6. Ketoacidosis

(1)

Professor of Medicine, Department of Medicine, Chief, Division of Nephrology and Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA

Keywords

HyperglycemiaKetogenesisMetabolic acidosisKetonemiaKetonuria

Ketones are acetone, acetoacetic acid (acetoacetate), and β-hydroxybutyric acid (BHB). Of these, only acetoacetate and BHB cause acidosis, whereas acetone does not cause acidosis. Acetone is formed by nonenzymatic decarboxylation of acetoacetate, and does not contribute any acid load to the body (Fig. 6.1). Clinically, metabolic acidosis due to ketone overload is caused by diabetes, alcohol, and starvation. Therefore, this chapter focuses on only diabetic, alcoholic, and starvation ketoacidosis.

../images/480755_1_En_6_Chapter/480755_1_En_6_Fig1_HTML.png — Fig. 6.1

Formation of acetone and β-hydroxybutyric acid from acetoacetate

Diabetic Ketoacidosis

In general, diabetic ketoacidosis (DKA) is the most common presentation in patients with type 1 diabetes. It is also common in patients with type 2 diabetes. DKA is an important acute cause of morbidity and mortality in these patients. Symptoms of DKA were observed before the discovery of insulin by Kussmaul as early as 1874. An association between DKA and coma was established by the 1880s. After the discovery of insulin in 1922, deaths due to DKA have dramatically decreased from 60% to <2%. DKA is a condition that is characterized by hyperglycemia (>250 mg/dL), ketonemia, ketonuria, and high anion gap (AG) metabolic acidosis. Hyperglycemia causes hyperosmolality and glucosuria. Both glucosuria and ketonuria cause massive urinary losses of water, Na⁺, K⁺, and phosphate. As a result, severe volume depletion and electrolyte losses occur in DKA.

Pathogenesis of DKA

Hyperglycemia

DKA is produced due to absolute or relative deficiency of insulin with concomitant increase in hormones that oppose the action of insulin. These are called counterregulatory hormones, which are glucagon, epinephrine, norepinephrine, cortisol, and growth hormone. Of these hormones, glucagon plays a major role in DKA. However, it should be noted that DKA does not generate without insulin deficiency or its resistance. Insulin deficiency and glucagon cause hyperglycemia by impaired peripheral glucose utilization, increased gluconeogenesis by the liver and kidney, and glycogenolysis. As stated above, hyperglycemia causes glucosuria with resultant volume depletion and prerenal azotemia.

Ketogenesis

Two organs are involved in ketogenesis: adipose tissue and liver. Insulin deficiency causes lipolysis. During lipolysis, free fatty acids (FFAs) are formed from triglycerides by hormone-sensitive lipase activity. Epinephrine stimulates this enzyme (Fig. 6.2). Once FFAs are formed in the adipocyte, they are released into the blood and transported to the liver. Long-chain fatty acids such as palmitic acid cannot enter the liver mitochondria where β-oxidation occurs to form ketones. Therefore, these long-chain FFAs need to be activated. This process of activation involves ATP, coenzyme A, and FFA to form an activated fatty acid or acyl-coenzyme A (acyl-CoA). This reaction is catalyzed by the enzyme acyl-CoA synthetase or thiokinase and occurs in the cytoplasm of hepatocyte. Acyl-CoA can enter the intermembrane space but cannot penetrate the inner mitochondrial membrane. Entrance into the inner mitochondrial membrane is facilitated by carnitine via transfer of acyl groups to carnitine to form acylcarnitine. This transfer is catalyzed by the enzyme carnitine palmitoyl transferase 1 (CPT1) present in the mitochondrial outer membrane. The acylcarnitine is then carried to the mitochondrial matrix by the inner membrane transporter carnitine/acylcarnitine translocase in exchange for carnitine. From acylcarnitine, acyl group is transferred to CoA to reform acyl-CoA, and carnitine is released. Carnitine is transported back to combine with acyl-CoA to form acylcarnitine for the cycle to continue. This transfer is facilitated by CPT2 located in the inner mitochondrial membrane.

