Diabetic Ketoacidosis

Chapter 67 Diabetic Ketoacidosis



Rebecka S. Hess, DVM, DACVIM



KEY POINTS



• Diabetic ketoacidosis (DKA) is a severe form of complicated diabetes mellitus that requires emergency care.

• Acidosis and electrolyte abnormalities can be life threatening.

• Fluid therapy and correction of electrolyte abnormalities are the two most important components of therapy.

• Concurrent disease increases the risk for DKA and must be addressed as part of the diagnostic and therapeutic plan.

• Bicarbonate therapy usually is not needed and its use is controversial.

• About 70% of treated dogs and cats are discharged from the hospital after 5 to 6 days of hospitalization.

• The degree of base deficit is associated with outcome in dogs with DKA. Additionally, dogs that have concurrent hyperadrenocorticism are less likely to be discharged from the hospital.


INTRODUCTION


Diabetic ketoacidosis (DKA) is a severe form of complicated diabetes mellitus that requires emergency care. Ketones are synthesized from fatty acids as a substitute form of energy, because glucose is not transported into the cells. Excess ketoacids result in acidosis and severe electrolyte abnormalities, which can be life threatening.



PATHOPHYSIOLOGY


Ketone bodies are synthesized as an alternative source of energy when intracellular glucose concentration can not meet metabolic demands. Ketone bodies are synthesized from acetyl-coenzyme A (acetyl-CoA) which is a product of mitochondrial β-oxidation of fatty acids. This adenosine triphosphate (ATP)-dependent catabolism of fatty acids is associated with breakdown of two carbon fragments at a time and results in formation of acetyl-CoA. Synthesis of acetyl-CoA is facilitated by a decreased insulin concentration and increased glucagon concentration. The anabolic effects of insulin include conversion of glucose to glycogen, storage of amino acids as protein, and storage of fatty acids in adipose tissue. Similarly, the catabolic effects of glucagon include glycogenolysis, proteolysis, and lipolysis. Therefore a low insulin concentration and elevated glucagon concentration contribute to decreased mobilization of fatty acids into adipose tissue and increased lipolysis, resulting in elevated acetyl-CoA concentration. In nondiabetics acetyl-CoA and pyruvate enter the citric acid cycle to form ATP. However, in diabetics, glucose does not enter the cells in adequate amounts, and production of pyruvate by glycolysis is decreased. The activity of the citric acid cycle is therefore diminished, resulting in decreased utilization of acetyl-CoA. The net effect of increased production and decreased utilization of acetyl-CoA is an increase in the concentration of acetyl-CoA, which is the precursor of ketone body synthesis.1


The three ketone bodies synthesized from acetyl-CoA are β-hydroxybutyrate, acetoacetate, and acetone. Acetyl-CoA is converted to acetoacetate by two metabolic pathways, and acetoacetate is then metabolized to β-hydroxybutyrate or acetone. One of the pathways of acetoacetate synthesis involves condensation of two acetyl-CoA units and the other utilizes three units of acetyl-CoA. Ketone bodies are synthesized in the liver.1


Acetoacetate and β-hydroxybutyrate are anions of moderately strong acids. Therefore accumulation of these ketone bodies results in ketotic acidosis. Metabolic acidosis may be worsened by vomiting, dehydration, and renal hypoperfusion.1 Metabolic acidosis and the electrolyte abnormalities that ensue are important determinants in the outcome of patients with DKA.2


One of the beliefs regarding the pathophysiology of DKA had been that individuals that develop DKA have zero or undetectable endogenous insulin. However, in a study that included seven dogs with DKA, five had detectable endogenous serum insulin concentrations, and two of these dogs had endogenous serum insulin concentration within the normal range.3 Therefore it is possible that other factors, such as an elevated glucagon concentration (or less likely cortisol or catecholamines), contribute to DKA. Glucagon concentration may be elevated as a result of concurrent disease.



RISK FACTORS


The median age of dogs with DKA is 8 years (range 8 months to 16 years).2 The mean age of cats with DKA is 9 years (range 2 to 16 years).4 Breed or sex has not been shown to increase the risk of DKA in dogs or cats.2,4,5


Concurrent disease has been documented in about 70% of dogs with DKA and 90% of cats with DKA. The most common concurrent diseases noted in dogs with DKA are acute pancreatitis, bacterial urinary tract infection, and hyperadrenocorticism.2 The most common concurrent diseases noted in cats with DKA are hepatic lipidosis, chronic renal failure, acute pancreatitis, bacterial or viral infections, and neoplasia.4 It is possible that concurrent disease results in an elevated glucagon concentration and increased risk of DKA. The role of cortisol and catecholamines remains to be elucidated.


