Abstract

Lipids are a vast group of heterogenous molecular compounds that include fatty acids and their derivatives (such as triglycerides, sphingolipids, phospholipids, lipid mediators) or sterol compounds (such as cholesterol and esters, steroid hormones, fat-soluble vitamins, bile acids). They are also the main biomolecular constituents of plasma and occupy a central place in the pathophysiology of several common diseases of captive parrots. Two main groups of lipid disorders commonly seen in captive parrots are:

• Disorders characterized by excess lipid accumulation, such as obesity, hepatic lipidosis, atherosclerosis, lipomas, xanthomas, and hyperlipidemia
• Disorders related to reproductive diseases in female parrots, such as dysregulated vitellogenesis, egg yolk coelomitis, and emboli

While lipid disorders are common in captive parrots, especially pet parrots, diagnostic and therapeutic options are poorly validated and overall limited. Plasma cholesterol and triglyceride biochemical tests are the most commonly used clinically. Lipoprotein testing is limited because the analytical methods are either unpractical methods mainly used in research or unvalidated and inaccurate methods used in the clinical laboratory. As LDL is difficult to measure directly and the Friedewald formula is not accurate in parrots, it is recommended to only request HDL (for which analytical techniques are more robust across species) and non-HDL (which encompasses all atherogenic lipoproteins). Lipidomics is a new mass-spectrometry method that will likely revolutionize our understanding of lipid disorders in parrots, as it can measure hundreds to thousands of lipid species from minute plasma samples.

Therapy of lipid disorders mainly relies on correcting risk factors (diet, lifestyle) and using pharmacological interventions (GnRH agonists, statins, fibrates).

A Brief Overview of Lipid Diversity in Plasma

The diversity of biological lipid is staggering, and the reader is referred to the LIPID MAPS® website (https://lipidmaps.org) for the most up-to-date lipid classification and lipid species listing.

Lipids are predominant in psittacine plasma, as is the case in mammals. Lipids represent about 40% of plasma biomolecules in psittacine plasma (on a molar basis) with, for comparison, carbohydrates and proteins representing another 30% each. There are different types of lipids that have many functions.

Some lipids are in high concentration (measured in mmol/L or µmol/L) in the plasma and are part of what can be called the macrolipidome and typically include constitutive (such as cholesterol, cholesteryl esters, glycerophospholipids, and sphingolipids) or storage lipids (such as triacylglycerols). Their plasma concentrations get affected by a variety of metabolic disorders, and they also act as the precursors of many bioactive and signaling lipid molecules (most notable precursors are arachidonic acid and cholesterol, for instance).

On the other hand, numerous lipid species are bioactive molecules that act as mediators in various functions and are in very low concentration (measured in nmol/L or pmol/L, so a thousandth or millionth less concentrated than other lipids) and part of what can be called the microlipidome (or the mediator lipidome). The most important lipid mediators include inflammatory mediators (prostaglandins, leukotrienes, eicosanoids), prothrombotic molecules (thromboxanes), vitamins (vitamins A, D, E), pain mediators (endocannabinoids: anandamide and 2-AG), and steroid hormones (corticosterone, estradiol).

Most lipid species of the macrolipidome are transported within either lipoproteins (almost all lipids) or bound to albumin (free fatty acids), whereas lipid mediators are typically free in the plasma, bound to albumin, or transported by specific proteins.

Important plasma lipids of the lipidome are part of these five large groups of lipids:

