Article #2 CE Hyperlipidemia Disorders in Dogs Mark C. Johnson, DVM, DACVP (Clinical Pathology) Texas A & M University ABSTRACT: Lipid disorders are common in dogs, with most arising from secondary causes such as endocrine imbalances, cholestatic liver disease, or protein-losing nephropathies.Two pri- mary lipid disorders—idiopathic hyperlipidemia in miniature schnauzers and hypercho- lesterolemia in briards—are also recognized. Visualization of a lipemic fasted blood sample or elevated plasma cholesterol or triglyceride in combination with clinical assess- ment is the method by which most lipid disorders are diagnosed. Cholesterol and triglyceride are components of larger molecules called lipoproteins, which have a complex and highly regulated metabolism that is important to understand when altered by lipid disorders. ipid disorders are relatively common in vet- cholesterol and triglyceride are water insoluble erinary medicine, particularly in dogs. The in plasma, so they are transported via water-sol- L presence of a lipid disorder provides clues uble lipoproteins in plasma. There are four gen- regarding underlying disease and presents a risk eral types of lipoproteins: chylomicrons, factor for other problems. In dogs, lipid disorders very–low-density lipoprotein (VLDL), low- are either primary or secondary, of which the lat- density lipoprotein (LDL), and high-density ter is by far the most common.1–4 Primary disor- lipoprotein (HDL). Intermediate-density ders are considered hereditary in some breeds of lipoprotein is also recognized but is considered dogs.1,3–6 Secondary disorders can be dietary less important. Humans have two HDL mole- related or more often of endocrine origin, result- cules: HDL2 and HDL3. Dogs have HDL2 and ing from an imbalance of homeostatic mecha- HDL3 but are unique in that they have HDL1, 1–4 nisms that normally regulate plasma lipids (see which is recognized by a distinct α2 band on box on p. 362). Unfortunately, it is not always lipoprotein electrophoresis.1,3,7 easy to separate these two based on clinical Lipoproteins exist in plasma as spherical assessment or biochemical analysis. Therefore, it structures composed of an outer shell and an is imperative that signalment, clinical presenta- inner core (Figure 1). The outer shell has both tion, and biochemical information for each ani- hydrophilic and hydrophobic properties con- mal be analyzed collectively when suspecting one taining free cholesterol, apoproteins, and phos- of these disorders. This article discusses basic pholipids.3,7 Apoproteins serve as cofactors for concepts of lipid metabolism, addresses labora- cholesterol-shuttling enzymes, receptors for tory evaluation of plasma lipids, and examines uptake and delivery of tissue cholesterol and the causes of hyperlipidemia disorders in dogs. triglyceride, and receptors for removal of rem- nant lipoproteins by the liver. The inner core Full-text articles and CE testing at LIPID METABOLISM consists of hydrophobic lipids, primarily choles- CompendiumVet.com. Send comments/ Cholesterol and triglyceride terol esters and triglyceride.3,7 questions via email compendium@ medimedia.com, fax 800-556-3288, are clinically relevant plasma Chylomicrons are created by intestinal or web CompendiumVet.com. lipids (Figures 1 and 2). Free epithelial cells following fatty meal ingestion. May 2005 361 COMPENDIUM 362 CE Hyperlipidemia Disorders in Dogs Causes of Primary and Secondary Lipid Disorders in Dogs A Primary • Idiopathic hyperlipidemia in miniature schnauzers • Hypercholesterolemia in briards P Secondary • High-fat diets • Diabetes mellitus • Hyperadrenocorticism • Hypothyroidism • Acute pancreatitis CCCE TG • Protein-losing nephropathy • Cholestasis may be removed from circulation by the liver or may undergo further triglyceride depletion by lipoprotein lipase or a second enzyme called hepatic triglyceride lipase, forming smaller and denser LDL.3,7 There are notable differences in how dogs and humans Figure 1. Basic lipoprotein structure. (A = apoprotein; process LDL and form HDL. LDL, the “bad lipopro- C = cholesterol; CE = cholesterol ester; P = phospholipid; tein,” primarily transports cholesterol with smaller TG = triglyceride) amounts of triglyceride for delivery to tissues. Subse- quently, remnant LDL particles can be removed from circulation by the liver in both species, similar to rem- They are large molecules composed primarily of triglyc- nant VLDL. In humans, a process called cholesterol shut- eride with smaller amounts of cholesterol. Chylomi- tling, which is mediated by cholesterol ester transfer crons transport triglyceride to tissue, such as muscle or protein, enables triglyceride to be transported directly fat. A critical enzyme called lipoprotein lipase, which is from LDL or VLDL to HDL3 in plasma in exchange located on the endothelium in many tissues, mediates for cholesterol esters, consequently forming cholesterol 3,7,8 this transport. Lipoprotein lipase hydrolyzes triglyc- ester–rich LDL and triglyceride-rich HDL2, respec- Understanding basic lipoprotein metabolism is important because many diseases alter this process, leading to elevated plasma lipid levels. eride within chylomicrons to long-chain fatty acids and tively. 