../images/480755_1_En_6_Chapter/480755_1_En_6_Fig2_HTML.png — Fig. 6.2

Simplified diagram showing the formation of free fatty acids in the adipose tissue and ketones in the liver. HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A

Once acyl-CoA is in the mitochondrial matrix, it undergoes β-oxidation to yield acetyl-CoA. Two molecules of acetyl-CoA react to form acetoacetyl-CoA. Subsequently, another molecule of acetyl-CoA combines with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction is catalyzed by HMG-CoA synthetase. The HMG-CoA is further cleaved into acetoacetate and acetyl-CoA by HMG-CoA lyase. Acetoacetate is subsequently reduced to β-hydroxybutyrate by the enzyme β-hydroxybutyrate dehydrogenase. This reaction is controlled by high NADH/NAD⁺ ratio (see Fig. 6.1). Among counterregulatory hormones, glucagon plays an important role in ketogenesis in diabetic patients. It has been reported that 1000–2000 mEq/L/day of ketones are formed in patients with severe diabetic ketoacidosis.

Ketogenesis is under the control of a substrate for fatty acid synthesis called malonyl-CoA. In fed state, fatty acid synthesis occurs because of high circulating levels of insulin. During this fatty acid synthesis, malonyl-CoA inhibits the enzyme CPT1. When insulin levels are deficient or low, the synthesis of malonyl-CoA decreases, and its level falls. As a result, the inhibitory effect of malonyl-CoA on CPT1 is removed. This facilitates the action of CPT1 so that acyl-CoA can combine with carnitine for entry into the mitochondrion. Thus, ketogenesis is regulated by malonyl-CoA.

In summary, ketones are formed in diabetes from elevated levels of FFAs released from triglycerides. Long-chain fatty acids must be activated before they enter liver mitochondria, where they undergo β-oxidation to form acetoacetate. Subsequently, acetoacetate is reduced to β-hydroxybutyrate. Also, acetoacetate undergoes spontaneous nonenzymatic decarboxylation to form acetone, which is removed by the lungs causing acetone breath in patients with DKA. The kidneys also excrete ketones until glomerular filtration rate (GFR) is decreased substantially.

Metabolic Acidosis

Metabolic acidosis results from excess production of acetoacetic acid and β-hydroxybutyric acid. Both these acids dissociate at body fluid pH to yield H⁺, which are buffered by HCO₃ ⁻ ions. As a result, serum [HCO₃ ⁻] decreases, and a high AG metabolic acidosis develops. In uncomplicated DKA, the increase in serum AG above normal approximates the decrease in serum HCO₃ ⁻ from normal levels of 24 mEq/L. In other words, the ⧍AG/⧍HCO₃ ⁻ ratio is 1:1.

In mild DKA, the body volume is relatively preserved due to intake of fluids by the patient because of thirst. If the patients drink fruit juice which contains citrate, depletion of serum HCO₃ ⁻ level may not decrease that much because of citrate conversion into HCO₃ ⁻. This results in mild AG metabolic acidosis. Also, the kidneys play an important role in maintaining mild acidosis by excreting large quantities of ketones. However, when the patient develops severe volume depletion, excretion of ketones is diminished with resultant accumulation of these ketones in the serum and development of very high AG metabolic acidosis. In severe acidosis, the serum HCO₃ ⁻ level may diminish to as low as 5 mEq/L.

Besides ketones, the diabetic patients also generate other acids such as L-lactic acid. It was suggested that D-lactic acid also contributes to metabolic acidosis in DKA. Because of ketones, and L- as well as D-lactic acids, the patients develop a very high AG metabolic acidosis at presentation of severe DKA.

Ketonemia and Ketonuria

As stated above, ketones are generated and excreted by the kidneys until GFR is substantially reduced. In DKA, production of β-hydroxybutyrate is more than the production of acetoacetate. As stated above, the ketones are excreted if volume depletion is mild and GFR is near normal. Under these conditions, ketonemia is less than ketonuria. When volume depletion is severe and GFR is substantially decreased, excretion of ketones is decreased, and ketonemia predominates ketonuria.

Precipitating Factors

Several epidemiologic studies have shown that noncompliance or poor adherence to insulin regimen is the most common precipitating factor for DKA in adults. However, infection (urinary tract infection, sepsis, pneumonia, etc.) seems to be the common cause for DKA worldwide. DKA is an initial manifestation of DKA more in children than in adults. Several other precipitating causes for DKA have been reported, as shown in Table 6.1.