Table 1. Important lipid groups found in parrot plasma

Sterol Lipids

These include free cholesterol, cholesteryl esters (CE), bile acids, and steroid hormones. Cholesterol and cholesteryl esters are the predominant lipid species in parrot plasma (about 50–60% on a molar basis). About one-third of total cholesterol is non-esterified (free) while two-thirds is esterified to various acyl chains, the most abundant by far being linoleic acid (18:2). CE (18:2) constitutes more than 70% of all cholesteryl esters. Cholesterol is synthetized in the liver (through a process involving the key enzyme HMG-CoA reductase, the target of statins), and exogenous sources of cholesterol are low in parrots as they are mainly frugivorous or granivorous animals (cholesterol is not present in plants). Cholesterol is mainly used for cellular membranes and as a precursor for other metabolites. Bile acids are cholesterol derivatives produced by the liver that assist in the emulsion and digestion of fat in the digestive system. The most common bile acid in parrot plasma is taurochenodeoxycholic acid and constitutes about 70% of all plasmatic bile acids. Bile acids are used as markers of liver health. Steroid hormones are synthesized from cholesterol and include hormones such as glucocorticoids (the main one being corticosterone in birds), mineralocorticoids (aldosterone), and sex hormones (produced by the gonads and adrenal glands) such as androgens (testosterone, androstenedione), estrogens (estradiol), and progestins (progesterone). They can affect the overall lipid metabolism and regulate vitellogenesis in hens.

Fatty Acyls

These include simple lipids such as free fatty acids and fatty acid derivatives. They typically have an even carbon chain in vertebrates. Fatty acids can be saturated or unsaturated (presence of double bonds in the hydrocarbon chain). The location of the double bond is important in terms of diet and health (omega-3 such as alpha-linolenic acid, DHA, EPA and omega-6 fatty acids such as linoleic acid). Linoleic (18:2) and alpha-linolenic acid (18:3) are essential fatty acids and must be supplied in the diet. Fatty acids are used as energy through mitochondrial beta-oxidation. Very long-chain PUFA (DHA, EPA, arachidonic acid) are the precursors of the eicosanoid lipid mediators such as prostaglandins, leukotrienes, thromboxanes and others. Non-esterified (free) fatty acids (NEFA) in the plasma come from either intestinal absorption or lipolysis (from triacylglycerols). To enter the beta-oxidation pathway occurring in the mitochondria, they are typically esterified to carnitine for transport through the mitochondrial membranes. Several acyl-carnitine species can be detected and quantified in parrot plasma. Beta-oxidation results in ketone bodies (with beta-hydroxybutyric acid being the most common in birds) that get elevated in the plasma when ketolysis processes are overwhelmed (such as with a large production of ketone bodies). The plasma concentration of NEFA can also be used clinically to assess the degree of lipolysis and negative energy balance. Eicosanoids are not routinely measured but can be useful to understand inflammatory pathways induced with various diseases. Fatty acyls represent only 5–10% of plasma lipids. The most preponderant fatty acid in the plasma is palmitic acid (16:0). In much lower concentrations, oleic acid (18:1) is the most common monounsaturated fatty acid, and linoleic acid (18:2) is the most common polyunsaturated fatty acid. Fatty acids produced by the preen gland are particular in that they are branched-chain fatty acids.

Glycerolipids

Glycerolipids include triacylglycerols (TAG, commonly called triglycerides in medicine even though it is an outdated term), diacylglycerols (DAG), and monoacylglycerols (MAG) and their alkylglycerol (glyceryl ethers) counterparts. They are composed of a molecule of glycerol esterified to one to three fatty acids in a specific order. The first fatty acid tends to be a saturated fatty acid (typically palmitic acid), the second a monounsaturated fatty acid (typically oleic acid), and the third is much more variable and is where polyunsaturated fatty acids are typically located. TAG composition typically reflects the diet as well as contribution of metabolism (“de novo” lipogenesis). “De novo” lipogenesis mainly occurs in the liver in birds with minimal contribution of the adipose tissues, unlike in mammals.¹ The main function of TAG is energy storage. Because of the large number of potential combinations of esterified fatty acids, glycerolipids species are very diverse in the plasma, and hundreds of distinct lipid species are present in the plasma. Glycerolipids constitute about 10% of plasma lipids on a molar basis, and TAG are the most abundant by far. TAG with 52 or 54 carbons—most being combinations of palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), alpha-linolenic acid (18:3) and arachidonic acid (20:4)—are the predominant in parrot plasma. DAG and MAG are in much lower concentrations and are metabolic intermediates. A MAG of particular significance is 2-arachidonoyl-glycerol or 2-AG, which is the main endocannabinoid present in parrot plasma.