3,7 Cholesterol ester–rich LDL is removed from the glycerol for active uptake by cells.8 Insulin and thyroxine bloodstream by the liver but can also be actively removed are known to enhance the activity of this enzyme.8 After from circulation by macrophages lining large arteries, triglyceride is delivered to tissue, remnant chylomicron potentially leading to atherosclerosis. Unlike humans, particles are removed from circulation by the liver. dogs have no documented activity of cholesterol ester VLDL is produced by hepatocytes and is smaller than transfer protein, which likely contributes to their general chylomicrons but also contains similar cholesterol and resistance to this detrimental phenomenon.3,7,9 triglyceride proportions. Lipoprotein lipase also Native HDL, the “good lipoprotein,” is produced by hydrolyzes triglyceride within VLDL, subsequently the liver and transports cholesterol from tissue back to forming remnant VLDL. Remnant VLDL particles the liver (i.e., the so-called “reverse cholesterol trans- COMPENDIUM May 2005 Hyperlipidemia Disorders in Dogs CE 363 Circulation Tissue Lipoprotein lipase Intestine CM Triglycerides CM CM remnant Lipoprotein lipase VLDL VLDL Triglycerides VLDL Liver remnant Lipoprotein Hepatic lipase triglyceride lipase LDL Cholesterol Native HDL LDL remnant Lecithin–cholesterol Native HDL acyltransferase Cholesterol HDL1 HDL3 Figure 2. Canine lipoprotein metabolism. Cholesterol and triglycerides are transported in plasma via four lipoproteins: chylomicrons (CMs),VLDL, LDL, and HDL. CMs are made in the intestine. Lipoprotein lipase releases triglycerides into the tissue. Remnant CMs are removed from circulation by the liver. VLDL is made by the liver. Lipoprotein lipase releases triglycerides into the tissue. Remnant VLDL is removed by the liver or degraded by the enzymes lipoprotein lipase or hepatic triglyceride to LDL, which transports cholesterol to the tissue. Remnant LDL is removed by the liver. Native HDL is made by the liver and transports tissue cholesterol to the liver with the help of lecithin–cholesterol acyltransferase. Native HDL then becomes HDL3, which incorporates additional cholesterol esters and becomes HDL1, which is removed from the blood by the liver. port” mechanism). Lecithin-cholesterol acyltransferase lesterol esters for incorporation into HDL molecules.3,7 (LCAT), which is an enzyme bound to native HDL in These cholesterol ester–rich molecules are called HDL3 circulation, converts free cholesterol from tissue to cho- in both species. Because dogs do not have cholesterol May 2005 COMPENDIUM 364 CE Hyperlipidemia Disorders in Dogs 1,12,13 ester transfer protein activity, most HDL3 continues to disorder may be present. From a laboratory perspec- acquire cholesterol esters and results in formation of the tive, lipemia can interfere with certain biochemical tests unique HDL1 molecule. Consequently, HDL1 is usually that use endpoint or kinetic assays and can falsely increased with hypercholesterolemia in dogs.3,7 Choles- increase tests using refractometry or spectrophotometry, terol ester–rich HDL can be removed from the blood by such as plasma protein and hemoglobin testing, respec- receptor-mediated endocytosis in the liver for possible tively.14 Spurious biochemical results reported in reuse. Recent evidence in cultured mouse adrenal cells patients with lipemia are increased total bilirubin, total also shows that cholesterol esters can be removed from protein, albumin, globulin, glucose, calcium, phosphorus cholesterol ester–rich HDL by scavenger receptors and bile acid levels.3,14 Falsely decreased assays can be (class B, type 1) without endocytosis of the HDL mole- seen with electrolyte levels and serum activity of amy- cule.10 This receptor has been characterized in humans, lase, lipase, alanine aminotransferase, aspartate transam- but a canine counterpart has not been identified in the inase, and alkaline phosphatase.3,14 literature.11 Lipemia is always associated with elevated plasma triglycerides. However, hyperlipidemia does not always LABORATORY FEATURES OF induce lipemia because hypercholesterolemia by itself LIPID DISORDERS does not cause lipemia.13 Consumption of fatty diets can Increased plasma lipids are often discovered in dogs induce transient lipemia for up to 12 hours after eat-