Diabetic Ketoacidosis and Ketone Bodies

Dr. Clinical Chemistry Unit, Pathology Dept. College of Medicine, King Saud University Dr. Reem Clinical Chemistry Unit, Pathology Dept. College of Medicine, King Saud University Reem Sallam Sallam, MD, MSc, PhD , MD, MSc, PhD

Diabetic Ketoacidosis (DKA) Diabetic Ketoacidosis (DKA) Hyperosmolar Hyperosmolar hyperglycaemic hyperglycaemic state (HHS)= state (HHS)= Hypperosmolar Hypperosmolar non non- -ketotic ketotic acidosis (HONK) acidosis (HONK) Hypoglycemia Hypoglycemia

Triad of hyperglycemia, high anion gap Triad of hyperglycemia, high anion gap metabolic acidosis, and metabolic acidosis, and ketonemia ketonemia Characteristically associated with T1DM Characteristically associated with T1DM It has become increasingly common in T2DM It has become increasingly common in T2DM DKA may be the first presentation of T1DM DKA may be the first presentation of T1DM

1. 1. Acetoacetate Acetoacetate 2. 2. Acetone Acetone 3. -Hydroxybutyrate Hydroxybutyrate They are produced by the liver ( They are produced by the liver (ketogenesis ketogenesis) ) and utilized for energy production by and utilized for energy production by peripheral tissues ( peripheral tissues (Ketolysis Ketolysis) )

Normally, glucose is the primary fuel for the brain. It can penetrate the blood brain barrier. The brain s GLUT is insulin-independent. If glucose is not available for the brain, the brain can utilize plasma ketone bodies, that can penetrate the blood brain barrier, and serve as fuel molecules.

Occurs in the hepatocyte mitochondria In uncontrolled DM there is lipolysis in adipose tissue hepatic FA oxidation will be HMG CoA synthase The first KB to be synthesized is acetoacetate Acetoacetate can be: Occurs in the hepatocyte mitochondria In uncontrolled DM there is adipose tissue hepatic FA oxidation will be channeled synthase is the rate limiting enzyme lipolysis in mobilization to liver acetyl CoA into KB synthesis is the rate limiting enzyme [FFA] mobilization to liver acetyl CoA which channeled into KB synthesis [FFA] which HMG CoA The first KB to be synthesized is acetoacetate. . Acetoacetate can be: reduced to reduced to - -Hydroxybutyrate Hydroxybutyrate, , or or spontaneously spontaneously decarboxylated decarboxylated to to acetone acetone. .

hepatic FA oxidation be Acetyl CoA Acetyl carboxylase Pyruvate carboxylase OAA OAA is used for gluconeogenesis Krebs cycle) Acetyl CoA hepatic FA oxidation be channeled CoA + Acetyl CoA carboxylase carboxylase converts OAA acetyl CoA KB synthesis + oxaloacetate CoA production activates acetyl CoA which will which will channeled into into KB synthesis oxaloacetate (OAA) production activates pyruvate Acetyl (OAA) Krebs cycle pyruvate Krebs cycle Pyruvate converts pyruvic pyruvic acid into acid into OAA is used for Krebs cycle) CoA is gluconeogenesis (rather than (rather than Acetyl is channeled channeled into into KB synthesis KB synthesis

Takes place in extrahepatic tissues Occurs in the mitochondria (so cannot occur in RBCs) Does not occur in the liver (as the liver lacks the thiophorase enzyme required for ketolysis) -Hydroxybutyrate is oxidized to acetoacetate (by a dehydrogenase) Acetoacetate is converted to acetoacetyl CoA (catalyzed by thiophorase) Acetoacetyl CoA is converted to acetyl CoAs.

Mechanisms of DKA: In uncontrolled DM there is lipolysis in adipose tissue [FFA] mobilization of FFA to liver hepatic FA oxidation hepatic acetyl CoA which will be utilized in KB synthesis (ketogenesis) ketoacidosis

Mechanisms & Manifestations of DKA In uncontrolled DM the rate of ketogenesis is > the rate of ketolysis blood) urine). Manifestations of DKA: Fruity odor on the breath (acetone) Acidosis (low pH of blood because KBs are acids) Dehydration (due to In uncontrolled DM the rate of ketogenesis is > the rate of ketolysis blood) urine). Manifestations of DKA: Fruity odor on the breath (acetone) Acidosis (low pH of blood because KBs are acids) Dehydration (due to glucosuria ketonemia ketonuria ketonemia ( ( [KB] in ketonuria ( ( [KB] in [KB] in [KB] in glucosuria) )

