Hypertriglyceridemia and other disorders of lipid metabolism (Proceedings)

The fed camelid supplies most of its body energy needs through the short chain fatty acid products of gastric fermentation. These are made in roughly the same proportion as in ruminants on similar diets, with the difference that the camelid gastric wall does not appear to convert butyrate to its ketone form. Short chain fatty acids may be oxidized by most tissues.

The feed-deprived camelid mobilizes peripheral adipose stores for energy. As far as we know, this intracellular lipolysis occurs under similar hormonal conditions as in other species; that is, catecholamines and possibly some other hormones stimulate lipolysis, whereas insulin inhibits it. Glucocorticoids appear to have little effect.

The free fatty acids liberated from adipose tissue circulate bound to albumin. The consequences of hypoalbuminemia, a common finding in sick camelids, on this transport is unknown. The fatty acids are taken up be cells in proportion to their blood concentrations, and can be oxidized by most tissues for energy. However, more metabolically active cells are unable to enhance uptake of these substrates.

The liver plays a central role in modifying free fatty acids for use by other tissues. Several types of conversion are possible, the most important of which are modification to water-soluble ketone bodies or reesterification to triglyceride for export as Very Low Density Lipoproteins. Lipoproteins carry triglyceride through the bloodstream, where free fatty acid may be liberated locally (intravascular lipolysis) by the action of lipoprotein lipase. Insulin, insulin-like growth factors, and thyroid hormone stimulate lipoprotein lipase activity, whereas some inflammatory mediators inhibit it.

Disorders of Lipid Metabolism

Starvation/Dietary insufficiency results in mobilization of adipose stores. In general, camelids are quite resilient to pathologic effects of starvation. Experimentally, pregnant and/or lactating camelids on restricted diets may develop rapid fat mobilization, possibly resulting in hepatic lipidosis. Non-pregnant, non-lactating camelids develop a lower degree of fat mobilization and do not accumulate lipid in their liver.

Natural cases demonstrate that even non-pregnant, non-lactating camelids may develop lipidosis or lipemia, but it is assumed that some factor beyond dietary insufficiency is contributing.

Hepatic Lipidosis Although pregnant or lactating females make up the majority of camelids seen at our clinic with hepatic lipidosis, their proportion does not differ significantly from their proportion in the overall hospital population. Most show an increase in blood NEFA and ketones, reflective of peripheral fat mobilization and oversupply to the liver. Some also have hyperlipemia (an increase in triglycerides and cholesterol) with concurrent hyperketonemia and hyperglycemia. Blood glucose is rarely low, except in pregnant or lactating females, and is frequently even high. This suggests that pregnant or lactating females may develop hepatic lipidosis when their blood glucose supply does not match demand, a similar situation to ketosis in cattle or sheep. Non-pregnant and non-lactating camelids, which have no particularly remarkable energy demand, may have some end-utilization problem.

In addition to simple starvation or competition for food, various stressors may promote lipolysis. These include transport, extreme temperatures, hypoproteinemia, and illness. Concurrent or previous liver disease may compromise its function in energy meatoblism. Hormonal mechanisms may also play a role, especially suppression of insulin production or increase in catecholamines.

Protein deficiency appears to play a greater role than in cattle. Hypoalbuminemic hypoproteinemia is common in sick camelids, including those with lipidosis. Healthy camelids seek out high-protein plants in an environment, and appear to tolerate intermittent starvation well. It is our belief that they tolerate caloric malnutrition (marasmus) much better than they tolerate protein-calorie malnutrition (kwashiorkor). The reasons for this are unknown but may include the following: as in cows, vital amino acid deficiencies may prevent lipoprotein formation and result in hepatic lipidosis; amino acid deficiencies may inhibit the production of vital protein hormones, such as insulin; and the enzymatic pathways that direct glucose and pyruvate away from the citric acid cycle may increase need for other components (amino acids) to enter that cycle to replenish oxaloacetate and to produce energy.

Hyperlipemia may be seen with other indicators of negative energy balance, or as the sole abnormality. With more severe hyperlipemia, it becomes more likely that other blood fat fractions are high. As with lipidosis, all ages and signalments of camelid are affected by hyperlipemia.(ref) Camelids appear to be either more capable than cattle of exporting liver triglyceride as lipoprotein, or they have greater problems with end-utilization. In camelids with hepatic lipidosis, hyperlipemia appears to be a late condition, almost terminal, and likely reflects extreme catecholamine stimulation and inhibition of intravascular lipolysis. In other camelids, hyperlipemia appears to relate to inflammation, so prostaglandin inhibition of lipoprotein lipase must be considered.

Recent findings suggest mild hyperlipemia tends to worsen unless specifically treated, even if any underlying disorders are appropriately addressed. Thus, even mild hyperlipemia may represent the beginning of a serious, progressive metabolic derangement.

Monitoring disorders of lipid metabolism

Lipid disorders are more difficult to detect than carbohydrate disorders, because they are more diverse and some assays are not readily available. Triglycerides and cholesterol are among the more widely available assays, but the minority of camelids with lipid disorders have hyperlipemia. When they do, changes in triglyceride are more pronounced than changes in cholesterol, reflective of the higher proportion of VLDL among lipoproteins. The amount of VLDL may be estimated by calculating the triglyceride/cholesterol ratio. Blood triglyceride concentrations >500 mg/dl are of major concern. Triglyceride concentrations between 150 and 500 mg/dl are still of concern, because they tend to worsen without treatment.

Blood beta-hydroxybutyrate increases with increased delivery of free fatty acids to the liver, but the magnitude of this increase is smaller than that usually seen in cattle with ketosis.

