Hyperlipidemia in dogs and cats

Hyperlipidemia is the increased concentration of triglyceride (hypertriglyceridemia), cholesterol (hypercholesterolemia), or both in the blood.1-3 Hyperlipidemia in dogs and cats can be physiological (postprandial) or pathological. Pathological hyperlipidemia can result from increased lipoprotein synthesis or mobilization or decreased lipoprotein clearance.1 It can be primary (genetic or idiopathic) or secondary to other disease processes.1 Veterinarians should be familiar with how to recognize and manage this clinical disorder.

NORMAL LIPID METABOLISM

Lipids are large, heterogeneous, naturally occurring fatty and related compounds that are insoluble in water but soluble in ether and alcohol.4-6 Lipoproteins, which are lipid and protein complexes, are essential components of cell membranes and are critical in the stabilization and transport of lipids in plasma.4 Once in plasma, lipoproteins deliver lipids to appropriate tissues via specific cell receptors.4,7 That is, cell membrane receptors in different tissues bind to specific lipoproteins.

ESSENTIAL ELEMENT

Classification

Lipoproteins are classified by size, density, electrophoresis, and apoprotein content.4 The four classes of lipoproteins are chylomicrons, very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs) (Table 1).4,7 Triglycerides (glycerol and fatty acids) are transported as chylomicrons and VLDLs.4 Cholesterol is transported as LDLs and HDLs.4

Table 1: Major Lipoproteins and Characteristics*

Digestion and absorption

Lipid digestion is more complex than carbohydrate and protein digestion because fat must be solubilized in the water environment of gastric chyme to allow for enzymatic digestion.5 Lipid digestion requires pancreatic lipase, pancreatic colipase, and bile from the gallbladder.5

Once in the duodenum, lipid is solubilized, with the assistance of gastric peristalsis, in bile and gastric chyme into lipid droplets.8 Pancreatic colipase then binds to these lipid droplets and anchors pancreatic lipase.5,8 Pancreatic lipase is then activated and degrades triglycerides to monoglycerides and free fatty acids and hydrolyzes dietary cholesterol.8 The monoglycerides, cholesterol, and free fatty acids along with bile acids form mixed micelles, with the more polar substances on the surface and the more hydrophobic substances (fat-soluble vitamins A, D, E, and K) in the core.5,8 The micelles diffuse passively into the enterocytes.5,8

Once absorbed by enterocytes, fatty acids and glycerol are repackaged into triglycerides and are bound to apolipoprotein to form chylomicrons.5,7,8 The absorbed cholesterol is also incorporated into the chylomicrons.8 Chylomicrons transport fat in the aqueous environment of lymph and plasma. They originate exclusively from the diet and are present in the plasma 30 minutes to two hours after a fat-containing meal is consumed.3 Lipoprotein lipase, which is present in high concentrations near the endothelial cells of muscle and adipose tissue, is activated and hydrolyzes the triglyceride of chylomicrons to fatty acids and glycerol within six to 10 hours.3,4,7 The activity of lipoprotein lipase is enhanced by heparin, insulin, and thyroid hormone.3,9 The free fatty acids diffuse into cells and are either resynthesized to triglycerides and stored in adipocytes or used for energy in myocytes and other cells.7 The remnants of the chylomicrons remain in the plasma and are removed by the liver.3,4,7

Fatty acids in the remnant chylomicrons and those endogenously mobilized from adipocytes are removed by the liver, resynthesized into triglycerides, and packaged into VLDL particles.3,7 Adipocytes mobilize fatty acids for release into the plasma by activating intracellular hormone-sensitive lipase.3,7 Hormones that stimulate this lipase include epinephrine, norepinephrine, ACTH, corticosteroids, growth hormone, and thyroid hormone.3 An increased ratio of glucagon-to-insulin activity also stimulates fatty acid mobilization.3 VLDLs are important triglyceride transporters during fasting.7 In plasma, endothelial lipoprotein lipase splits the VLDL molecules into free fatty acids plus glycerol.3,4,7 The fatty acids of the VLDLs are removed via lipoprotein lipase.7 As the VLDLs lose fatty acids, their density increases and VLDLs become LDLs.7

