Browse the corpus

CHAPTER 226: Ketoacidotic Syndromes 1441 hospital stay. In urban settings, insulin noncompliance is a major trigger for recurrent DKA. Cocaine is an independent risk factor for DKA, and patients who use illicit drugs may benefit from drug rehabilitation. 6,7 Using social workers to assist patients with drug access and affordability, drug rehabilitation when indicated, and education provided by the dia betic care team can promote improved glycemic control.  PATIENTS WITH INSULIN PUMPS See Chapter 223 for a detailed discussion of insulin pumps (See Video: Insulin Pump). Patients with insulin pumps who are suspected to have DKA should have their pumps disconnected and turned off and should be treated just like any other patient. Reinstitution of pump therapy should start in the same time frame as switching over to SC insulin in the non–pump user.  DKA IN PREGNANCY DKA in pregnancy is a leading cause of fetal loss, with a fetal mortality rate of approximately 30%. 36,37 Several physiologic changes make dia betic pregnant women prone to DKA. Maternal fasting serum glucose levels are normally lower than in the nonpregnant state, which leads to relative insulin deficiency and an increase in baseline free fatty acid levels in the blood. 38 DKA is triggered at lower sugar levels in pregnancy, so the provider should recognize signs and symptoms of DKA and check a serum βHB level. 35,38 Pregnant women normally have increased levels of counterregulatory hormones. In addition, the chronic respiratory alkalosis seen in pregnancy leads to decreased bicarbonate levels due to a compensatory renal response, resulting in a decrease in buffering capacity. Pregnancy is associated with vomiting and urinary tract infections, which can precipitate DKA. 38 Maternal hyperglycemia causes fetal hyperglycemia and osmotic diuresis. Maternal acidosis causes fetal aci dosis, decreases uterine blood flow and fetal oxygenation, and shifts the oxygen-hemoglobin dissociation curve to the right. Maternal hypokalemia also can lead to fetal dysrhythmias and death. Correcting maternal hyperglycemia, acidosis, and electrolyte balance is the first priority. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Ketoacidotic Syndromes Debra Perina William A. Woods INTRODUCTION Ketones form a viable energy source used daily by the body in response to variations in carbohydrate intake and energy demand. There are several conditions that may result in excessive production of ketoacids that can result in a significant metabolic acidosis. The challenge for the clinician is to differentiate states of excessive, uncontrolled ketoacidosis from physiologic ketonemia, from states where excessive ketones may be produced, or from conditions or a toxin altering normal metabolism. The pathophysiology of ketoacidosis is poorly understood. Authors speculate about the hormonal milieu and pre-existing glycogen stores that, under some circumstances, will tip certain patients into pathologic ketoacidosis. The benefits of controlled metabolic access to ketones (i.e., ketogenic diet) have been recently advocated for several conditions. Unfortunately, the timing and triggers for the exact tipping point from controlled to uncontrolled ketone production are not well understood. This chapter will discuss important conditions of uncontrolled ketone production and treatment of this pathologic state.

