Metabolic Disorders

Metabolic diseases may be inherited or acquired, the latter being more common and significant. Metabolic diseases are clinically important because they affect energy production or damage tissues critical for survival.

Congenital erythropoietic porphyria (CEP) is a rare, hereditary disease of cattle, pigs, cats, and people that results from a significant yet variable decrease in uroporphyrinogen III synthase (URO-synthase) activity. URO-synthetase is the fourth enzyme in the heme biosynthesis pathway, and it normally converts hydroxymethylbilane to uroporphyrinogen III. With decreased URO-synthase activity, hydroxymethylbilane accumulates primarily in erythrons and is nonenzymatically converted to uroporphyrinogen I. Further decarboxylation of uroporphyrinogen I leads to the formation of various porphyrinogen I isomers, with coproporphyrinogen I occurring as the final product. Coproporphyrinogen I cannot be further metabolized to heme and is thus nonphysiologic.

Hypocalcemic tetany in horses is an uncommon condition associated with acute depletion of serum ionized calcium and sometimes with alterations in serum concentrations of magnesium and phosphate. It occurs after prolonged physical exertion or transport (transport tetany) and in lactating mares (lactation tetany). Signs are variable and relate to neuromuscular hyperirritability.

Magnesium (Mg) homeostasis is not under direct hormonal control but is mainly determined by absorption from the GI tract; excretion by the kidneys; and the varying requirements of the body for pregnancy, lactation, and growth. Magnesium is the second most common intracellular cation after potassium, with 50%–60% of total body Mg distributed in bone, 40%–50% in soft tissues, and <1% in the extracellular fluid. Therefore, plasma Mg does not provide an indication of intracellular or bone Mg stores. Intracellular Mg is required for activation of enzymes involving phosphate compounds such as ATPases, kinases, and phosphatases; and for synthesis of RNA, DNA, and protein. Magnesium is a cofactor for >300 enzymatic reactions involving ATP, including glycolysis and oxidative phosphorylation. It is also important in the function of the Na+/K+-ATPase pump, membrane stabilization, nerve conduction, ion transportation, and calcium channel activity. Magnesium also regulates the movement of calcium into smooth muscle cells, giving it a pivotal role in cardiac contractile strength and peripheral vascular tone. Low ionized Mg concentrations accelerate the transmission of nerve impulses. Clinical manifestations of severe hypomagnesemia include muscle weakness, muscle fasciculations, ventricular arrhythmias, seizures, ataxia, and coma.

Phosphorus (P) is a macromineral with a plethora of important biologic functions. In addition to being essential for the structural stability of bones and teeth, cell membranes (phospholipids), and nucleic acid molecules, phosphorus plays an important role in metabolic activity such as carbohydrate and energy metabolism that inherently depends on the capacity to phosphorylate intermediate metabolites and to store energy released during oxidation in high-energy phosphate bonds such as ATP or phosphocreatine. Phosphorus is an integral component of 2,3-DPG, a compound that regulates oxygen release from hemoglobin and therefore is critical for oxygen delivery to tissues. Inorganic phosphorus (phosphate, PO4, or Pi) is also an important buffer in the body.

Potassium homeostasis is mainly determined by the balance between absorption of potassium from the GI tract and subsequent excretion by the kidneys (all animals) and saliva (in adult ruminants). Transport of potassium is passive in the small intestine and active in the colon under the influence of aldosterone. The most important hormone affecting renal and salivary potassium excretion is aldosterone, which is released from the zona glomerulosa of the adrenal gland in response to hyperkalemia and other factors. One of aldosterone’s primary actions is to enhance the secretion of potassium ions in the distal renal tubules and collecting ducts. At least 95% of whole body potassium is intracellular, with skeletal muscle containing 60%–75% of the intracellular potassium. Marked changes in serum or plasma potassium concentrations alter the resting membrane potential of cells, because the potassium gradient generated by Na+/K+-ATPase is the main cause for the negative electric potential across cell membranes. Therefore, hypokalemia or hyperkalemia alters the resting membrane potential, resulting in clinically significant changes in cellular and organ function. Hypokalemia usually indicates whole body depletion of potassium, whereas in hyperkalemia, whole body potassium status cannot be inferred because many animals with hyperkalemia have concurrent acidemia and whole body potassium depletion.