LDL is VLDL minus triglyceride. LDLs are rich in cholesterol and phospholipids, and their major function is to transport cholesterol to tissues.4,7 Cholesterol is an important component of cell membranes and hormone synthesis.4,7 Excess LDLs eventually bind to LDL receptors on hepatocytes and are removed from the plasma.7

HDL is the smallest and highest density lipoprotein.4 It is synthesized and secreted from both the liver and intestine.7 HDL comprises most of the cholesterol in dogs and cats. It serves as a reverse cholesterol transporter and scavenges excess cholesterol from cells, returning it to the liver for excretion into the bile.4 Increased risk of cardiovascular disease is associated with increased LDL and insufficient HDL concentrations in people. In people, LDL is considered the bad cholesterol, and HDL is considered the good cholesterol.7

Pathophysiology

Hyperlipidemia can result from dietary intake of lipids (postprandial), excessive endogenous production or mobilization of lipids, or ineffective clearance of lipids from the serum (Table 2).3 In cases of idiopathic hyperlipidemia, the cause is not identified; however, the mechanism will be either excessive production or mobilization or ineffective clearance.

Table 2: Common Causes of Hyperlipidemia in Dogs and Cats*

The dietary intake of lipids is a common cause of hyperlipidemia. Hyperlipidemia can be a physiological finding in blood samples from non-fasted animals.3 Dietary hyperlipidemia is characterized by increased chylomicron concentrations. Because chylomicrons contain mostly triglycerides and only a small amount of cholesterol, the serum cholesterol concentration of patients with postprandial hyperlipidemia is usually normal or only mildly increased (< 500 mg/dl). Within 30 minutes to two hours after a fat-containing meal is ingested, chylomicrons are apparent in the plasma as a transient increase in plasma or serum turbidity.3,4 The turbidity should clear six to 10 hours after a meal.3 To avoid confusion caused by postprandial lipidemia, we recommend a 12-hour fast when evaluating blood lipid concentrations.

ESSENTIAL ELEMENT

Endogenous mobilization of lipids results from increased intracellular hormone-sensitive lipase activity.7 Hormone-sensitive lipase activity is increased with poor nutrition (starvation, nephrotic syndrome); increased concentrations of ACTH and corticosteroid (hyperadrenocorticism, exogenous corticosteroid administration), growth hormone (acromegaly), and thyroid hormone (hyperthyroidism); and increased glucagon-to-insulin activity (diabetes mellitus, pancreatitis).1,3 Although hyperthyroidism increases the VLDL concentration, the concomitant increased lipoprotein lipase activity minimizes hyperlipidemia.4 Lipoprotein lipase facilitates the movement of fatty acids from the VLDLs into cells, leaving increased serum LDL concentrations.7 Thus, hyperthyroid patients may have mildly to moderately increased serum cholesterol concentrations because of increased LDL concentrations.1

Lipoprotein lipase is necessary for removing VLDL and chylomicron fatty acids from the blood.4,7 Lipoprotein lipase activity is increased by heparin, insulin, and thyroid hormone.3,9 So patients with diabetes mellitus, pancreatitis, or hypothyroidism tend to have hyperlipidemia.9 In addition, familial lipoprotein lipase deficiency in cats and dogs is reported.1 Increased VLDL concentrations caused by increased serum triglycerides results in increased production of LDLs when the fatty acids are removed.7 Because of the cholesterol in LDLs, lipoprotein lipase deficiency can result in a mild to moderate increase in total serum cholesterol (500 to 750 mg/dl). Severe hypercholesterolemia may occur in association with cholestasis because excretion in the bile is the major route for removal of excess cholesterol from the body.1 In our experience, severe hypercholesterolemia can also occur secondary to hypothyroidism.