iet) have been recently advocated for several conditions. Unfortunately, the timing and triggers for the exact tipping point from controlled to uncontrolled ketone production are not well understood. This chapter will discuss important conditions of uncontrolled ketone production and treatment of this pathologic state. CHAPTER PATHOPHYSIOLOGY Ketones may be produced through metabolism of long-chain fatty acids for energy within cells or made within the perivenous hepatocytes and then displaced into the serum for use by cells without mitochondria (i.e., red blood cells). Serum ketones are also used as an energy source for the brain because long-chain fatty acids cannot cross the blood–brain barrier and neurons cannot generate their own ketones. Once gener ated, ketones can be used as an additional energy source, entering the citric acid cycle as acetyl coenzyme A and taking the place of pyruvate generated through glucose metabolism. Ketone production is typically tightly regulated to prevent excessive ketoacid production and metabolic acidosis. Lower serum levels of insulin and ketones coupled with higher levels of cortisol and epinephrine may trigger an increase in ketone production. 2 Regulation of ketone production is complex and incompletely understood. Additionally, the rate of ketone consumption can vary over time (minutes, hours, days) for unknown reasons. 3 In general, with the exception of DKA, low levels of insulin are not found in ketoacidotic syndromes. To understand ketone metabolism, first remember that ketones are made daily by the body for energy, and that production is tightly regulated to limit serum levels (Figure 226-1). The normal blood ketone level is about 1 milligram/dL. Ketones are metabolized as rapidly as they are formed. Pathologic states arise when production exceeds metabolism or consumption, resulting in metabolic acidosis. Second, it is important to understand the ketone forms normally present in the human body. Acetyl coenzyme A, an energy source that can enter the citric acid cycle for metabolism, is produced in the liver and then converted to the ketones β-hydroxybutyrate and acetoacetate. These ketones spontane ously decay to acetone, which is a volatile chemical and thus exhaled and detected on the breath. Finally, the ratio of ketone production may vary. Typically, in most conditions (pathologic or normal physiology), the balance of β-hydroxybutyrate and acetoacetate is relatively equal (1:1), with a little higher concentration of β-hydroxybutyrate. One notable exception is alcoholic ketoacidosis, where β-hydroxybutyrate exceeds acetoacetate (see below). In all other pathologic ketoacidosis conditions, urinary or serum ketones are present and are necessary to diagnosis pathologic ketoacidosis. Ketones are osmotically active, and an elevation may result in an increased osmolal gap. Ethanol metabolism results in nicotinamide adenine dinucleotide depletion manifesting as a higher ratio of the reduced form of nicotin amide adenine dinucleotide to the nonreduced form. This high ratio also results in increased lactate production, so lactate levels are higher than normal in alcoholic ketoacidosis but not as high as seen in shock or sepsis. COMMON KETOACIDOTIC SYNDROMES Identifying the cause of excessive ketone levels producing metabolic acidosis may be complicated. Table 226-1 lists several possible conditions associated with elevated serum ketones. DKA is discussed in detail in Chapter 225, “Diabetic Ketoacidosis, ” and toxins are discussed in their specific chapters.  ALCOHOLIC KETOACIDOSIS Alcoholic ketoacidosis is a condition occurring in alcoholic patients who enter a period of fasting after a dramatic period of ethanol binging.

with elevated serum ketones. DKA is discussed in detail in Chapter 225, “Diabetic Ketoacidosis, ” and toxins are discussed in their specific chapters.  ALCOHOLIC KETOACIDOSIS Alcoholic ketoacidosis is a condition occurring in alcoholic patients who enter a period of fasting after a dramatic period of ethanol binging. Alcoholic ketoacidosis results in metabolic acidosis and dehydration, with variable levels of serum glucose, depending on the amount of gly cogen stored in the liver. Serum glucose levels may even be elevated. Nausea, vomiting, abdominal pain, and constitutional complaints are common.4 Notably, the ratio of β-hydroxybutyrate to acetoacetate is elevated in both DKA and alcoholic ketoacidosis. However, the ratio is much higher in alcoholic ketoacidosis and may approach 10:1. This is largely due to the presence of more acetoacetate in DKA. Since urine tests for ketones detect acetoacetate only, patients with alcoholic keto acidosis may have dramatic ketoacidosis with low or even undetectable levels of urine ketones. 4 Point-of-care blood testing for ketones primarily measure β-hydroxybutyrate. Tintinalli_Sec17_p1419-1460.indd 1441 8/2/19 12:23 PM