Glycerophospholipids

Glycerophospholipids (commonly abbreviated as phospholipids) are very diverse amphiphilic molecules that are made of a glycerol backbone with usually two esterified fatty acids (like glycerolipids) and an esterified phosphoryl part. The phosphoryl part can simply be phosphoric acid [glycerophosphates (PA)] or additional head groups to form more complex glycerophospholipid such as choline [glycerophosphocholine, also known as phosphatidylcholine (abbreviated PC) or lecithin], phosphatidylserines (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), phosphatidylethanolamines (PE) and others. The main function of phospholipids is structural as part of the cellular membranes. They can also function as signaling molecules (e.g., PIP2). The vast majority of phospholipids in plasma, both in number of lipid species and concentration, are the PC. Phospholipids are the second most abundant plasma lipid class in parrots after the sterols (around 14–15% of lipids). Lyso-PC (and other lysophospholipids) are metabolites generated by the loss of one of the two acyl chains. They are detected in the plasma too, but in much lower concentration. They are considered as metabolic intermediates.

Sphingolipids

Sphingolipids are incredibly diverse and complex lipids that are also structural lipids (membranes, myelin). They are in relatively low concentrations in the parrot plasma compared to other lipid classes (around 0.6%). While glycerolipids and phospholipids are based on glycerol, sphingolipids use long-chain sphingoid bases as backbones. Several sphingoid bases are possible, but sphingosine (abbreviated as d18:1) is the most common by far (as in mammals). When sphingosine is esterified to one fatty acyl chain, it is called a ceramide. Ceramides are intermediaries or byproducts of sphingolipid metabolism, but some may also serve as signaling molecules. On top of a fatty acyl chain (ceramides), other head groups may be found on the sphingosine backbone and determine the type of sphingolipid subclass such as the sphingomyelin (additional phosphocholine), sugars (cerebrosides, globosides, gangliosides). Sphingomyelins are the most abundant sphingolipids in parrot plasma.

A Brief Overview of Avian Lipoprotein Metabolism

Almost all lipids in the plasma are transported in the form of macromolecular aggregates of mixed lipid species and proteins known as lipoproteins. The exception is nonesterified fatty acids, which are transported bound to albumin. As avian lipoprotein metabolism has been comprehensively reviewed elsewhere,^1,2 only a brief recapitulative will be given here.

Lipoproteins are classified based on their density and size and are involved in different lipid transport pathways. They are of micellar lipid structure with a surface monolayer mainly composed of free cholesterol and phospholipids and a hydrophobic core composed of triacylglycerols and cholesteryl esters. Proteins called apolipoproteins are also present on the surface and have structural and signaling properties. Apolipoproteins are especially used for lipoprotein trafficking. Lipoproteins are classified based on their density into portomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).

Portomicrons are the avian equivalent to mammalian chylomicrons. The main differences are that portomicrons are not released into the lymphatic system (being poorly developed in birds) but in the portal vein. Portomicrons and VLDLs are very large lipoproteins that participate in the exogenous lipid pathway in birds, in which lipids absorbed through the intestinal walls are transported to the liver. They are therefore high in triglycerides. VLDLs and LDLs participate in the endogenous cholesterol/lipid pathway, in which cholesterol synthesized in the liver is transported into effector tissues. Two important enzymes that hydrolyze triacylglycerol within VLDL and IDL shrinking them into LDL at the effector sites are lipoprotein lipase and hepatic lipase. LDL is particularly high in cholesteryl esters. LDL particles are then picked up by the liver through LDL receptors for recycling. Apolipoprotein B100 is the main apolipoprotein of portomicrons, VLDL, and LDL. In humans, ApoB48 is present in chylomicrons but is not present in birds and is replaced by ApoB100.

