Diabetic Ketoacidosis & Hyperosmolar Hyperglycemic State Disease Background

Introduction

Diabetic ketoacidosis (DKA) is the presence of ketoacidosis and hyperglycemia while hyperosmolar hyperglycemic state (HHS) is characterized by more severe hyperglycemia but without ketoacidosis. 

Epidemiology

DKA and HHS remain important causes of morbidity and mortality among diabetic patients despite the presence of a diagnostic criteria and treatment protocols. The estimated annual incidence of DKA ranges from 4-8 cases per 1000 diabetic patient admissions. It is characteristically associated with type I diabetes mellitus (T1DM), but also occurs in type 2 DM (T2DM) under extreme conditions (eg serious infection, trauma, cardiovascular or other emergencies).  

DKA is also more commonly seen in the young, highest rates seen in <45 years of age, and rare in those ≥65 years of age. In recent years, the incidence of DKA has been noted to be continually increasing, with increasing rates of hospitalization at an annual rate of 6.3%. On the other hand, HHS is more frequently reported in adult and elderly patients >65 years of age with T2DM with an intercurrent illness. As much as 90% of HHS patients have a known history of T2DM. Although HHS is less common than DKA, accounting for <1% of all diabetic related admissions, HHS has a higher mortality rate (5-20%) than DKA (1-5%). 

Pathophysiology

Both DKA and HHS arise from a setting of relative or absolute insulin deficiency combined with an increase in circulating counterregulatory hormones such as glucagon, cortisol, growth hormone, and catecholamines. In DKA, there is absolute insulin deficiency and increased counterregulatory hormones which result in hyperglycemia and ketosis. Hyperglycemia develops because of increased gluconeogenesis, accelerated glycogenolysis, and reduced glucose utilization by peripheral tissues. The presence of absolute insulin deficiency and elevated counterregulatory hormones lead to high levels of circulating free fatty acids. With increased glucagon-insulin ratio, these fatty acids are oxidized at an accelerated pace, resulting in ketonemia and metabolic acidosis. In the case of HHS, there is a greater degree of dehydration in the absence of significant ketosis. This is explained by the relative insulin deficiency such that there is greater endogenous insulin secretion in HHS than in DKA, where it is negligible, to prevent lipolysis and the subsequent ketogenesis. Lastly, hyperglycemic crises have been found to be associated with a severe proinflammatory state, characterized elevated levels of various cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-5,-6,-8, C-reactive protein (CRP), reactive oxygen species, and lipid peroxidation. In turn, this proinflammatory state leads to further impaired insulin secretion and insulin sensitivity, capillary perturbation, cellular damage of lipids, membranes, proteins, and DNA and a thrombotic state.  

Diabetic Ketoacidosis & Hyperosmolar Hyperglycemic State_Disease Background

Risk Factors

The following are the precipitating factors of DKA and HHS:

• Infections are the most common
• Inadequate, poor compliance to or discontinuation of insulin therapy
• Burns
• Cerebrovascular accident (CVA)
• Cocaine use
• Drugs (eg corticosteroids, Pentamidine, sodium-glucose co-transporter 2 [SGLT2] inhibitors, sympathomimetic agents, thiazides, second-generation atypical antipsychotic agents)
• Myocardial infarction (MI)
• New onset type 1 DM
• Omission or discontinuation of insulin in established type 1 DM in setting of gastroenteritis
• Pancreatitis
• Psychological problems associated with eating disorders and omission of insulin due to fear of weight gain, fear of hypoglycemia, rebellion from authority and stress of chronic disease
• Sepsis
• Surgery
• Trauma

Classification

Classification of DKA  

Mild DKA presents without alteration in sensorium, plasma glucose of >250 mg/dL, arterial pH of 7.25-7.30, serum bicarbonate of 15-18 mEq/L, presence of serum and urine ketones, and anion gap of >10.  

Moderate DKA presents with or without alteration in sensorium or drowsiness, plasma glucose of >250 mg/dL, arterial pH of 7 to <7.24, serum bicarbonate of 10 to <15 mEq/mL, presence of serum and urine ketones, and anion gap of >12.  

Severe DKA presents with stupor or coma, plasma glucose of >250 mg/dL, arterial pH of <7, serum bicarbonate of <10 mEq/L, presence of serum and urine ketones, and anion gap of >12.