Treatment of Hyperlipidemia

6. Treatment of Hyperlipidemia

Because of the potential risks associated with persistent hyperlipidemia, hyperlipidemia should be treated aggressively. The underlying disorder in secondary hyperlipidemias should be treated, but there is no specific therapeutic regimen for dogs with idiopathic hyperlipoproteinemias. Unfortunately since little is known regarding the mechanisms of primary hyperlipidemia, and multiple syndromes most likely exist, no single treatment regimen has been effective in all cases.

Caution must be exercised when considering dietary fat content on only a percentage basis. For example, a diet containing 10% fat with an ME of 4000 kcal/kg provides only 25 g fat/1000 kcal, whereas a diet containing 8% fat with an ME of 2700 kcal/kg provides 30 gfat/1000 kcal.

Nutritional Treatment of Hyperlipidemia

A Fat-restricted Diet

Initial treatment of primary hyperlipidemia involves a switch to a low-fat diet (<25 g/1000 kcal) with moderate protein content (generally greater than 18%, or 60 g protein/1000 kcal). Diets low in protein may cause an increase in serum cholesterol concentration (Polzin et al., 1983; Hansen et al., 1992) and are therefore not recommended unless the presence of other conditions warrant their use. Numerous nutritionally complete, low-fat canine diets are commercially available, but one must be careful to choose a diet that is low in fat based on a metabolizable energy (ME), and not strictly on the percent fat present in the diet. Most diets with a fat content less than 8% will provide less than 25g fat/1000 kcal. However, some diets appear low in fat on a percentage basis (<8%), but actually provide substantially more than 25 g fat/1000 kcal when the amount of fiber in the diet and metabolizable energy are taken into account, and thus are not low-fat diets.

After feeding a low-fat diet for 6 to 8 weeks, the presence of hyperlipidemia should be re-evaluated. Low-fat diets alone may not cause resolution of hyperlipidemia, especially when there is a high concentration of endogenous triglyceride (VLDL-TG) (Bauer, 1995).

Omega-3 Fatty Acid Supplementation

If hyperlipidemia is still present after 6 to 8 weeks, then fish oil at a dose of 220 mg/ kg of body weight (BW) once daily should be added to the treatment regimen. Fish oil capsules may be obtained over-the-counter, but labels should be read carefully to ensure that the dog receives 220 mg/kg BW of a combination of alpha-linolenic acid, and the long chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Some products claim to be "omega-3 supplements", but contain a high percentage of other non-omega-3 fatty acids.

In the author's experience the only side effect noted with this level of fish oil supplementation is that the dog may have a noticeable "fishy" odor which may be objectionable to some owners. If hyperlipidemia resolves with this level of fish oil supplementation and the owner complains about the fishy odor, a half-dose (110 mg fish oil/kg BW/day) can be evaluated. A few dogs can be managed at this dose; however, most will require a minimum of 170 mg fish oil/kg BW/day to maintain the absence of hyperlipidemia. In one particular case in the author's experience, a 6 year-old Shetland Sheepdog with idiopathic hyperlipoproteinemia and multiple lipomas showed complete resolution of serum hyperlipidemia, hypertriglyceridemia, and hypercholesterolemia after 4 weeks on a low-fat diet and 220 mg fish oil/kg BW/day. In addition, most of the lipomas resolved. Due to the dog's fishy odor, the dosage of fish oil was dropped to 110 mg/kg BW/day, with a return of hyperlipidemia. A dosage of 170 mg fish oil/kg BW/day in combination with a low-fat diet has maintained the absence of hyperlipidemia for over one year.

The use of fish oil and EPA & DHA in the treatment of hyperlipidemia and atherosclerosis has been extensively studied in a number of species.

• EPA supplementation resulted in a 31% decrease in serum triglyceride in human patients (Okumura et al., 2002).
• Rats fed diets containing EPA and DHA exhibited a decrease in serum cholesterol and triglyceride and the development of atherosclerosis was prevented (Adan et al., 1999).
• Fish oil supplementation decreased serum triglyceride, total cholesterol, VLDL-triglyceride and VLDL-cholesterol in chicks (Castillo et al., 2000).
• In dogs with renal insufficiency, fish oil supplementation resulted in a decrease in serum cholesterol concentration (Brown et al., 2000).
• Watanabe heritable hyperlipidemia (WHHL) rabbits exhibited a decrease in serum triglyceride and cholesterol with a decrease in VLDL-triglyceride (Mortensen et al., 1998).

Fish oil and omega-3 fatty acids. Synthesis of triglyceride and VLDL in the liver is decreased by omega-3 fatty acids (Harris et al., 1990; Connor et al., 1993), and the effectiveness of fish oils in dogs with hyperlipidemia suggests that the hypertriglyceridemia may be partly due to overproduction of VLDL (Bauer, 1995).