HDLs participate in the reverse cholesterol transport pathway, in which cholesterol is brought back to the liver from effector tissues. Cholesterol is then recycled or excreted through the bile. HDLs are high in phospholipids and proteins and have apolipoprotein A as their main apolipoproteins. The plasma enzyme cholesteryl ester transfer protein (CETP) can move cholesterol from HDL to LDL in exchange for triglycerides. CETP has been measured in Quaker parrots and seems to increase with dyslipidemia.³ In parrots, as in most birds and unlike humans, HDL is the main lipoprotein present in the plasma. Most of parrot HDL particles are small to medium in size, with a mean diameter of about 9.8 to 10.9 nm, much like in humans.⁴ In female birds, another pathway (not present in mammals) is the egg lipid transport pathway, in which specialized, very low-density lipoproteins (the phospholipid-rich vitellogenin and triglyceride-rich VLDLy) transport lipid to the developing oocyte. It is under estrogenic influence. Vitellogenin and VLDLy have smaller diameters (around 30 nm) than regular VLDL (most being >31–36 nm) to be able to go through the granulosa basal lamina. These lipoproteins are not susceptible to lipoprotein lipase, unlike other lipoproteins.

Figure 1. Avian lipoprotein metabolism

Lipidologic Diagnostic Methods

In terms of diagnostic tests and monitoring tools of fatty disorders, blood lipid analysis takes a center stage. Most if not all lipid-related disorders are either directly associated with dyslipidemic changes or secondarily through metabolic dysfunction and alterations of broad metabolic pathways. Most commonly used blood diagnostic tests in veterinary medicine and a fortiori in avian medicine tend to focus on plasma protein biomarkers, enzyme activities, electrolytes, or small metabolites instead of lipids. However, lipids are preponderant in the plasma, and lipidomic studies in parrots have shown that close to 1000–1500 distinct lipid species could be detected in Quaker parrot plasma. Consequently, lipids can serve as novel biomarkers for several diseases, mainly lipid-related and metabolic diseases. Unfortunately, there is a vast gap of knowledge for naturally occurring dyslipidemia and the association with common lipid-accumulation disorders in pet birds. Furthermore, most lipidologic diagnostic tests are not validated in Psittaciformes.

Lipidologic tests currently used and commercially available for birds include total cholesterol, total triglycerides, and lipoprotein wet-chemistry tests. Total cholesterol and triglycerides are the most useful tests to date in parrots and are expected to cross-react relatively well with tests developed for humans, as the cholesterol molecule is the same across species and the triglycerides test only targets the glycerol backbone of the molecule, which is also the same across species.

The cholesterol assay does not distinguish between free cholesterol and cholesteryl esters and in which lipoprotein the cholesterol is from, so it is a total cholesterol assay. Likewise, the triglycerides test does not distinguish between free glycerol, glyceryl ethers (DG-O), monoacylglycerols, diacylglycerols, and triacylglycerols. It is therefore more of a total glycerides test than a triacylglycerol test. Non-triacylglycerol glycerolipids account for only about 3–4% of plasma glycerolipids in parrots and could be considered negligible. However, in normal parrots, about 30% of what is measured as triglycerides is actually free glycerol (on a molar basis).⁴ So it seems to be much more than in humans where free glycerol constitutes only 5–8% of total glycerides. This can interfere with clinical interpretation or the use of the triglycerides assay to estimate other values, such as VLDL or ratios. Pseudohypertriglyceridemia is caused by elevated blood free glycerol concentration in humans but has not yet been described in parrots. Point-of-care analyzers do not seem to perform well in parrots to measure total cholesterol or total triglycerides.^5,6