Familial hyperlipidemia occurs most often in miniature schnauzers and beagles.10,11 In cats, familial hyperlipidemia is associated with lipoprotein lipase deficiency and hyperchylomicronemia.1,11,12

CLINICAL SIGNS

The clinical manifestations of hyperlipidemia in dogs are associated with dysfunction in the gastrointestinal, neurologic, and ocular systems. The primary clinical findings include vomiting, diarrhea, abdominal pain, abdominal distention, anorexia, seizure activity, lipemia retinalis, and lipemic aqueous humor.1-3 Although clinical signs and history may be consistent with pancreatitis, laboratory data and imaging studies may fail to support a diagnosis of pancreatitis. Because of the large size of chylomicrons, severe hyperchylomicronemia (> 1,000 mg/dl) can result in the occlusion of organ blood vessels.1 If the pancreatic vessels are occluded, subsequent pancreatic ischemia results in a vicious cycle of lipase leakage, fatty acid degeneration, free radical production, and tissue damage with secondary pancreatitis.1 In people and animals, sustained hyperlipidemia is a principal risk factor for developing pancreatitis, and patients that present with pancreatitis should be evaluated for hyperlipidemia.1,2

In cats, hyperlipidemia can cause cutaneous lesions and peripheral neuropathies. The most common clinical finding is cutaneous xanthoma, a painless raised lesion caused by an accumulation of lipid-laden macrophages or foam cells in the skin.1-3,13,14 Although sites of nerve involvement vary, Horner's syndrome, tibial nerve paralysis, and radial nerve paralysis are common.2

Increased LDL and VLDL cholesterol are risk factors for atherosclerosis in people.8,15 Dogs and cats are considered resistant to atherosclerosis associated with hypercholesterolemia for two reasons: First, unlike in people, the preponderant circulating lipoprotein in dogs and cats is HDL.9,11 Second, most dogs and cats maintain relatively low LDL concentrations because of unique hepatic metabolism that promotes increased HDL and decreased LDL production.9 Nonetheless, when the cholesterol concentration exceeds 750 mg/dl in dogs and 650 mg/dl in cats, there is a relative increase in the LDL particles that predisposes the animals to atherosclerosis.9

DIAGNOSIS

Consider hyperlipidemia in dogs or cats that present for evaluation of clinical signs compatible with hyperlipidemia or with fasting lipemia (lactescent serum). A variety of diagnostic tests are available. See Table 3 for an overview of the test results that indicate hyperlipidemia.

Table 3: Diagnostic Tests and Expected Results for Patients with Hyperlipidemia*

Gross appearance of plasma or serum

Gross observation of the serum or plasma may assist in the diagnosis.1,2 The presence of fasting lipemia confirms hypertriglyceridemia. Lipemia becomes grossly detectable at triglyceride concentrations greater than 300 to 400 mg/dl (normal triglyceride concentration = 50 to 150 mg/dl in dogs and 50 to 100 mg/dl in cats) and is a result of the high concentration of large lipoproteins (chylomicrons and VLDLs).1 Elevated concentrations of cholesterol, without increases in chylomicrons or VLDLs, result in increases of LDLs and HDLs and do not affect the gross appearance of the serum or plasma.1

Chylomicron test

A patient that presents with fasting lipemia can have elevations of chylomicrons, VLDLs, or both. To further evaluate such patients, a chylomicron test can be performed on lactescent serum by allowing the serum or plasma sample to sit undisturbed in a refrigerator for 12 to 14 hours.2 Chylomicrons are less dense than VLDLs and will float to the top of a chilled sample.2 The VLDLs are denser and tend to stay suspended within the serum or plasma. The formation of a creamy layer indicates the presence of chylomicrons. The absence of a creamy layer in a lipemic sample confirms increased VLDLs when the infranatant is cloudy. Formation of a creamy top-layer and cloudy plasma is indicative of excessive chylomicrons and VLDLs.2

ESSENTIAL ELEMENT

The presence of chylomicrons alone can result from either familial or acquired diseases that result in reduced or absent lipoprotein lipase activity.2 However, the presence of VLDLs suggests that the hyperlipidemia is secondary to decreased or absent lipoprotein lipase activity or increased VLDL production.2 Both chylomicrons and VLDLs may be present in poorly regulated diabetic dogs.2