Most dogs and cats with DKA are newly diagnosed diabetics. It is possible that insulin treatment reduces the risk of DKA in dogs and cats.2,4



CLINICAL SIGNS AND PHYSICAL EXAMINATION FINDINGS


Clinical signs and physical examination findings may be attributed to chronic unmanaged diabetes mellitus, concurrent disease, and the acute onset of DKA. The most common clinical signs in dogs or cats with DKA are polyuria and polydipsia, lethargy, inappetence or anorexia, vomiting, and weight loss.2,4 Common abnormalities noted on physical examination of dogs with DKA are subjectively overweight or underweight body condition, dehydration, cranial organomegaly, abdominal pain, cardiac murmur, mental dullness, dermatologic abnormalities, dyspnea, coughing, abnormal lung sounds, and cataracts.2 Common abnormalities noted in cats with DKA are subjectively underweight body condition, dehydration, icterus, and hepatomegaly.4



CLINICAL PATHOLOGY


Approximately 50% of dogs with DKA have a nonregenerative anemia (which is not associated with hypophosphatemia), left shift neutrophilia, or thrombocytosis.2 Anemia and left shift neutrophilia are also common features of feline DKA.4 These cats also have significantly more red blood cell Heinz body formation than do normal cats, and the degree of Heinz body formation is correlated with plasma β-hydroxybutyrate concentration.6


Persistent hyperglycemia is apparent in all dogs and cats diagnosed with DKA, unless they receive insulin.2 Alkaline phosphatase activity is elevated in almost all dogs with DKA.2 Alanine aminotransferase activity, aspartate aminotransferase activity, and cholesterol concentration are increased in about half of the dogs with DKA.2 Elevations in alanine aminotransferase activity and cholesterol concentration are also commonly observed in cats with DKA.4 Azotemia is reported more commonly in cats than in dogs with DKA.2,4


Electrolyte abnormalities are common in both dogs and cats with DKA.2,4 Initially, an animal with DKA may appear to have extracellular hyperkalemia due to dehydration, decreased renal excretion, hypoinsulinemia, decreased insulin function, hyperglycemia, and acidemia (leading to movement of hydrogen ions into the cells and potassium ions out to maintain cellular electronegativity). However, with rehydration, potassium ions are lost from the extracellular fluid and a true hypokalemia from depletion of total body potassium stores becomes apparent. Hypokalemia may be exacerbated by binding of potassium to ketoacids, vomiting, inappetence, and anorexia, and osmotic diuresis. Insulin therapy may worsen extracellular hypokalemia as insulin shifts potassium into cells.7 The most important clinical manifestation of hypokalemia in DKA is profound muscle weakness, which may result in respiratory paralysis in extreme cases.


An apparent hypophosphatemia often develops when phosphate shifts from the intracellular space to the extracellular space as a result of hyperglycemia, acidosis, and hypoinsulinemia. Dehydration and decreased phosphorus excretion by the kidneys also contributes to this finding. Osmotic diuresis or fluid therapy along with insulin therapy causes extracellular phosphate depletion, leading to whole body phosphate depletion.7 Hypophosphatemia related to DKA has been associated with hemolysis (in a cat) and seizures (in a dog).8 Additional clinical signs that may develop because of hypophosphatemia include weakness, myocardial depression, and arrhythmias.


Decreased plasma ionized magnesium (iMg) concentration has been documented in four of seven cats with DKA, and may be due to increased urinary excretion of magnesium.9 The clinical significance of hypomagnesemia in cats is unknown. The clinical consequence of hypomagnesemia in humans with diabetes includes insulin resistance, hypertension, hyperlipidemia, and increased platelet aggregation. Dogs with DKA usually do not have low iMg concentrations at the time of initial examination.2,10 In one study of 78 dogs with uncomplicated diabetes mellitus, 32 dogs with DKA, and 22 control dogs, plasma iMg concentration at the time of initial examination was significantly higher in dogs with DKA than in dogs with uncomplicated diabetes mellitus and control dogs.10 Hyponatremia, hypochloremia, and decreased ionized calcium concentration have also been documented in about 50% of dogs with DKA. Low sodium concentration may be secondary to the hyperglycemia, leading to a 1 mEq/L decrease in sodium concentration for every 62 mg/dl increase in glucose concentration in humans, and is often referred to as pseudohyponatremia. Venous pH is less than 7.35 in all dogs and cats with DKA. Lactate concentration is elevated in about one third of dogs with DKA and is not correlated with degree of acidosis.2


Urinalysis is usually indicative of glucosuria. Proteinuria or ketonuria may also be apparent. Ketonuria may not be detected because the nitroprusside reagent in the urine dipstick reacts with acetoacetate and not with β-hydroxybutyrate, which is the dominant ketone body in DKA. Measurement of serum β-hydroxybutyrate is more sensitive than measurement of urine ketones.11 On urinalysis, the number of white blood cells per high-power field is usually five or fewer, although 20% of dogs with DKA have aerobic bacterial growth on culture of urine obtained by cystocentesis.2 This is likely a result of immunosuppression of diabetics and decreased ability to mobilize white blood cells to the site of infection.


Results of additional clinicopathologic or imaging tests such as urine culture, abdominal ultrasonography, thoracic radiographs, adrenal or thyroid axis testing, pancreatic lipase immunoreactivity, liver function tests, or liver biopsy depend on concurrent disorders.

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Diabetic Ketoacidosis

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