Hyperlipidemic states in the dog and cat (Proceedings)

In 1985, the National Institutes of Health established the National Cholesterol Education Program (NCEP) with the goal of reducing the prevalence of high blood cholesterol in the United States. The program, which is still in effect today, is aimed at increasing the general public's awareness of the fact that there is an undisputed risk of coronary heart disease associated with elevated cholesterol levels, particularly low-density lipoprotein (LDL) cholesterol. The NCEP has also stressed the importance of every adult's knowing his or her cholesterol level. With over 5.4 million Americans having symptomatic coronary heart disease and a large number of others with undiagnosed coronary heart disease, it is estimated that one in four American adults has a cholesterol level high enough to increase individual risk of coronary heart disease. [Consensus Conference, 1985].

Elevations in blood lipid levels are certainly recognized in dogs and cats; however the relationship between hyperlipidemia and clinical disease is not well understood. Despite the paucity of literature addressing the clinical significance of hyper- lipidemia, at least three facts are clear: 1) hyperlipidemia in the fasted (> 12 hours) dog or cat is abnormal, 2) there appears to be significant morbidity, and occasional mortality, associated with hyperlipidemia in dogs and cats, and 3) specific dietary and/or drug intervention can eliminate or at least diminish the morbidity associated with hyperlipidemia.

Hyperlipidemia Defined

The term hyperlipidemia applies to those patients with concentrations of blood cholesterol and/or triglyceride. Although standardized values for these analytes have not been strictly defined in veterinary medicine, most laboratories report the normal serum total cholesterol to be in the range of 120 to 270 mg/dL for the dog and 70 to 200 mg/dL for the cat. It must be assumed that these values apply only to adult dogs and cats in the fasted state; lipid values in dogs and cats less than 6 months of age have not been reported. Those animals with values exceeding the upper range of normal are considered hyperlipidemic. However, it is important to note that abnormal elevations of blood lipids do not necessarily reflect a significant health risk for the affected dog or cat, hyperlipidemia may represent an early signal for underlying disorders affecting lipid and lipoprotein metabolism, e.g. diabetes mellitus, hyperadreocorticism (canine Cushings), hypothyroidism.

Visual Inspection. Lipemia is the term used to describe samples of whole blood, serum, or plasma in which lipid is grossly visible (appearing white to cloudy...in whole blood, lipemic samples may appear pink-ish). Lipemic serum is caused by excessive concentrations of triglyceride, as opposed to cholesterol, and is the type of hyperlipidemia most commonly recognized in companion animal medicine. Lactescence refers to serum or plasma that contains elevations of triglyceride sufficient to cause the sample to be milk-like in appearance and opaque. Patients with lactescent serum typically have extreme elevations of triglyceride-rich chylomicrons. Measured triglyceride levels typically exceed 1000 mg/dL. Regardless of the underlying cause, patients with lactescent serum, especially if fasted, must be regarded as being at risk of developing acute pancreatitis and signs of gastrointestinal distress (dogs) and eruptive cutaneous xanthomata (cats).

The Diagnosis of Hyperlipidemia

Until uniform procedures for separation of the various lipoprotein classes becomes standardized and commercial laboratories are able to provide comprehensive lipoprotein profiles for animals, diagnosis of hyperlipidemia should be based on laboratory determination of serum triglyceride (TG) and total cholesterol (CH). Hypertriglyceridemic animals usually have lipemic serum and can be identified on the basis of visual inspection of a serum sample.

Some reference laboratories that provide services to both physicians and veterinarians include HDL and/or estimated LDL cholesterol levels (mg/dL) as part of a standard biochemical profile on dogs and cats. In humans, these values are an important in risk assessment for coronary heart disease; the clinical value of these test results in veterinary medicine have not yet been determined.

In additional, some reference laboratories offer lipoprotein electrophoresis (LPE) as a means of further characterizing abnormalities of lipid metabolism in animals. The value of LPE has been in question in human for several years and is justifiably question in veterinary medicine. Compared to the quantitative assays currently available, LPE appears to have limited value in the routine evaluation of lipid disorders in the dog and cat.

Laboratory Considerations: Hyperlipidemic serum is a well-known source of both positive and negative laboratory interference. However, the clinician must acknowledge the fact that hyperlipidemic serum is not merely a consequence of a recent meal; it may also represent an important, early sign of disease in an affected patient. Veterinarians attempting to assess a dog or cat for hyperlipidemia should submit serum, rather than plasma or whole blood. The laboratory should not clear lipemic serum prior to performing assays for TG and CH; doing so can reduce TG levels significantly and, to a lesser extent, can lower CH levels.