As lipoproteins are the main lipid carriers and lipid distribution across lipoproteins varies, lipoprotein testing and profiling are routine in human medicine. The gold standard for lipoprotein analysis is separation by density gradient ultracentrifugation. This technique is extremely time consuming, requiring 6–30 hours of very high-speed centrifugation and specialized equipment.⁷ It is not offered commercially for animals, but has been used for research in pigeons, chickens, quails, geese, Quaker parrots, and cockatiels.^1,8-14 While this method allows separation and isolation of lipoprotein classes and subclasses, it does not allow the determination of lipoprotein particle numbers and particle sizes. In order to analyze lipid contents of lipoprotein classes, a relatively large volume of blood is also needed, and each fraction must be carefully collected from the centrifugal tubes prior to analysis; therefore, ultracentrifugation of small volumes to obtain a lipoprotein panel, typically by analytical ultracentrifugation, can only allow the determination of relative distribution (% of total lipids). Absolute values are then determined from the total blood cholesterol levels and are not directly measured from each lipoprotein fraction.^9-11 Moreover, parrot-specific density gradient cut-offs have not been established.⁹ Other techniques to measure lipoproteins include electrophoresis and nuclear magnetic resonance, but these techniques have not been described in parrots yet. Recently, a high-resolution technique using gel-permeation HPLC (LipoSEARCH®) has been reported to provide full lipoprotein profiling in parrots with a panel of 20 subclasses and particle sizes reported from just one drop of plasma.⁴ Particle numbers can be obtained through NMR (not available because the algorithm to analyze the NMR spectrum is proprietary and based on humans) or the LipoSEARCH® panel. However, while these reference techniques are applicable to any animal species, they are not used or practical for clinical practice.

Avian lipoproteins present a large number of differences from mammals, and no lipoprotein diagnostic test has been validated in birds for routine use in practice. In addition, lipoproteins tend to degrade with any kind of storage, including in ultra-low freezers; therefore, it is best to perform lipoprotein analysis on fresh samples.¹⁵ Direct LDL and HDL wet-chemistry analytes have been developed for human plasma and typically only measure their cholesterol content. These tests typically focus on HDL and use either selective precipitation or selective complexation methods. The Friedewald formula (LDL = cholesterol – HDL – VLDL/x with x = 5 in US units and x = 2.18 in SI units), an indirect method used most commonly for determination of LDL-C, is based on the assumption that the ratio between triglycerides and VLDL is the same across species. While being widely used, this formula is not accurate in Quaker parrots⁴ and likely shows a similar lack of accuracy in other psittacine species. More studies are needed to determine a parrot-specific formula for indirect LDL estimation, but preliminary findings suggest using LDL = 0.75*non-HDL in healthy parrots.⁴ The Friedewald formula is also known to be inaccurate with respect to hypertriglyceridemia in mammals, and avian vitellogenesis is expected to prevent its use in female birds.

Apolipoproteins (ApoB, ApoB/ApoA) are commonly measured, as they directly reflect lipoprotein particle numbers since there is only one apolipoprotein B molecule per non-HDL lipoprotein particle.¹⁶ Birds lack Apo-E and ApoB-48. In addition, the parrot ApoB-100, the predominant apolipoprotein in portomicrons, VLDL, and LDL has only about 50% sequence homology with human Apo-B100. Therefore, apolipoprotein diagnostic tests based on human plasma are also unlikely to be useful in parrots.

Comprehensive lipid analysis by mass spectrometry, known as lipidomics, is rapidly revolutionizing the way metabolic disorders are investigated. Further, in the context of dyslipidemia, specific lipid species of complex lipids may be better targets or biomarkers than crude measurements of a single lipid molecule such as cholesterol and glycerol (for triglycerides). Thousands of species of triglycerides, phospholipids, and cholesteryl esters with a variety of saturated and unsaturated fatty acyl chains can be measured in plasma. Lipidomic analysis provides an important alternative approach that bypasses many limitations of conventional tests while providing considerably more information. The lipidome of male and female parrots also tends to be different. While it is not yet used on clinical patients, lipidomic research is underway in parrots (see presentations at this conference) and may lead to improved lipidologic diagnostic tests in the future. Specific biomarkers or lipidomic signature for specific diseases may be discovered with these techniques.

