naturally occurring or experimentally induced.

Within the lipoprotein structure, there are changes in lipid and protein content in pancreatitis. LDL exhibits an increase in triglyceride, total cholesterol, and phospholipid, and an increase of apoprotein B100 (Chikamune et al., 1998). VLDL shows an increase in total cholesterol and phospholipid. HDL particles have decreased total cholesterol and phospholipid, with an increase in apoprotein A-IV and a decrease in apoprotein A-I (Chikamune et al., 1998).

11 year old Labrador bitch with hypothyroidism (only clinical sign: obesity). (© L. Martin).

Naturally occurring atherosclerosis has been noted in dogs with hypothyroidism. In a family of Beagles with hypothyroidism, there was evidence of moderate to severe atherosclerosis which occurred mainly in the coronary and renal arteries (Manning, 1979). Arteries were stenotic but patent, with no evidence of prior occlusion. Even with therapy for hypothyroidism, no regression of atherosclerotic plaques was seen despite a decrease in serum cholesterol concentration (DePalma et al., 1977). (© Lenfant).

In humans, there is evidence that pancreatitis is associated with decreased lipoprotein lipase activity (Hazzard et al., 1984). This decreased activity of lipoprotein lipase may result in increased triglyceride concentrations with slower clearance of chylomicrons. Two dogs with pancreatitis also exhibited a moderate decrease in lipoprotein lipase activity, which returned to normal with treatment and resolution of the pancreatitis (Schenck, unpublished observations).

Diabetes Mellitus

In diabetes mellitus, elevations of both serum triglyceride and cholesterol concentration are typically observed (Rogers et al., 1975b; Renauld et al., 1998) (Table 4).

Cholesterol concentration increases in VLDL and IDL, and decreases in HDL (Wilson et al., 1986). Insulin therapy will usually decrease serum triglyceride concentration, but serum cholesterol concentration may remain elevated due to increased cholesterol synthesis (Gleeson et al., 1990) (Figure 8).

In humans with diabetes mellitus, lipoprotein lipase activity is decreased, with an increase in free fatty acids (Steiner et al., 1975) and hepatic lipase activity (Muller et al., 1985). Urinary mevalonate concentration is elevated approximately 6-fold, indicating an increase in whole-body cholesterol synthesis, and HMGCoA reductase activity is increased (Kwong et al., 1991; Feingold et al., 1994). Intestinal cholesterol absorption may also be increased in diabetes mellitus (Kwong et al., 1991; Gylling et al., 1996). There is impaired removal of VLDL from the circulation (Wilson et al., 1986), and a decrease in the number and affinity of LDL receptors (Takeuchi, 1991). Prolonged retention of lipoprotein remnants may contribute to an increased delivery of cholesterol to extrahepatic tissues, and the increased concentration of HDL1 reflects a disturbance in cholesterol transport from peripheral cells back to the liver (Wilson et al., 1986).

Naturally occurring atherosclerosis has been observed at necropsy in a dog with diabetes mellitus (Sottiaux, 1999). Atherosclerotic plaques were noted in the terminal aorta, coronary arteries, renal arteries, and arteries of the brain, but there was no evidence of thrombosis or complete occlusion of any vessel.

Nephrotic Syndrome

Lipoprotein abnormalities have been poorly characterized in dogs with nephrotic syndrome. Dogs with nephrotic syndrome show a mild increase in serum cholesterol concentration early in the course of disease, with a mild elevation of serum triglyceride concentration occurring later. Dogs with secondary hyperparathyroidism due to chronic renal failure exhibit a decrease in lipoprotein lipase activity, resulting in impaired removal of lipid from the circulation (Akmal et al., 1990).

Lipoprotein abnormalities in nephrotic syndrome and chronic renal disease have been well characterized in humans, and the progression of renal dysfunction has been shown to correlate with serum total cholesterol (Washio et al., 1996). Lipoprotein lipase activity is decreased which may account for the hypertriglyceridemia due to a decrease in lipoprotein clearance (Olbricht, 1991). There is decreased clearance of LDL (Shapiro, 1991; Vaziri et al., 1996) due to decreased LDL receptor expression (Portman et al., 1992). LDL may also be increased due to an increase in synthesis (de Sain-van der Velden et al., 1998). HMGCoA reductase activity is increased in the liver (Szolkiewicz et al., 2002; Chmielewski et al., 2003), and the increased cholesterol does not up-regulate LDL receptors (Liang et al., 1997). Reverse cholesterol transport is impaired (Kes et al., 2002), and ACAT activity within the liver is increased with a decrease in LCAT activity (Liang et al., 2002).