Infection ( Inadequate insulin treatment or non compliance ( Severe illness e.g., Myocardial infarction Trauma Drugs: e.g., steroids Infection (30 Inadequate insulin treatment or non- - compliance (20 Severe illness e.g., Myocardial infarction Trauma Drugs: e.g., steroids 30- -40 40%) %) 20%) %)

Little or no accumulation of ketone bodies Little or no accumulation of ketone bodies Serum [glucose] is often > Serum [glucose] is often >50 50 mmol mmol/L /L Plasma osmolality may reach Plasma osmolality may reach 380 380 mosmol mosmol/Kg (normal /Kg (normal 275 275- -295 295) ) Neurological abnormalities are frequently present Neurological abnormalities are frequently present Insulin levels are insufficient to allow appropriate glucose utilization but are adequate to prevent lipolysis and subsequent ketogenesis Insulin levels are insufficient to allow appropriate glucose utilization but are adequate to prevent lipolysis and subsequent ketogenesis Usually occurs in elderly patients with T Usually occurs in elderly patients with T2 2DM DM Has a substantially higher mortality than DKA (up to Has a substantially higher mortality than DKA (up to 15 15%) %)

Common complication of treatment with insulin or oral hypoglycaemics More common in patients with T Characterized by: 1. 2. 3. administration of glucose Common complication of treatment with insulin or oral hypoglycaemics More common in patients with T1 1DM Characterized by: 1.CNS Symptoms (confusion, aberrant behavior, or coma) 2.Low blood [Glucose] 3.Symptoms resolved within minutes following the administration of glucose DM CNS Symptoms (confusion, aberrant behavior, or coma) Low blood [Glucose] Symptoms resolved within minutes following the

The brain has absolute requirement for a The brain has absolute requirement for a continuous supply of glucose continuous supply of glucose Transient hypoglycemia dysfunction Transient hypoglycemia dysfunction cerebral cerebral Severe, prolonged hypoglycemia death Severe, prolonged hypoglycemia death brain brain

Hypoglycemia occurs due to impaired protective responses to hypoglycemia: Insulin is supplied exogenously and its release cannot be turned off Glucagon & adrenaline response to hypoglycemia becomes impaired later in the course of DM Clinical presentation: Symptoms of sympathetic mmol Symptoms of mmol ultimately loss of consciousness or seizures [glucose] < Hypoglycemia occurs due to impaired protective responses to hypoglycemia: Insulin is supplied exogenously and its release cannot be turned off Glucagon & adrenaline response to hypoglycemia becomes impaired later in the course of DM Clinical presentation: Symptoms of sympathetic overactivity mmol/L, abrupt fall): Symptoms of neuroglycopenia mmol/L, gradual fall): ultimately loss of consciousness or seizures (at plasma [glucose] <1.5 overactivity ( (plasma [glucose] < anxiety, tremors, sweating & palpitation neuroglycopenia ( (plasma [glucose] < /L, gradual fall): headache, confusion, plasma [glucose] <3.6 3.6 /L, abrupt fall): anxiety, tremors, sweating & palpitation plasma [glucose] <2.6 headache, confusion, drowziness 2.6 drowziness and (at plasma and 1.5 mmol mmol/L) /L)

Hormonal mechanisms to prevent or correct hypoglycemia: Hormonal mechanisms to prevent or correct hypoglycemia: Production of Production of insulin insulin production of: - Epinephrine & glucagon - Growth hormone - Cortisol

Glycemic thresholds for the various responses to hypoglycemia:

A A 14- -year children stated until she fever generally was coma had been weeks previously, sore throat subsequently lost generally did 14 year- -old old hospital the girl admitted Her in good previously, when throat and lost her feel well girl girl was coma. . been in admitted Her good health to to a a children s s stated that until approximately she developed fever. . She did not hospital in in mother health when moderate appetite and mother that the approximately 2 2 weeks developed a a sore She subsequently not feel girl had and moderate her appetite and well. .

Several days before admission she began to complain of undue thirst and also started to get up several times during the night to urinate. However, on the day of admission the girl had started to vomit, had become drowsy and difficult to arouse, and accordingly had been brought to the emergency department. Several days before admission she began to complain of undue thirst and also started to get up several times during the night to urinate. However, on the day of admission the girl had started to vomit, had become drowsy and difficult to arouse, and accordingly had been brought to the emergency department.