Until new tests are offered and validated, for now, total cholesterol and triglycerides remain the mainstay of reliable plasma lipidologic diagnostic tests in psittacine birds. Lipoprotein measurement using standard reference analyzers is likely not accurate, despite its use in multiple reference interval and experimental studies. If lipoproteins are still measured, they should be done on fresh plasma if possible and limiting the analysis to HDL-C without employing the Friedewald formula for LDL-C. Non-HDL-C can be used as a surrogate for VLDL/LDL cholesterol and encompasses all atherogenic lipoproteins. It has been shown to be an important risk factor for a number of diseases in humans and is now widely used in conjunction or replacement of LDL-C measurement. HDL measurement using standard reference analyzers uses a selective precipitation/complexation technique for non-HDL lipoproteins that may be more reliable across species than other lipoprotein analysis methods. However, this has not been studied in psittacine birds. Some other tests routinely available in the diagnostic laboratory, but seldom used, are beta-hydroxybutyrate (BHBA) and total non-esterified fatty acids (NEFA). BHBA is the main ketone in birds and is a marker of increased (and somewhat overwhelmed) fatty acid oxidation, whereas NEFA is a marker of lipolysis and negative energy balance. Both tend to get elevated in diabetes.

Another important point is that blood lipidologic tests are used to characterize dyslipidemia and risk factors for some diseases, but do not directly diagnose lipid-accumulation disorders such as atherosclerosis and hepatic lipidosis. While they may raise the suspicion for these disorders when biomarkers are elevated, other diagnostic tests should be used to diagnose these conditions (typically diagnostic imaging and tissue biopsies).

Lipid-Related Diseases

Dyslipidemia

Dyslipidemias (abnormal blood lipid concentrations) are extremely common in Psittaciformes and lead to a variety of primary and secondary disorders. The prevalence of hypercholesterolemia is estimated to be 20% in psittacine birds (n=5625, Beaufrère, unpublished, cut-off of 8 mmol/L). In addition, dyslipidemias are strongly associated with lipid-accumulation disorders in parrots, such as atherosclerosis, hepatic lipidosis, fatty tumors, obesity, as well as with chronic reproductive diseases in females.^9,17 Dyslipidemias have been poorly characterized other than for total hypercholesterolemia and hypertriglyceridemia. Likewise, spontaneous lipoprotein abnormalities are poorly characterized in pet birds.

Female birds undergoing vitellogenesis have an increased cholesterol and triglyceride level in the plasma. Their lipids are within vitellogenin and VLDLy, which are resistant to the action of lipoprotein lipase. This means that in dysregulated vitellogenesis, the dyslipidemia may be more long lasting and harder to control.

Diet undoubtedly plays an important role in the emergence of dyslipidemia either through increased calorie or fat intake and through multiple deficiencies. A moderate increase in fructose intake has not been associated with dyslipidemia in zoo macaws (Desmarchelier, unpublished). A seed-based diet may lead to chronic dyslipidemia and nutritional deficiencies. For instance, sunflower seeds are composed of more than 50% fat even if its fatty acid profile is good.

Results of studies on cholesterol in parrots have been inconsistent in terms of sex difference, with females being found to have higher HDL than males in some studies, higher LDL, or no difference at all (most commonly). Other factors may also affect blood lipid interpretation, such as postprandial hyperlipidemia, aging, and hepatobiliary diseases that may cause an elevation in cholesterol subsequent to cholestasis. Hypothyroidism is also a well-known cause of dyslipidemia but is rare in pet birds. In psittacine birds reported to have spontaneous or experimental hypothyroidism or goiter, hypercholesterolemia was frequently encountered.