Fish oils may exert a beneficial effect on hyperlipidemia by stimulating lipoprotein lipase activity (Levy et al., 1993), decreasing the intestinal absorption of glucose and lipid (Thomson et al., 1993), increasing cholesterol secretion into bile (Smit et al., 1991) and by decreasing cholesterol absorption (Thompson et al., 1989). Fish oils also decrease serum concentration of free fatty acids (Singer et al., 1990) which may be important in the prevention of pancreatitis and diabetes mellitus. Development of atherosclerosis may be prevented by fish oil due to an inhibition of mitogen-induced smooth muscle cell proliferation (Pakala et al., 2000).

Unfortunately there are no long-term studies to verify the safety and efficacy of any lipid-lowering agent in dogs, and any therapy should be used with caution. One concern with fish oil therapy is that fish oil increases the concentration of lipoperoxides in LDL (Puiggros et al., 2002). The addition of vitamin E to the fish oil therapy regimen may enhance beneficial effects by increasing glutathione reductase activity and decreasing peroxide levels (Hsu et al., 2001).

In severe cases of lipoprotein lipase deficiency in human patients, fish oil and other dietary therapies result in some improvement, but serum lipids may remain elevated (Richter et al., 1992).

Interest of Medium Chain Triglycerides

In human patients, in addition to fish oil therapy, medium chain triglycerides (MCT) in combination with low-fat diets cause a decrease in hypertriglyceridemia (Rouis et al., 1997; Chou et al., 2002; Nagasaka et al., 2003). MCT administration results in increased lipoprotein lipase activity (Shirai et al., 1992) and may prevent hyperlipidemia associated pancreatitis (Mizushima et al., 1998). MCT administration does not lower, and may even elevate serum cholesterol concentration (Asakura et al., 2000). Therefore, MCT therapy should only be used in cases where there is elevation of serum triglyceride concentration without a high elevation in serum cholesterol. Unfortunately, MCT oil is not very palatable, limiting its use.

Fermentable Fiber Intake

The presence of a blend of fructooligosaccharides and beet pulp in the diet may also be desirable, since this blend can decrease serum triglyceride and cholesterol concentrations in the dog (Diez et al., 1997).

Antioxidant Treatment

Since the pathogenesis for idiopathic hyperlipoproteinemia has been at least partly determined (Schenck, 2002), treatments that have been effective in human patients with lipoprotein lipase deficiency may be worthy of investigation.

Several humans with familial lipoprotein lipase deficiency treated with a combination of oral antioxidant therapy (OAT) showed prevention of recurrent pancreatitis even though there was no effect on circulating lipids (Heaney et al., 1999). Antioxidant therapy consisted of a combination of α-tocopherol, β-carotene, vitamin C, selenium, and methionine.

Medical Treatment of Hyperlipidemia

Other treatment regimens have been attempted with variable results.

Gemfibrozil has been used to stimulate lipoprotein lipase activity and decrease VLDL secretion (Santamarina-Fojo et al., 1994).

Niacin therapy has also been used in a few dogs; however, adverse effects have been noted in both dogs (Bauer, 1995), and humans (Kashyap et al., 2002).

Dextrothyroxine administration significantly decreased serum lipids in dogs with induced hyperlipidemia and atherosclerosis (Nandan et al., 1975), though these effects may have been due to contamination of dextrothyroxine with L-thyroxine (Young et al., 1984). Dextrothyroxine administration in humans results in an approximately 18% decrease in serum total cholesterol (Brun et al., 1980), but is not vastly utilized as a treatment for hyperlipidemia due to a concurrent lowering of HDL cholesterol (Bantle et al., 1984). A major mechanism of cholesterol-lowering by thyroxine in humans is an increase in cholesteryl ester transfer protein (Berti et al., 2001); however, since dogs have little cholesteryl ester transfer protein, thyroxine may not be as effective. Thyroxine does have other lipid-lowering mechanisms, including an increase in hepatic lipase activity and increased conversion of IDL to LDL (Asami et al., 1999), and is effective in lowering lipid concentrations in hypothyroid dogs (Rogers et al., 1975b; Cortese et al., 1997). Since thyroxine is fairly well tolerated in the dog, an investigation of lipid-lowering properties in euthyroid dogs with primary hyperlipoproteinemia may be warranted.

Gene therapy has been effective in mice (Zsigmond et al., 1997) and may become a clinical reality in the future for patients with severe dyslipidemias (Rader et al., 1999).

a. Lipoprotein lipase activity.
b. Presumptive decrease based on literature report and human findings.
c. Presumptive decrease based on human findings.
N : normal value
- : no specific data

Conclusion

Many conditions may cause hyperlipidemia in the dog. Postprandial hyperlipidemia should always be verified, and secondary causes of hyperlipidemia must be ruled out before a diagnosis of primary hyperlipidemia can be made. Hyperlipidemias are characterized by a number of different changes in lipoprotein concentrations, depending on cause (Table 5). Treatment of the underlying cause of hyperlipidemia is usually effective at resolving the secondary hyperlipidemia. Primary hyperlipidemias should be aggressively treated because of the potential complications of persistent hyperlipidemia.