On examination: She was dehydrated Her skin was cold She was breathing in a deep sighing manner (Kussmaul respiration) Her breath had a fruity odor Her blood pressure was 120 Her pulse rate She could not be aroused A provisional diagnosis of T complicating made by the intern on duty On examination: She was dehydrated Her skin was cold She was breathing in a deep sighing manner (Kussmaul respiration) Her breath had a fruity odor Her blood pressure was 90 120/ /80 Her pulse rate 115 She could not be aroused A provisional diagnosis of T1 1DM with complicating ketoacidosis made by the intern on duty 90/ /60 60 mmHg (N: mmHg (N: 80) ) 115/min. /min. DM with ketoacidosis and coma (DKA) was and coma (DKA) was

The admitting diagnosis was confirmed by the laboratory findings shown below: Plasma Plasma analytes analytes Patient Patient s results s results Normal levels Normal levels Glucose (mmol Ketoacids Bicarbonate (mmol Glucose ( Ketoacids Bicarbonate ( mmol/L) /L) 50 ++++ 6 6 50 ++++ 4.2- -5.6 (trace) 22- -30 4.2 (trace) 22 5.6 mmol/L) /L) 30 Arterial blood pH Na Cl Arterial blood pH Na+ +( (mmol Cl- -( (mmol 7.07 136 100 7.07 136 100 7.35 136 102 7.35- -7.45 136- -146 102- -109 7.45 146 109 mmol/L) mmol/L) /L) /L)

Plasma PCO * *Anion K K+ +( (mmol Urea nitrogen ( Creatinine Albumin (g/L) Osmolality Hematocrit Plasma analytes PCO2 Anion gap ( mmol/L) Urea nitrogen (mmol Creatinine ( ( mol/L) Albumin (g/L) Osmolality ( (mOsm Hematocrit analytes 2 ( (kPa gap (mmol /L) Patient 2.7 35.5 5.5 15 200 50 325 0.500 Patient s results 2.7 35.5 5.5 15 200 50 325 0.500 s results Normal levels 4.3 7 7- -16 3.5 2.5 44 41 275 0.354 Normal levels 4.3- -6.0 16 3.5- -5.0 2.5- -7.1 44- -80 41- -53 275- -295 0.354- -0.444 kPa) ) 6.0 mmol/L) /L) 5.0 7.1 80 53 295 mmol/L) mol/L) /L) mOsm/kg) /kg) 0.444 * *Anion gap (A Anion gap (A- -)= (Na )= (Na+ ++ K + K+ +) (HCO (HCO3 3- -+ + Cl Cl- -) )

Urine analyte Glucose Ketoacids Urine analyte Patient results ++++ ++++ Patient s s results Normal level Normal level - -

Results Hyperglycemia Glucosuria Ketonemia Ketonuria pH Results Hyperglycemia Glucosuria Ketonemia Ketonuria pH Interpretation Interpretation Confirm the diagnosis of DKA Confirm the diagnosis of DKA Severe metabolic acidosis due to bodies Metabolic acidosis with partial respiratory compensation (the hyperventilation) Due to 1. renal perfusion) 2. Uptake Due Severe metabolic acidosis due to production of bodies Metabolic acidosis with partial respiratory compensation (the hyperventilation) Due to ketone 1. Renal impairment (dehydration renal perfusion) 2. Degradation of protein (for urea) Uptake of potassium by cells in the absence of insulin Due to hyperglycemia and fluid loss production of ketone ketone bicarbonate and PCO anion gap urea & creatinine bicarbonate and PCO2 anion gap urea & creatinine 2 ketone bodies in the blood Renal impairment (dehydration bodies in the blood blood volume blood volume Degradation of protein (for urea) of potassium by cells in the absence of insulin to hyperglycemia and fluid loss K K+ + Plasma o osmolality Plasma smolality

Multiple effects Multiple effects Lipid Lipid , Water & pH entry of K+ +into the cells Water loss secondary to glycosuria Acidosis due to production of ketone bodies K K+ +, Water & pH entry of K the cells Water loss secondary to Acidosis due to production of bodies CHO CHO Protein metabolism protein synthesis protein degradation Protein metabolism protein synthesis protein degradation metabolism lypolysis fatty acid oxidation production of Ketone bodies metabolism lypolysis fatty acid oxidation production of bodies metabolism glucose uptake by certain tissues (adipose tissue & muscle) glycogenolysis gluconeogenesis metabolism glucose uptake by certain tissues (adipose tissue & muscle) glycogenolysis gluconeogenesis into glycosuria ketone Ketone DKA DM