Table 6.1

Precipitating factors for DKA

Factor	Comment
1. Noncompliance or poor adherence to insulin administration	Inadequate insulin initiates DKA
2. Infection	Urinary tract infection, septicemia, and other infections demand additional insulin requirements
3. First episode of DKA	Indicates new onset of type 1 diabetes mostly in children
4. Other factors Myocardial infarction Acute pancreatitis Stress Consumption of fluids with high sugar content Stroke Intestinal obstruction	All of these conditions cause insulin resistance or higher insulin dose requirements
5. Drugs Glucocorticoids Thiazide diuretics First and second generation antipsychotics	Raise glucose levels
6. Sodium-glucose cotransporter-2 inhibitors	These drugs cause “euglycemic DKA” (see further discussion)

Clinical Manifestations

History and physical examination, including precipitating factors of DKA, is extremely important. Initial presentation of patients with DKA is attributable to hyperglycemia such as polydipsia, polyuria, thirst, weight loss, nausea, and vomiting. Abdominal pain mimicking acute abdomen is also a common complaint, which is due to acidosis, and the pain is related to the severity of acidosis. This complaint should be differentiated from diabetic gastroparesis which does not improve after correction of acidosis, whereas abdominal pain does improve following correction of acidosis.

Signs include tachycardia, tachypnea, Kussmaul breathing (deep and frequent breathing), hypothermia, hypotension, and altered mental status. Stupor and coma are seen mostly in children. Altered mental status is usually attributed to acidosis and hyperosmolality.

On physical examination, the patients look ill and volume depleted. Acetone breath (fruity odor) is common. Hypotension with orthostatic blood pressure and orthostatic pulse changes suggest severe volume depletion.

Laboratory Findings

By definition, DKA is a triad of hyperglycemia, metabolic acidosis, and ketonemia as well as ketonuria. The initial laboratory tests should include complete blood count, serum electrolytes, glucose, creatinine, BUN, Ca²⁺, Mg²⁺, phosphate, total protein, albumin, ketones, and osmolality. Urinalysis that includes ketones should be obtained. ABG is needed in patients with very low HCO₃ ⁻ levels and hypoxia. Venous ABG may be sufficient in patients with mild-moderate DKA and normal mentation. AG should always be calculated. Serum needs to be diluted for ketones for appropriate testing. Determination of β-hydroxybutyrate by an analyzer is appropriate in severe ketosis. Common laboratory findings are shown in Table 6.2.

Table 6.2

Laboratory findings in DKA

Lab value	Commonly observed value	Comment
WBC	Elevated up to 15 to 17000	Due to stress, demargination, and elevated levels of cortisol and catecholamines
Hgb, hematocrit	Elevated	Due to volume depletion
Serum glucose	>250 mg/dL	Insulin deficiency/resistance
Serum HCO₃ ⁻	<20 mEq/L	Low because of buffering ketone anions
Serum and urine ketones	Positive	Reagent strips (Ketostix, Acetest) contain nitroprusside, which reacts with acetoacetate and acetone but not with β-hydroxybutyrate
Serum Na⁺	Usually <140 mEq/L	Depletion of body stores and due to high glucose levels
Serum K⁺	Usually >5.2 mEq/L	Due to volume depletion and movement from ICF to ECF compartment
Serum Cl⁻	Usually normal	Depletion of body stores common
Serum creatinine and BUN	Elevated	Due to volume depletion. Note that acetoacetate may falsely elevate creatinine levels
Serum Ca²⁺ and Mg²⁺	Usually low unless volume depleted	Mild depletion of body stores
Serum phosphate	Usually low unless volume depleted	Severe depletion of body stores

Based on the above laboratory findings, the severity of DKA is classified into mild, moderate, and severe forms. The criteria for this classification are shown in Table 6.3.

Table 6.3

Diagnostic criteria for DKA

Lab value	Mild	Moderate	Severe
Serum glucose (mg/dL)	>250	>250	>250
Arterial pH	7.25–7.30	7.00–7.24	<7.00
Serum HCO₃ ⁻ (mEq/L)	15–18	10–15	<10
Anion gap	>10	>12	>12
Serum ketones	Positive	Positive	Positive
Urine ketones	Positive	Positive	Positive
Mental status	Alert	Alert-drowsy	Stupor