Triglyceride and cholesterol concentrations

Gross lipemia may not be evident in some patients with clinical signs compatible with hyperlipidemia. In these patients, determining fasting serum or plasma triglyceride and cholesterol concentrations is recommended. Total cholesterol is included on many serum chemistry profiles. A triglyceride concentration must be requested as an additional test. When assessing a patient for hyperlipidemia, submit refrigerated or frozen serum rather than plasma or whole blood.2

Lipemia can alter serum biochemical analysis. Chylomicronemia can interfere with other analytes determined by colorimetric methods (Table 4).2,3 Hyperlipidemia can also lead to in vitro hemolysis resulting from altered erythrocyte membrane fragility.2,12 Because of this interference, some laboratories clear lipemic samples by removing chylomicrons. If the laboratories do not report this, false negative results are possible. Therefore, submit paired lipemic samples to the laboratory—one for determining the triglyceride concentration and one to be cleared of chylomicrons and used to perform routine biochemical testing.

Table 4: Effect of Lipemia on Serum Chemistry Parameters in Dogs and Cats*

Reference ranges for serum lipids vary widely depending on the specific laboratory methodology.1 So use species-specific reference ranges provided by the laboratory whenever possible. The guidelines used in our laboratory to assess the severity of hyperlipidemia in dogs and cats are presented in Table 5.

Table 5: Classification of Hyperlipidemia in Dogs and Cats*

Tests for secondary hyperlipidemia

Once hyperlipidemia is confirmed and recognizing that lipemia is usually secondary, additional testing aimed at identifying the primary cause is recommended. Additional testing (including a complete blood count, serum chemistry profile, and urinalysis) may include a low-dose dexamethasone suppression test, thyroid function testing (serum T4 and thyroid-stimulating hormone concentrations), and serum pancreatic lipase immunoreactivity.

ESSENTIAL ELEMENT

Tests for primary hyperlipidemia

If secondary hyperlipidemia is ruled out, primary hyperlipidemia is likely, and additional testing may include lipoprotein electrophoresis and lipoprotein lipase activity. However, lipoprotein electrophoresis has limited value in the clinical evaluation of lipid disorders in dogs and cats because validation of lipoprotein classes by electrophoresis is incomplete.2 Furthermore, it is unlikely that electrophoretic patterns are disease-specific.2

The absence or decreased activity of lipoprotein lipase can be evaluated by determining the plasma activity of this enzyme. Indirect activity can be determined by collecting serum samples both before and 15 minutes after an intravenous injection of heparin (90 IU/kg) in dogs.1 In cats, samples should be collected before and 10 minutes after an intravenous injection of heparin (45 IU/kg).1 Heparin causes lipoprotein lipase release from vascular endothelium, stimulating the hydrolysis of chylomicrons and VLDLs.7 Cholesterol and triglyceride concentrations are measured in pre- and post-heparin samples. A post-heparin decrease in triglyceride and cholesterol concentrations confirms lipoprotein lipase activity. Similar pre- and post-heparin triglyceride and cholesterol concentrations are compatible with decreased or absent lipoprotein lipase activity.1 Molecular polymerase chain reaction analysis is available for lipoprotein lipase deficiency in cats with hyperchylomicronemia.16

TREATMENT

Treatment options for hyperlipidemia include treatment of inciting diseases, diet modification, and pharmacologic intervention. The importance of testing for inciting causes of hyperlipidemia cannot be overemphasized. Hyperlipidemia secondary to an underlying disorder will probably resolve or improve after the metabolic disturbance is corrected.