Clinical experience shows that both non-HDL and HDL increase in dyslipidemia, but the ratio HDL/non-HDL tends to shift. Some species tend to have higher blood lipid values than others, in particular Quaker parrots and Amazon parrots. Other risk factors include the diet and lack of activity. The normal diet of most parrots should not include animal products, which are rich in saturated fat and cholesterol (the latter not being present in plants). Strong dyslipidemia has also been experimentally induced in Quaker parrots fed a 1% cholesterol pelletized diet.³ In the same species, a seed diet led to elevation in triglycerides and lipemia, and overweight birds had higher cholesterol, triglycerides, lipemia, and non-HDL cholesterol.⁹

Hepatic Lipidosis

Hepatic lipidosis is characterized by the accumulation of triglycerides in hepatocytes, which may progress to liver dysfunction when severe. The prevalence seems higher in some species such as Amazon parrots and particularly in Quaker parrots with a reported prevalence of 21%.¹⁸ The background prevalence in psittacine species seems to be around 6%.¹⁸ The pathophysiology is poorly understood in pet birds and seems to be associated with high-fat diet. Possible etiology includes increased fatty acid uptake (from food or adipose tissue lipolysis), increased de novo synthesis (from carbohydrates or vitellogenesis), decreased fatty acid degradation (from impaired or saturated mitochondrial beta-oxidation), or decreased hepatic excretion (impaired VLDL excretion). In laying chicken, the disease is strongly associated with estrogen-induced lipogenesis in the liver, so it could be a risk factor in some female parrots with reproductive disorders as well. However, in Quaker parrots, the disorder is more common in males, and no sex predisposition was found in a group including Amazon parrots, cockatoos, cockatiels, macaws, and African grey parrots.¹⁸ Hepatic lipidosis is associated with dyslipidemic changes, mainly hypertriglyceridemia, in most species. However, this has not been well demonstrated in parrots. Standard hepatic biomarkers may also be useful, in particular bile acids, but they tend to have low sensitivity except in severe disease. Radiographs and ultrasound may show hepatomegaly and a hyperechoic liver, respectively, but cannot confirm the diagnosis. On the other side, CT scan will confirm the increased fat content of the liver (with low HU). While a diagnosis of fatty liver can be made on CT alone, the histologic characterization will not be known, such as the degree of fibrosis and inflammation. Hepatic biopsies are relatively easy to take in birds via coelioscopy, either through a midline approach into the ventral hepato-peritoneal cavities or through a lateral approach through the air sacs.

Atherosclerosis

Atherosclerosis is an inflammatory and degenerative disease of the arterial wall characterized by disorganization of the arterial intima from the accumulation of inflammatory cells, fat, cholesterol, calcium, cellular debris, and inflammatory cells and potentially leading to complications such as stenosis, ischemia, thrombosis, hemorrhage, and aneurysm. Atherosclerosis is probably an underlying lesion in the majority of noninfectious cardiovascular diseases diagnosed in pet birds and is undoubtedly the most common lesion of the cardiovascular system. The centrally located arteries (brachiocephalic trunk, ascending aorta, pulmonary arteries) are most often affected, but lesions can be found in any artery. Known and suspected risk factors include age, female sex, species (Amazon parrots, African grey parrots, cockatiels), increased plasma total cholesterol and triglycerides, high-energy and high-fat diet, and physical inactivity.¹⁷ However, in Quaker parrots, males are predisposed.¹⁸ Clinical signs are uncommon in psittacine atherosclerosis but, when present, consist of sudden death, congestive heart failure, dyspnea, neurologic signs, respiratory signs, exercise intolerance, and ataxia. Atherosclerotic disease in parrots is caused by arterial luminal stenosis and rarely by atherothrombosis (clots). While atherosclerosis and hepatic lipidosis share some risk factors, no statistical associations have been found between the two disorders in epidemiological studies (contrary to popular belief).^18,19

The diagnosis of atherosclerosis mainly relies on imaging to detect arterial calcification, strongly associated with the lesions. A subjective increased arterial size on x-rays or CT scan is not reliable to diagnose atherosclerotic lesions. Arteries are not accessible to ultrasound evaluation, as they are suspended between air sacs. Blood lipid diagnostics only assess risk factors.