Blood or urine ketones may be measured using various assays. Blood is usually easier to obtain than urine, and urine assays may not be sensitive enough in milder cases. Blood beta-hydroxybutyrate concentrations >2.5 mg/dl are of major concern.

Free fatty acids may be measured directly using automated chemistry analyzers. They provide direct evidence of intracellular lipolysis, and hence either negative energy balance or catecholamine stimulation.

Indirect evidence of a lipid disorder may be obtained by measuring liver damage and function. Enzyme changes appear to precede lipidosis. Camelids with any of the following abnormalities: GGT > 60 IU/L, AST > 500 IU/L, SDH > 50 IU/L, free fatty acids > 1 mEq/L, beta-OH butyrate > 5 mg/dl, bile acids > 30 mg/dl should be considered at high risk. In rare cases, blood chemistry abnormalities may have normalized by the time of examination, but lipidosis persists. Direct evidence of hepatic lipidosis may be achieved by biopsy, but very sick camelids occasionally die during or shortly after this procedure.

General assessment of renal function, protein and electrolyte concentrations, and so forth are recommended, especially in camelids on intravenous fluids. Refractometers may not provide accurate estimates of blood protein in camelids with severe hyperlipemia.

Treatment for Disorders of Fat Metabolism

General medical care is very important. Dehydration, shock, and metabolic derangements, including acidosis, hypokalemia, azotemia, hypocalcemia, and hypoproteinemia are common and potentially life-threatening. By increasing catecholamine secretion and inhibiting insulin production, some of these problems may be contributing to fat mobilization. These problems are best corrected with judicious administration of intravenous fluids. Because of the frequency of hypoproteinemia in camelids, crystalline fluids are usually not administered at much above a maintenance rate. Plasma transfusion may be necessary to maintain intravascular oncotic pressure. Inflammation or infection may also play a role or be a complication of disorders of fat metabolism, and should be addressed if present.

Improving appetite will decrease reliance on body fat stores or nutritional supplements. Correction of dehydration and metabolic abnormalities is again usually the first priority. High carbohydrate feeds may be detrimental, as highly fermentable feeds promote forestomach acidosis. Instead, palatable, high protein feeds (leafy browse) should be feed. Alfalfa leaves, fresh grass, and blackberry leaves are among the best feeds under these circumstances. Milk and high-quality milk replacers fulfill the same role in unweaned animals. Transfaunation of approximately 500 ml of rumen fluid from a cow may improve appetite in camelids that have been off feed for several days, but due to the stress of passing an orogastric tube, I reserve this for camelids that are already regaining their strength.

There are a variety of other techniques to increase appetite. These include limiting stress and keeping companion camelids close by, probiotics, diazepam, and B-vitamin injections. All of these may have some applicability with the basic caveat that an intervention should do more good than harm. Buddy animals are helpful in some cases, but allowing an animal to eat without competition is often better. Probiotics have had limited affects in my hands, and may not work as well as rumen fluid. Diazepam (0.05 mg/kg, IV) works very well in some camelids and not at all in others. B-vitamin injections are supposed to stimulate appetite and improve glucose utilization.

Trying to provide complete oral nutrition to an anorexic adult camelid is very difficult. Camelids eat about 2% of the their body weight a day, meaning a 150 kg llama requires 3 kg of feed and a 50 kg alpaca requires 1 kg. Some of this can be passed down a stomach tube in the form of alfalfa meal, but clogging of the tube and the stress involved in the procedure make this more suitable for an occasional attempt to "jump-start" the stomach after transfaunation than a real provision of nutrition. Trying to maximize the energy in tubed feed is not likely to be helpful because of its fermentability and because many camelids with disorders of lipid metabolism are not especially energy deficient. Propylene glycol (2 to 4 fl.oz. up to twice a day) may be better than carbohydrate: it is not fermentable and directly enters the citric acid cycle at a point that replenishes oxaloacetate. However, propylene glycol is gluconeogenic, and glucose is rarely lacking.

Parenteral administration of sufficient energy is also difficult. It is easiest to give energy as fats, but animals in negative energy balance (except neonates) usually are mobilizing large quantities of their own fats. Carbohydrate is the next easiest form (0.25 to 0.5 gm/kg of dextrose as a bolus or a constant 5% dextrose infusion), but given alone, camelids take up very little glucose, and most simply acts as an osmotic diuretic. Insulin may be given together with carbohydrates to improve uptake. We have had success with regular insulin (0.2 to 0.4 U/kg given IV with glucose or if blood glucose is > 400 mg/dl; lasts about 2 hours) and PZI insulin or ultralente (0.2 to 0.4 U/kg given SC with glucose; lasts 8 to 16 hours) both in moving glucose into cells and reducing fat fractions. Blood glucose concentrations should be checked about every 4 hours in camelids treated either with glucose or insulin to avoid pathologic hypo- or hyperglycemia. Blood potassium concentrations should also be monitored carefully in camelids given insulin: anorexic camelids are likely to have hypokalemia and this can worsen after insulin injection.

After initial stabilization, we give intravenous fluids containing amino acid additives (500 ml per 3 L bag for an adult alpaca or 1000 ml per 5 L bag for an adult llama) at rates of about 5% of body weight in 24 hours. The amino acids appear to help, possibly for some of the reasons outlined above concerning protein deficiency, but may be deleted. We also preferentially choose intravenous fluids with acetate as the base buffer instead of lactate, because acetate can be used as immediate energy by most tissues, while lactate not only requires hepatic processing, but also results in glucose production. Glucose is rarely lacking and appears to be poorly utilized, so it may be of little benefit to the patient – we add it to fluids only if we are also administering insulin. With this treatment strategy, we have had good success reversing the precursors to lipidosis, as well as treating advanced cases.