Hypertriglyceridemia

In cases of familial or idiopathic hyperlipidemia with elevated triglyceride concentrations, combined dietary and pharmacologic intervention may be necessary. We recommend treating patients with moderate to severe hyperlipidemia. Dogs that require cataract surgery (diabetic patients) should ideally have a fasted triglyceride concentration < 500 mg/dl. In our experience, triglyceride enters the aqueous chamber at an approximate serum concentration of 500 mg/dl and causes severe uveitis. So we treat patients with fasting triglyceride concentrations > 500 mg/dl aggressively before cataract surgery. The goal of therapy is not to reduce triglyceride and cholesterol concentrations to the normal range. Instead, triglyceride and cholesterol concentrations should be reduced so that clinical signs are ameliorated while avoiding drug-induced side effects.

Dietary modification. In some patients, switching the patient to a low-fat diet may be the only therapy needed. It is generally recommended that diets should contain less than 20% fat on a metabolizable energy basis for dogs and less than 25% for cats (Table 6).3,17 However, obtaining a good diet history to estimate the level of consumed fat is important before deciding the degree of fat restriction. The patient should be fed a diet with a fat level lower than the previous diet. Treats should be restricted to 5% of the daily caloric intake and changed to low-fat varieties (carrots or brown rice crackers).3,17

Table 6: Selected Low-Fat Commercial Diets for Dogs and Cats*

Evaluate the plasma triglyceride concentration four weeks after beginning a reduced-fat diet. If the reduction in triglycerides is inadequate, ask the owner about compliance (e.g. excess or inappropriate treats, access to other foods), reevaluate the diet's fat content, and reevaluate the medical record to ensure other diseases were ruled out (especially hypothyroidism and hyperadrenocorticism). For patients with poor response to low-fat commercial diets, consultation with a nutritionist for a balanced ultra-low-fat home-cooked diet may be beneficial. When low-fat diets are not adequate, lipid-reducing pharmacologic agents can be considered.

Pharmacologic intervention. Lipid-lowering agents used in people include chitosan, omega-3 fatty acids, niacin, fibric acid derivatives, and statins.18 Evidence for their effectiveness and safety in veterinary medicine is lacking.

Chitosan is a calorie-free, animal-derived fiber supplement that not only passes through the intestines without being digested but also absorbs and removes fat.19 There are no clinical trials reporting the benefit or side effects of chitosan.

Diets rich in omega-3 fatty acids can lower hypertriglyceridemia in people by decreasing the production of VLDLs.18 Menhaden oil can be used in dogs at a dosage of 200 mg/kg/day.3,10

Niacin (100 mg/day in dogs) may also reduce hypertriglyceridemia by decreasing fatty acid release from adipocytes and reducing the VLDL production.3,10 Potential side effects of niacin include erythema, pruritus, abnormal hepatic function test results, vomiting, and diarrhea.3,10 In our experience, these side effects and the lack of convincing evidence of efficacy limit niacin use in dogs and cats.

Fibric acid derivatives lower triglycerides by stimulating lipoprotein lipase, which decreases the production of fatty acids and, in turn, reduces VLDL concentrations.18 We commonly use gemfibrozil (Lopid—Pfizer) at a dosage of 200 mg/day in dogs and 10 mg/kg every 12 hours in cats.3,10 Potential side effects include abdominal pain, vomiting, diarrhea, myositis, and abnormal hepatic function test results.3,18

The statins can be used to lower VLDLs, LDLs, and HDLs in people.18 Statins are usually prescribed for hypercholesterolemia in people; however, they are modestly effective at lowering triglyceride concentrations.18 Adverse effects in people include lethargy, diarrhea, muscle pain, and hepatotoxicity. Because of these potential side effects in dogs and cats and the lack of convincing efficacy in lowering triglyceride concentration, we rarely use statins to treat hypertriglyceridemia.

Hypercholesterolemia

Treatment of hypercholesterolemia relies largely on diet and occasionally on pharmacologic intervention. As mentioned previously, dogs and cats transport most of their cholesterol as HDLs, minimizing the risk of atherosclerosis. Thus, we do not recommend treating hypercholesterolemia until the concentration is above 750 mg/dl in dogs or 650 mg/dl in cats because of the likely increase in LDL that may predispose them to atherosclerosis at these concentrations.9 As with hypertriglyceridemia, the search for secondary causes is a must. In our experience, severe hypercholesterolemia in cats is rarely encountered and in dogs is usually secondary to hypothyroidism.