Fatty Tumors

Fatty tumors are frequently diagnosed in captive psittacine birds and include lipoma, liposarcoma, myelolipoma, and xanthoma (a pseudotumor). The prevalence of lipomas is fairly high, and they are some of the most common neoplasia of parrots. In Quaker parrots, the prevalence for lipoma/liposarcoma was 1.9% on necropsy and 11.5% on biopsy samples.¹⁸ The prevalence of xanthomas was 0.7 and 4.9%, respectively. Other epidemiological studies in other parrot species confirmed that these tumors were the most commonly encountered neoplasia.

Reproductive-Associated Lipid Disorders

Psittacine birds have a high prevalence of female reproductive-associated disorders, especially in smaller species such as cockatiels, lovebirds, and budgerigars. Most of these conditions are associated with unregulated vitellogenesis or lesions resulting from egg yolk deposition or embolization. Addressing the underlying issue will most often correct the associated dyslipidemia.

Other Less Common Disorders

Lipids are also involved in numerous metabolic pathways, endocrine diseases and nutritional diseases, which will consequently lead to secondary lipid disorders and dyslipidemic changes. In addition, a constellation of other less prevalent lipid disorders has been reported in various species of birds including parrots, such as corneal lipid deposition, endogenous lipid pneumonia, lipid storage disorders (lysosomal storage disease), and lipodystrophies. Lysosomal storage disease is uncommonly reported in parrots, with a single case in an African grey parrot with a massive spleen, suspected of having Niemann-Pick disease (accumulation of sphingomyelins).

Therapy

For most lipid-accumulation disorders, dyslipidemia is a strong contributing factor, thus treating dyslipidemia is strongly recommended. Likewise, blood lipid diagnostics can be used to monitor therapeutic progress. Dietary improvement and lifestyle changes are the easiest ways to manage most of these disorders. Having primarily a pelletized diet supplemented with fresh fruits and vegetables as well as discontinuing animal products will help. Low-fat pellets are also commercially available. Omega-3 fatty acids as found in fish and flaxseed oil have shown some positive effects on blood lipid in studies in psittacine birds.¹¹ Increased exercise was associated with weight loss and increased HDL cholesterol in laboratory Amazon parrots.²⁰

In female birds, vitellogenesis and reproductive disorders should first be addressed by decreasing reproductive stimuli and by using GnRH-agonist therapy (deslorelin implants).

The main family of hypolipidemic drug that has been studied and used in Psittaciformes is the statins. They are cholesterol inhibitors that target the rate-limiting enzyme HMG-Co reductase in the liver. Rosuvastatin at 10 mg/kg PO q 12 h did not reach therapeutic plasma concentration in Hispaniolan Amazon parrots. Atorvastatin at 10 mg/kg PO q 24 h in hypercholesterolemic Hispaniolan Amazon parrots led to decreased plasma total cholesterol, but this change was not statistically significant.

Atorvastatin at 10 mg/kg PO q 12 h is preferred by the author and seems safe. Scientific information is still limited, but preliminary findings suggest that some hypolipidemic effect can be seen in parrots. Statins also have anti-atherosclerotic effects and beneficial effects in hepatic lipidosis that go beyond their primary hypocholesterolemic effect. Fibrates (e.g., gemfibrozil) are hypotriglyceridemic agents that can also be used, but there is no data on their use in Psittaciformes. Statins and fibrates should not be combined, and both may lead to muscular adverse effects. Grapefruit should not be given to birds on statins, as it may drastically increase plasma concentrations and side effects. It is linked to the presence of furanocoumarin, a cytochrome P450 inhibitor, which is particularly high in grapefruit.

Acknowledgement

We acknowledge the support of Rolf C. Hagen Inc. to the University of Guelph research parrot colony.

Disclosure Statement

Some of the research results summarized in this handout were obtained from funding from the Morris Animal Foundation (grant ID: D19ZO-301) and the OVC Pet Trust.

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Author’s note: References were limited to 20. Additional references are available upon request.