in DKA. Since urine tests for ketones detect acetoacetate only, patients with alcoholic keto acidosis may have dramatic ketoacidosis with low or even undetectable levels of urine ketones. 4 Point-of-care blood testing for ketones primarily measure β-hydroxybutyrate. Tintinalli_Sec17_p1419-1460.indd 1441 8/2/19 12:23 PM 1442 SECTION 17: Endocrine Disorders  STARVATION KETOSIS The human body goes through various rates of ketone production throughout the normal course of daily activities. During periods of fasting (overnight) or increased energy demands (exercise), local ketone production increases. 3 As the duration of carbohydrate fasting increases, hepatic ketone production and intracerebral ketone utilization increase. Typically, prolonged fasts of 14 days are well tolerated in those with adequate endogenous insulin and no other coexisting condition that alters the serum hormonal milieu. “Well tolerated” in this context implies that ketone production does not dramatically exceed metabolic demand, limiting any resultant metabolic acidosis and/or ketonuria with dehydration. Pregnancy is the most frequently described condition where starvation ketosis may result in excessive ketone production with metabolic acidosis, ketonuria, and dehydration. This can occur with only 24 to 48 hours of vomiting and inadequate oral intake. 5 Speculations regarding the increased susceptibility include the effect of additional mater nal hormones as well as fetal/placental hormone secretion. However, conditions of higher metabolic demand have also been identified as triggers (e.g., breastfeeding, hyperthyroidism). There is a case report of a 16-year-old patient with Duchenne muscular dystrophy and severe pre-existing malnutrition who developed significant ketoacidosis. 6 In addition, bariatric surgery may pose a risk for pathologic ketoacidosis after brief episodes of inadequate intake, secondary to mechanical complications of surgery.  NUTRITIONAL KETOSIS There are recent suggestions in the medical literature that athletic performance, especially endurance performance, may be enhanced by the ingestion of nutritional supplements rich in ketones in an attempt to alter intracellular energy preference. The safety of this practice is Acetone Acetoacetate Tissues except liver Deacylase (liver only) β-Hydroxybutyrate CH3 +2H –2H CHOH CH2 C O– + H+ Acetoacetate + H+ + Acetyl-CoAHMG-CoA 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Acetoacetate Acetoacetyl-CoA Acetoacetyl-CoA 2 Acetyl-CoA Acetyl-CoA + Acetoacetyl-CoA CH2 –CO2 CO2 + ATPC O– + H+ CH3 C CH3 CH3 C CH2 CH2 COO– CH3 C SC oA + H+ β-Ketothiolase CH2 C O– + H+ + HS-CoA CH3 C CH2 C SC oA + H2O CH3 C CSC oA + CH3 SC oA CH3 C C CH2 SC oA + HS-CoA CH3 C FIGURE 226-1. Formation and metabolism of ketone bodies. [Reproduced with permission from Barrett KE, Barman SM, Boitano S, Reckelhoff JF (eds.) Ganong’s Medical Physiology Examination & Board Review. New York, NY: McGraw-Hill Education; 2018, Fig 1-13.] TABLE 226-1 Differential Diagnosis of Ketosis with Metabolic Acidosis Acidosis Due to Ketoacidosis Acidosis from an Underlying Ketone-Producing Condition Acidosis from Chemicals Other Than Ketones; However, Ketonemia May Be Present DKA (see Chapter 225, “Diabetic Ketoacidosis”) Toxic ingestions: Acetone Isoniazid Isopropanol Propylene glycol Salicylic acid Dehydration Alcoholic ketoacidosis Inborn errors of metabolism: Error in carbohydrate metabolism Error in fatty acid metabolism Gastritis/upper GI bleeding Hepatitis Pancreatitis Pneumonia Seizures Sepsis Renal Failure Starvation ketosis and eating disorders

Acetone Isoniazid Isopropanol Propylene glycol Salicylic acid Dehydration Alcoholic ketoacidosis Inborn errors of metabolism: Error in carbohydrate metabolism Error in fatty acid metabolism Gastritis/upper GI bleeding Hepatitis Pancreatitis Pneumonia Seizures Sepsis Renal Failure Starvation ketosis and eating disorders Nutritional ketosis Ketogenic diet Tintinalli_Sec17_p1419-1460.indd 1442 8/2/19 12:23 PM