Etiology

In DKA, there is a reduction in the net effective concentration of circulating insulin along with an elevation of counter-regulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). These alterations lead to extreme manifestations of metabolic derangements that can occur in diabetes. The two most common precipitating events are inadequate insulin therapy or infection. Underlying medical conditions such as myocardial infarction or stroke that provoke the release of counter-regulatory hormones are also likely to result in DKA in patients with diabetes. Drugs that affect carbohydrate metabolism, such as corticosteroids, thiazides, pentamidine, sympathomimetic agents (e.g., dobutamine and terbutaline), second-generation antipsychotic agents, and immune checkpoint inhibitors may contribute to the development of DKA.[9][10][11] The use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors has also been implicated in the development of euglycemic DKA in patients with both type 1 and type 2 diabetes.[12][13][14][15]

Pathophysiology

Reduced insulin concentration or action, along with increased insulin counter-regulatory hormones, leads to the hyperglycemia, volume depletion, and electrolyte imbalance that underlie the pathophysiology of DKA. Hormonal alterations in DKA lead to increased gluconeogenesis, hepatic and renal glucose production, and impaired glucose utilization in peripheral tissues, which result in hyperglycemia and hyperosmolarity. Insulin deficiency leads to release of free fatty acids from adipose tissue (lipolysis), hepatic fatty acid oxidation, and formation of ketone bodies (beta-hydroxybutyrate and acetoacetate), which result in ketonemia and acidosis. Studies have demonstrated the elevation of proinflammatory cytokines and inflammatory biomarkers (e.g., CRP), markers of oxidative stress, lipid peroxidation, and cardiovascular risk factors with hyperglycemic crises. All of these parameters return to normal following insulin and hydration therapies within 24 hours of hyperglycemic crises. Elevation of proinflammatory cytokines, and markers of lipid peroxidation and oxidative stress, have also been demonstrated in non-diabetic patients with insulin-induced hypoglycemia.[16] The observed proinflammatory and procoagulant states in hyperglycemic crises and hypoglycemia may be the result of adaptive responses to acute stress and not hyperglycemia or hypoglycemia per se.[1][16][17] It has also been postulated that ketosis-prone diabetes comprises different syndromes based on autoantibody status, human leukocyte antigen (HLA) genotype, and beta-cell functional reserve.[18]com.bmj.content.model.Caption@13e8a68[Figure caption and citation for the preceding image starts]: Pathogenesis of DKA and HHS; triggers include stress, infection, and insufficient insulin. FFA: free fatty acid; HHS: hyperosmolar hyperglycemic stateFrom: Kitabchi AE, Umpierrez GE, Miles JM, et al. Diabetes Care. 2009,32:1335-43; used with permission [Citation ends].

Classification

Clinical DKA classification[1]

Diagnostic criteria and classification:

Mild DKA

  • Plasma glucose: >250 mg/dL

  • Arterial pH: 7.25 to 7.30

  • Serum bicarbonate: 15-18 mEq/L

  • Urine ketone: positive

  • Serum ketone: positive

  • Effective serum osmolality: variable

  • Anion gap: >10

  • Mental status: alert.

Moderate DKA

  • Plasma glucose: >250 mg/dL

  • Arterial pH: 7.00 to <7.24

  • Serum bicarbonate: 10 to <15 mEq/L

  • Urine ketone: positive

  • Serum ketone: positive

  • Effective serum osmolality: variable

  • Anion gap: >12

  • Mental status: alert and/or drowsy.

Severe DKA

  • Plasma glucose: >250 mg/dL

  • Arterial pH: <7.00

  • Serum bicarbonate: <10 mEq/L

  • Urine ketone: positive

  • Serum ketone: positive

  • Effective serum osmolality: variable

  • Anion gap: >12

  • Mental status: stupor and/or coma.

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