Effects of Persistent Hyperlipidemia

5. Effects of Persistent Hyperlipidemia

Long-term effects of hyperlipidemia in dogs are unknown. Dogs are resistant to the development of atherosclerosis as compared to humans, due to differences in lipoprotein metabolism between the species (Mahley et al., 1977). For atherosclerosis to develop in the dog, serum cholesterol concentrations greater than 750 mg/dL must be maintained for more than 6 months (Mahley et al., 1974b).

Hyperlipidemia and Atherosclerosis in Dogs

Atherosclerosis is a specific type of arteriosclerosis with deposition of lipid and cholesterol in arterial tunica intima and tunica media (Liu et al., 1986). The dog has been used as an experimental model for atherosclerosis lesions for more than 40 years, with experimental induction of atherosclerosis resulting from hypothyroid dogs fed high levels of cholesterol, fat, taurocholic acid and/or coconut oil (Duncan et al., 1960; Mahley et al., 1974b). However, naturally occurring atherosclerosis in the dog has also been reported.

Arteriosclerosis is often confused with atherosclerosis. Arteriosclerosis is a chronic hardening of the arteries, with loss of elasticity, and luminal narrowing. Lipid and cholesterol accumulation in arterial tunica intima and tunica media is not a feature of arteriosclerosis as opposed to atherosclerosis. Arteriosclerosis may be more common in the dog, but has not been associated with chronic hyperlipidemia.

Atherosclerosis and Hypothyroidism

An association of atherosclerosis and hypothyroidism in dogs was noted over 30 years ago (Manning, 1979). In a family of Beagles, moderate to severe atherosclerosis occurred in the coronary and renal arteries with no evidence of occlusion. Hyperlipidemia was present, even when feeding a diet low in fat and cholesterol. Treatment of hypothyroidism with thyroxine resulted in a decrease in serum cholesterol concentrations. However, dogs that have developed atherosclerosis do not have any regression of atherosclerotic lesions even with lowering cholesterol concentrations (DePalma et al., 1977).

Cerebrovascular atherosclerosis associated with hypothyroidism was observed in a 6 year old Doberman pinscher (Patterson et al., 1985). This dog presented with seizures, ataxia, circling and head tilt. At necropsy, severe generalized atherosclerosis and cerebrocortical necrosis were noted. Necrosis was due to tissue hypoxia secondary to cerebrovascular atherosclerosis.

Twenty one cases of atherosclerosis in dogs over a 14 year period were associated with hypothyroidism (Liu et al., 1986). Clinical signs included lethargy, anorexia, weakness, dyspnea, collapse and vomiting. Necropsy revealed myocardial fibrosis and infarction in the myocardium. Affected arteries included coronary, myocardial, renal, carotid, thyroidal, intestinal, pancreatic, splenic, gastric, prostatic, cerebral, and mesenteric. Arteries were thick and nodular with narrow lumens, and walls contained foamy cells or vacuoles, and mineralized material.

Atherosclerosis and Diabetes Mellitus

Atherosclerosis in the canine has also been associated with diabetes mellitus (Sottiaux, 1999). A 7 year old Pomeranian initially presented with poorly controlled insulin-dependent diabetes mellitus and anterior uveitis with lipid deposition in the anterior chamber of the eye. Both hypertriglyceridemia and hypercholesterolemia were present, with increases in chylomicrons and β-migrating lipoproteins. One year later the dog died from ketoacidosis. Atherosclerosis was observed in the abdominal aorta, coronary, renal, arcuate, and carotid arteries. Thyroid histology appeared normal with no evidence of atrophy.

Aging German Shepherd. Lipid accumulation may be age-related, and deposition of modified LDL may be a critical step in the development of atherosclerosis in the canine (Kagawa et al., 1998). (© Lanceau).

Thirty dogs with atherosclerosis confirmed at necropsy were retrospectively evaluated for the presence of hypothyroidism, diabetes mellitus, or hyperadrenocorticism (Hess et al., 2003). Dogs with atherosclerosis were 53 times more likely to have diabetes mellitus, and 51 times more likely to have hypothyroidism compared to dogs without atherosclerosis. An increased incidence of hyperadrenocorticism was not noted in dogs with atherosclerosis.

Pathogenesis of Atherosclerosis in Dogs

Recently, apoprotein B100 has been localized to the accumulation of lipids seen in the splenic arteries of aged dogs (Sako et al., 2001). Chlamydial antigens have also been noted in canine atherosclerotic lesions (Sako et al., 2002), and the Chlamydial organism may play a role in the pathogenesis of canine atherosclerosis. The ratio of apoprotein B100 to apoprotein A-I is increased in dogs with systemic atherosclerosis and hyperlipidemia, and this ratio could be important in the diagnosis of atherosclerosis in dogs (Miyoshi et al., 2000).

Hyperlipidemia and Pancreatitis in Dogs

There is also evidence that persistent hyperlipidemia may lead to pancreatitis (Dominguez-Munoz et al., 1991), and pancreatitis often occurs in humans with familial hyperchylomicronemia (Heaney et al., 1999). A burst of free radical activity in pancreatic acinar cells disrupts glutathione homeostasis and may be the initiating event in pancreatitis (Guyan et al., 1990). Increased free radical activity may relate to pancreatic ischemia resulting from sluggish pancreatic microcirculation due to high concentrations of chylomicrons (Sanfey et al., 1984). Free radical damage causes leakage of lipase into the pancreatic microcirculation. Lipase causes hydrolysis of triglyceride present in excess chylomicrons or VLDL resulting in release of free fatty acids which are intensely inflammatory. Free fatty acids can also cause activation of Hageman factor, or may bind calcium leading to micro-thrombi and capillary damage. Phospholipid present in chylomicrons and VLDL are also susceptible to free radical attack leading to lipid peroxidation, intensifying inflammation. This results in an increase in release of pancreatic lipase and further lipolysis, leading to pancreatitis (Havel, 1969).

Hyperlipidemia and Diabetes Mellitus in Dogs

Persistent hyperlipidemia may also cause diabetes mellitus (Sane et al., 1993). Increased triglyceride and free fatty acids may lead to insulin resistance due to inhibition of glucose oxidation and glycogen synthesis (Boden, 1997). Free fatty acids may stimulate glyconeogenesis which contributes to inappropriate glucose production (Rebrin et al., 1995). Increased free fatty acids early on act to stimulate insulin production even with low glucose concentrations. In the long term, increased free fatty acids modulate β-cell gene expression and inhibit insulin secretion (Prentki et al., 1996). By multiple mechanisms, increased serum triglyceride and free fatty acids can lead to hyperglycemia and diabetes mellitus. If hyperlipidemia is corrected, diabetes mellitus caused by hyperlipidemia can be reversed (Mingrone et al., 1999).

The effects of persistent hyperlipidemia in the canine on other organ systems have not been studied. In rats with nephrotic syndrome, persistent hyperlipidemia contributes to progressive renal injury (Hirano et al., 1992), and progression of renal dysfunction correlates to serum cholesterol concentration (Washio et al., 1996).