VLDL increases due to decreased catabolism (de Sain-van der Velden et al., 1998), and proteinuria may also stimulate VLDL synthesis by the liver, induced by hypoalbuminemia (D'Amico, 1991). Impaired clearance of VLDL may be due to deficiencies in apoprotein C-II, apoprotein C-III, and apoprotein E, creating smaller VLDL particles that are not cleared efficiently by receptors (Deighan et al., 2000). This altered structure of VLDL results in altered binding to endothelial bound lipoprotein lipase (Shearer et al., 2001), and proteinuria may also be associated with the urinary loss of heparan sulfate, an important cofactor for lipoprotein lipase (Kaysen et al., 1986). Synthesis of apoprotein A-I by the liver increases in response to proteinuria (Marsh, 1996), and protein catabolism in peripheral tissues is increased.

Hyperadrenocorticism

In hyperadrenocorticism, mild elevations of both serum cholesterol and triglyceride may be seen in dogs and humans (Friedman et al., 1996). Lipoprotein lipase activity is decreased with an increase in hepatic lipase activity (Berg et al., 1990). In addition, hypercortisolism stimulates production of VLDL by the liver (Taskinen et al., 1983). Excess glucocorticoids stimulate lipolysis, and this excess fat breakdown exceeds the liver's capacity for clearance. The occurrence of steroid hepatopathy in hyperadrenocorticism may lead to biliary stasis resulting in further lipid abnormalities.

In hyperadrenocorticism, mild elevations of both serum cholesterol and triglyceride may be seen (Ling et al., 1979; Reusch et al., 1991). In dogs, concentration of β-migrating lipoproteins (VLDL and LDL) are typically increased (Bilzer, 1991).

Cholestasis

In cholestasis, there is typically moderate hypercholesterolemia, and there may be a mild hypertriglyceridemia (Chuang et al., 1995). Concentration of LDL increases, and HDL1 concentration decreases (Danielsson et al., 1977). In LDL, phospholipid content increases and triglyceride concentration decreases, but there is no change in composition of HDL. Both plasma cholesteryl ester and LCAT activity increases (Blomhoff et al., 1978).

Obesity

Some obese dogs show an increase in serum triglyceride concentration (Bailhache et al., 2003), and a mild increase in serum cholesterol (Chikamune et al., 1995). Free fatty acids are increased, triglyceride concentration is increased in both VLDL and HDL, and HDL cholesterol may be decreased (Bailhache et al., 2003). Phospholipid concentration is increased in both VLDL and LDL, and is decreased in HDL2 (Chikamune et al., 1995). There is a moderate decrease in lipoprotein lipase activity in some obese dogs, and activity increases with weight loss (Schenck, unpublished observation). Lipid abnormalities observed in obese dogs may however be secondary to insulin resistance (Bailhache et al., 2003).

English Bulldog. Obesity may result in hyperlipidemia in a small percentage of dogs. (© M. Diez).

High Fat Diets

The feeding of high fat diets may result in hyperlipidemia and moderate elevation in serum cholesterol concentration. As serum cholesterol concentration increases, the majority of cholesterol is carried by HDLc (HDL1); thus an increase in α2-migrating lipoprotein is observed (Mahley et al., 1974b). A substantial portion of the HDL observed in response to cholesterol feeding is formed in the periphery (Sloop et al., 1983). Once this HDL reaches the plasma, it is converted to HDLc via the action of LCAT, which exhibits increased activity (Bauer, 2003). LDL and IDL concentrations increase, and the concentration of HDL2 decreases. Hypercholesterolemia results in the appearance of α-migrating VLDL, and cholesterol-enrichment also occurs in LDL, IDL and HDLc (Mahley et al., 1974b). Diets very high in fats (above 50%) may additionally cause an elevation in triglyceride (Reynolds et al., 1994) with a marked increase in circulating LDL and other abnormalities.