Etiology

Infection is the major precipitating factor, occurring in 40% to 60% of patients.[10]​ Pneumonia and urinary tract infections are the most common infections reported.​​[4][9][10][11]

In many instances, the trigger is an acute illness, such as stroke, myocardial infarction, or other medical-surgical illnesses, or trauma that provokes the release of counter-regulatory hormones (catecholamines, glucagon, cortisol, and growth hormone) and/or compromises water intake.[2]​​[10]

In elderly patients, being bedridden and having an altered thirst response compromise access to water and water intake, leading to severe dehydration and HHS.[10] HHS can be seen in postoperative patients with a known history of diabetes, especially after cardiac-bypass surgery or neurosurgery.[9]​​[20]

Patients with pre-diabetes or diabetes who require total parenteral nutrition in their postoperative state who are not started on appropriate insulin therapy may also present with HHS.[9] A patient with a strong family history of diabetes has been reported to be at high risk of developing HHS during total parenteral nutrition therapy if hyperglycemia is not treated with insulin.[9][21]

Rarely, endocrine disorders, such as hyperthyroidism and acromegaly, can lead to HHS.[9][22][23]​​ In patients with concomitant diabetes, hypercortisolism leads to insulin resistance and promotes HHS development.[22][24]​ Ectopic production of adrenocorticotropic hormone and Cushing syndrome have been associated with HHS.[25] Similarly, initiation of corticosteroids without adjustment of insulin doses or that of oral antidiabetic agents can trigger HHS.

Nonadherence to insulin or oral antidiabetic medication is common in patients admitted for HHS.​[4]​​ This association is much higher in urban African-American patients with diabetes, in whom nonadherence is the sole reason for HHS in 42% of cases.[15] Alcohol and cocaine abuse is a major contributing factor to nonadherence of diabetic therapy. Approximately 7% to 17% of patients have newly diagnosed diabetes.[15]

Corticosteroids, thiazide diuretics, beta-blockers, phenytoin and didanosine have all been associated with HHS.[26][27][28][29][30][31]​​​ These drugs are thought to induce HHS by affecting carbohydrate metabolism.[13] The risk of severe hyperglycemia increases when using a combination of these medications.[32] Atypical antipsychotic medications (in particular, clozapine and olanzapine) have also been implicated in producing diabetes and hyperglycemic crises.[33][34]​​ Approximately 1% to 2% of patients receiving immune checkpoint inhibitors as cancer treatment develop new-onset autoimmune diabetes, characterized by rapid onset of hyperglycemia and risk of diabetic ketoacidosis (DKA) or severe hyperglycemia (HHS or mixed DKA/HHS) if not detected and treated promptly with insulin therapy.[35][36]​​

Up to 20% of patients admitted with HHS have previously undiagnosed diabetes.[2]​[10]

Pathophysiology

HHS is characterized by extreme elevations in serum glucose concentrations and hyperosmolarity without significant ketosis. These metabolic derangements result from relative insulin deficiency and increased concentration of counter-regulatory hormones (catecholamines, glucagon, cortisol, and growth hormone).[2]​​[10]

HHS and diabetic ketoacidosis (DKA) are often discussed as distinct entities, but they represent opposite ends of the spectrum of metabolic derangements in diabetes, and the conditions can overlap.[4]​ Approximately one third of patients with hyperglycemic crises present with a mixed picture of DKA and HHS.[6][8]​​​​

The pathogenesis of HHS has been reported in the literature.​[1][2]​​​​ Measurable insulin secretion in patients with HHS is higher than in patients with DKA.[37]​​ This higher insulin concentration is believed to be sufficient to suppress lipolysis and ketogenesis but inadequate to regulate hepatic glucose production and promote glucose utilization. This concept is supported by clinical studies. These studies have shown that the half-maximal concentration of insulin for anti-lipolysis is lower than for glucose use by peripheral tissues.[10][38]​ Another potential mechanism for the lack of ketosis in HHS involves the effect of hyperosmolality on inhibiting lipolysis, insulin secretion, and glucose uptake.[37]

A reduction in the net effective concentration of insulin owing to any etiology leads to impaired carbohydrate, lipid, and ketone metabolism in hyperglycemic crises. Decreased insulin results in increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues.​[2]​​

Dehydration and electrolyte imbalance are of great importance in the pathogenesis of HHS. Because HHS evolves over several days, continued osmotic diuresis leads to hypernatremia, particularly in older patients with compromised renal function and/or inability to drink water to keep up with urinary losses. The resulting hypernatremia and hyperglycemia, coupled with inadequate water intake and excess water loss, result in profound volume contraction. Hypovolemia leads to a progressive decline in the glomerular filtration rate, which aggravates the hyperglycemic state.[39]​​

Counter-regulatory hormones, particularly epinephrine, are increased as a systemic response to infection, which results in insulin resistance, decrease insulin production and secretion, and increase lipolysis, and volume depletion, thereby contributing to the hyperglycemic crises in patients with diabetes.[2]​​[10]

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