The presence of excess triglyceride, particularly chylomicrons, is an important source of either positive (falsely elevated) of negative (falsely lowered) interference for analytes determined by colorimetric methods. It appears that some laboratories routinely attempt to clear lipemic serum prior to performing any assays while others do not. Furthermore, some laboratories report the fact that serum, once separated from the cells, was lipemic and was cleared prior to assay; others do not. When interpreting test results reported on biochemical profiles, the clinician must know whether or not the serum sample was lipemic and, if so, was the sample cleared prior to testing.

Hypertriglyceridemia

The most prevalent, and perhaps the most clinically significant, form of hypertriglyceridemia recognized in companion animals is hyperchylomicronemia. Affected animals have lipemic blood which, upon standing under refrigeration for 8-12 hours, will form an opaque "cream" layer above a clear serum infranatant. Serum TG levels are invariably elevated since chylomicrons are the lipoprotein class principally responsible for TG transport.

Most cases of mild to moderate hypertriglyceridemia encountered in practice can be attributed to hyperchylomicronemia subsequent to a recent (with 4-6 hours) meal, i.e. post-prandial or physiologic hyperlipidemia. However, hypertriglyceridemia in the fasted (>12 hours) dog or cat is an abnormal finding that justifies further clinical study. Not only does fasting hypertriglyceridemia indicate an underlying disorder affecting lipid metabolism but affected animals are at risk of developing serious clinical disease, particularly acute pancreatitis. Abdominal distension and distress, painful abdomen, diarrhea, cutaneous xanthomata, seizures, and behavioral changes have also been observed in hypertriglyceridemic patients. The correlation between the clinical signs and serum lipids is based on the fact that clinical signs resolve as TG levels reach normal levels and reoccur as TG levels become excessive.

(Miniature Schnauzer) Hyperchylomicronemia. Several reports have been published suggesting that the miniature schnauzer breed is predisposed to hyperlipidemia and that this is a primary, or familial, condition. While it is not definitively known that hyperlipidemia is a inherited disorder of miniature schnauzers, there appears to be a higher than expected incidence of hypertriglyceridemia in the breed. Other breeds are affected.

Although there is no sex predilection, the majority of affected dogs are middle age and older. The incidental discovery that a healthy dog has opaque serum is relatively common. However when clinical signs are manifest they characteristically include abdominal distress, pain, and diarrhea not associated with elevated amylase or lipase, or overt acute pancreatitis. Lipid profile of affected dogs reveal dramatic elevations of serum TG ranging from 500 mg/dL to over 8,000 mg/dL; the TG in these patients is composed predominantly of chylomicrons. Our studies have not shown any correlation between TG concentration and the onset of clinical signs. Nonetheless, dogs with TG levels of 1000 mg/dL or higher are considered to be at risk and, as such, are candidates for dietary intervention (see Therapy below).

It should also be noted that the occurrence of primary hyperlipidemia in dogs is by no means limited to the miniature schnauzer breed. Several other purebred dogs as well as mixed breed have been identified as having fasting hyperchylomicronemia yet have no detectable underlying disorders.

Hyperchylomicronemia in Kittens. An autosomal recessive disorder leading to hypertriglyceridemia is reported in families of kittens. Affected cats have lipemic serum (fasting), retention of chylomicrons, lipemia retinalis, and an unusual dermatologic manifestation called xanthomas, a chronic, festering lesion that bleeds intermittently. Occasionally, xanthomas will develop at the level of spinal nerves and, as such, can lead to significant neurologic deficits, including signs of peripheral nerve paralysis. Hyperlipidemic cats do not appear to be predisposed to pancreatitis.

Diabetes Mellitus. Insulin deficiency can cause and exacerbate hyperlipidemia in dog and, presumably, cats. This form of secondary hyperlipidemia is usually characterized by hypertriglyceridemia. Occasionally, diabetic dogs will present with significant hypercholesterolemia. Clearance of TG-rich chylomicrons in diabetes is assumed to result from insufficient activation of lipoprotein lipase (NOT pancreatic lipase)...a direct consequence of insulin deficiency. Examination of lipid profiles of affected dogs reveals that there is an increase in both chylomicrons and VLDL. Administration of exogenous insulin is generally sufficient to resolve the hyperlipidemia. Interestingly, there appears to be a correlation between diabetic regulation and control of the hyperlipidemia.

Hypercholesterolemia

Hypercholesterolemia of Unknown Etiology. In veterinary medicine, hypercholesterolemia is most commonly recognized as a secondary hyperlipidemia associated with an underlying disorder, e.g., hypothyroidism. However, a limited survey of dogs suggests that Doberman pinchers and rotweillers may have a higher than expected incidence of hypercholesterolemia, characterized by increased LDL-CH. It is not known whether hypercholesterolemia in these dogs is associated with clinical illness. At this time, treatment specifically intended to lower serum CH does not appear indicated.