Dietary modification. For severe idiopathic hypercholesterolemia, low-fat diets are the mainstay of therapy.3 In addition, soluble fiber (gums, pectins) can be added to diets to help decrease the cholesterol concentration.19 Soluble fiber interferes with the enteric absorption of bile acids and increases the hepatic use of cholesterol to synthesize bile acids.20

Pharmacologic intervention. For those patients unresponsive to diet alone, bile acid sequestrates and statins may be considered.

Bile acids are synthesized in the liver from cholesterol and excreted into the duodenum. Cholestyramine (Questran—Bristol-Myers Squibb) is an ion exchange resin that interferes with the enteric absorption of bile acids and is approved for use in people to lower cholesterol.18 Cholestyramine (1 to 2 g orally b.i.d.) results in increased cholesterol use for bile acid synthesis.3,18 As hepatic cholesterol concentration decreases, hepatic LDL receptors are upregulated to increase the removal of LDLs and HDLs from the blood.18 Potential side effects of this medication include constipation, interference of oral medication absorption, and increased VLDLs from uptake of LDLs.18 Because of the risk of increased VLDLs, use cholestyramine with caution in patients with concurrent hypertriglyceridemia.

The statins, which are methylglutaconyl-coenzyme A (HMG-CoA) reductase inhibitors, are the most potent cholesterol-lowering drugs in people.18 HMG-CoA reductase is the rate limiting step in cholesterol synthesis.18 Statins, by inhibiting HMG-CoA reductase, reduce hepatic cholesterol synthesis. A decreased hepatic cholesterol concentration results in the upregulation of hepatic LDL receptors and increased removal of LDLs from the blood.18 The statins also decrease the hepatic production of VLDLs and are modestly effective in the treatment of hypertriglyceridemia.18 Lovastatin (10 mg orally once a day) is effective for persistent hypercholesterolemia in dogs.3 Potential adverse effects include hepatotoxicity, vomiting, diarrhea, myopathy, and hyperesthesia.18 Perform a serum chemistry profile, including creatine kinase activity, before administering any statin, and frequent monitoring for hepatotoxicosis and myopathy is a must. Serum alanine aminotransferase and alkaline phosphatase activities along with serum creatine kinase activities (myopathy) should be measured after one month and then, if normal, at six-month intervals. The combination of a statin plus a fibric acid derivative (gemfibrozil) may increase the risk of skeletal myopathy. These drugs should not be used or should be discontinued in any patient with hepatic disease or that develops evidence of hepatic disease or myopathy during use. The benefit of statins in dogs and cats to reduce LDL is unproven because most of their total cholesterol is transported as HDL.

PROGNOSIS

The prognosis for patients with secondary hyperlipidemia is favorable with effective treatment of the underlying disorder. For patients with primary hyperlipidemia, a lifelong commitment by the owner and veterinarian is required. In our experience, most patients respond favorably to diet modification alone or in combination with pharmacologic agents. The pharmacologic intervention in patients with hyperlipidemia should not be taken lightly. All drugs are potentially toxic, and patients should be monitored carefully. With a committed owner and a veterinarian's thorough understanding of pharmacologic agents used, treating hyperlipidemia can be rewarding.

Justin D. Thomason, DVM, DACVIM (internal medicine)*

Department of Small Animal Medicine and Surgery

College of Veterinary Medicine

University of Georgia

Athens, GA 30602

Bente Flatland, DVM, DACVIM (internal medicine)

Department of Pathobiology

College of Veterinary Medicine

The University of Tennessee

Knoxville, TN 37996

Clay A. Calvert, DVM, DACVIM (internal medicine)

Department of Small Animal Medicine and Surgery

College of Veterinary Medicine

University of Georgia

Athens, GA 30602

*Dr. Thomason's current address is Department of Veterinary Clinical Sciences, Center for Veterinary Health Scieces, Oklahoma State University, Stillwater, OK 74078.

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