Equine metabolic syndrome (EMS) is a characteristic collection of clinical signs and clinicopathologic changes in equids that places them at high risk for developing laminitis, which is the most significant problem that results from EMS. Equids with EMS are highly prone to developing painful episodes when allowed on pasture or given high-carbohydrate feeds. Insulin dysregulation, the abnormal insulin response to oral or IV glucose and other hexose sugars, is the hallmark of EMS, and maintaining normal insulin concentrations in response to meals is the primary goal when treating a horse with EMS. Although most affected horses are obese, insulin dysregulation can occur in thinner animals as well. Often, the thin horse with EMS retains some degree of abnormal regional adiposity with a relatively increased amount of fat in the neck.

Muscular fatigue during exercise is the decline in the ability of a muscle to generate force of contraction, resulting in the inability of the animal to continue to perform at the same level of intensity. Alterations in cardiovascular parameters, serum electrolytes, and muscle tissue may be observed if physiologic compensatory mechanisms are exhausted. Treatment involves rest, rehydration, restoration of normal serum electrolyte concentrations, and cooling strategies.

In both veterinary and human patients, fever may indicate infectious, inflammatory, immune-mediated, or neoplastic disease. In most cases, the history and physical examination reveal the cause of the fever, or the fever resolves spontaneously or in response to antibiotic therapy. However, in a small percentage of patients, the cause of fever is not readily apparent, and the problem becomes persistent or recurrent. These patients are said to have fever of unknown origin (FUO).

Fatty liver results from a state of negative energy balance and is one of the important metabolic diseases of postparturient dairy cows. Although often considered a postpartum disorder, it usually develops before and during parturition. Periparturient depression of feed intake, and endocrine changes associated with parturition and lactogenesis contribute to development of fatty liver. Cows that are overconditioned at calving are at highest risk. Fatty liver can develop whenever there is a decrease in feed intake and may occur secondary to the onset of another disorder. Fatty liver at calving is commonly associated with ketosis (see Ketosis in Cattle).

Ketosis is a common disease of adult cattle. It typically occurs in dairy cows in early lactation and is most consistently characterized by partial anorexia and depression. Rarely, it occurs in cattle in late gestation, at which time it resembles pregnancy toxemia of ewes (see Pregnancy Toxemia in Ewes and Does). In addition to inappetence, signs of nervous dysfunction, including pica, abnormal licking, incoordination and abnormal gait, bellowing, and aggression, are occasionally seen. The condition is worldwide in distribution but is most common where dairy cows are bred and managed for high production.

Malignant hyperthermia (MH) is a rare, life-threatening, inherited disorder that can lead to metabolic disease of skeletal muscles in susceptible animals after exposure to triggering agents such as halogenated inhalation anesthetics, depolarizing neuromuscular blocking drugs, stress, and/or exercise. A mutation in the ryanodine receptors (RYR1 locus) on the sarcoplasmic reticulum that surrounds myofibrils of skeletal muscles alters the function of calcium release channels, which results in massive release of calcium into the cytoplasm of the myofibrils. As a result, generalized, extensive skeletal muscle contraction occurs, leading rapidly to a potentially fatal hypermetabolic state known as an MH episode. More than 300 RYR1 variants have been identified, and 31 of those mutations have been confirmed to cause MH according to the molecular genetic guidelines of the European Malignant Hyperthermia Group. Different mutation loci within the RYR1 receptors have been shown to be responsible for MH syndrome in different species.

Transport tetany occurs after the stress of prolonged transport, typically in cows and ewes in late pregnancy, although it is also seen in lambs transported to feedlots and in cattle and sheep transported to slaughter. Crowded, hot, poorly ventilated transport vehicles (railroad cars or trailers) with minimal or no access to feed or water appear to predispose animals to the condition; however, prolonged travel by foot is also a risk factor. The disease is characterized by recumbency, GI stasis, and coma, and is generally fatal.