Hypothyroidism. In dogs, hypercholesterolemia is reported in about 30% of hypothyroid dogs. The relationship of TG concentration to thyroid status is variable. Our clinical experience suggests that, given the availability of thyroid profiles, there is little value in using TG and CH levels to assess thyroid status.

Diabetes Mellitus. Patients with insulin-dependent diabetes mellitus (IDDM) are susceptible to several disorders of lipid metabolism as well as carbohydrate metabolism. Clinically, the most common finding is hypertriglyceridemia (see above). Yet there appears to be a distinct subset of dogs with IDDM that have normal a TG concentration but elevated total CH and LDL-CH. The value of distinguishing between hypertriglyceridemic and hypercholesterolemic diabetes mellitus is being studied at this time.

Treatment

In the management of hyperlipidemia of dogs and cats, it is at least as important to when to treat as it is to know how to treat. Primary, or familial, hyperlipidemic states do appear to exist among dogs and cats, yet the majority of lipid disorders recognized in practice are secondary to an underlying disorder, most often an endocrine disease. Resolution of the lipid disorder generally results if the underlying disorder is properly diagnosed and treated.

Hypertriglyceridemic patients, particularly those with fasting TG concentrations greater than 1000 mg/dL, should be treated. A realistic goal of therapy is TG level consistently between 500-1000 mg/dL. Therapeutic intervention is indicated to reduce the risks associated with elevated levels of TG, particularly acute pancreatitis.

The first line of treatment is reduction of dietary fat. Commercially available prescription diets to be consistently effective in reducing excessive serum TG to within the normal range as long as fat supplementation by the owner is restricted. However, feeding fat restricted diets can result in undesirable weight loss over time. Dietary supplementation is eventually indicated and can be accomplished through trial and error addition of carbohydrate, e.g. pasta, potato. Specific recommendations regarding the amount of total dietary fat, as a percentage of total calories, for hypertriglyceridemic patients are not available.

Fish oils are an important source of linolenic acid, an omega-3 polyunsaturated fat, and have recently been recognized for their ability to reduce serum lipids, particularly TG, in humans. However, in veterinary medicine neither the short-term or long-term effects of administering fish oil, available in capsules at health food stores, are known.

Clofibrate, gemfibrozil, and niacin are known to reduce TG levels in humans. However, none of these drugs is without some side effects. Indiscriminant use of these products in either dogs or cats cannot be recommended until such time that dosage and therapeutic efficacy can be established. In non-diabetic dogs, however, we have empirically recommended gemfibrozil (LOPID, Lily) as treatment for hypertriglyceridemic dogs that do not respond to dietary therapy. The recommended dose is 10 mg/kg, PO, twice daily. The tablets only come as 600 mg oblets...some compounding may be necessary for small patients. Side effects reported have been minimal and, if present, include transient GI upset. For affected cats, the dose of gemfibrozil is 7.5-10 mg/kg, orally, twice daily. The drug can be mixed with food.

References and Supplemental Reading

Armstrong, P. J. and Ford, R. B.: Hyperlipidemia. In Kirk, RW (ed): Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989, pp.1046-1050.

Boyd Jones. Feline hyperlipidemia. In Ettinger, SE (ed): Textbook of Veterinary Internal Medicine (4th Ed). Philadelphia, WB Saunders, 1995, pp. 1410-1414.

DeBowes, L. J.: Lipid metabolism and hyperlipoproteinemia in dogs. Comp. Cont Ed. Pract. Vet. 9:727, 1987.

Ford, R. B.: Idiopathic hyperchylomicronaemia in miniature schnauzers. J Small Animal Prac. 34:488-492, 1993.

Ford, R. B.: Canine hyperlipidemia. In Ettinger, SE (ed): Textbook of Veterinary Internal Medicine (4th Ed). Philadelphia, WB Saunders, 1995, pp. 1414-1419.

Ford, R.B.: Clinical management of the lipemic patient. Compendium on Continuing Educ. October, 1996.

Mahley, R. W. and Weisgraber, K. H.: Canine lipoproteins and atherosclerosis. Circ. Res. 35:713, 1974.

Rogers, W. A.: Lipemia in the dog. Vet. Clin. North Am: Sm Anim. Pract. 7:637, 1977.

Rogers, W. A., Donovan, E. F., and Kociba, G. J.: Idiopathic hyperlipoproteinemia in dogs. J.A.V.M.A. 166:1087, 1975.

Rogers, W. A., Donovan, E. F., and Kociba, G. J.: Lipids and lipoproteins in normal dogs and dogs with secondary hyperlipoproteinemia. J.A.V.M.A. 166:1092, 1975.

Schaefer, E. J.: When and how to treat the dyslipidemias. Hospital Pract. 23:69-84, 1988.

Zerbe, C. A.: Canine hyperlipidemias. In Kirk, R. W. (ed.): Current Veterinary Therapy IX. Philadelphia: W. B. Saunders, 1986, pp. 1045-1053.