Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is a serious complication of diabetes characterized by high blood sugar levels, ketone body metabolism disturbances, and metabolic acidosis. It can be a life-threatening condition if not promptly treated. DKA is commonly associated with type 1 diabetes but can also occur in type 2 diabetes. The triad of hyperglycemia, high anion gap metabolic acidosis, and ketonemia is a hallmark of DKA. Ketone bodies like acetoacetate, acetone, and β-hydroxybutyrate are produced by the liver and utilized for energy production by peripheral tissues. Understanding the metabolic changes in DKA, including alterations in carbohydrate, protein, and lipid metabolism, as well as changes in water, electrolytes, and pH, is essential for effective management and prevention of complications.
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Endocrine Block Endocrine Block
- Diabetic Complications - Ketone bodies metabolism - - DKA Definition Causes and Mechanisms Manifestations Precipitating Factors - - Hyperosmolar state ( non Definition Causes and Mechanisms Manifestations Diabetic Complications Ketone bodies metabolism DKA: - - Hypoglycemia: Causes Manifestations Hormonal mechanisms preventing or correcting hypoglycemia - - A case of DKA: Examination, Lab results & their interpretation) - - Metabolic changes in DKA - Changes in CHO, protein and lipid metabolism - Changes in water, electrolytes, and pH Hypoglycemia: A case of DKA: (Presentation, Hyperosmolar hyperglycaemic state (HHS) = non- -ketotic hyperglycaemic Hypperosmolar ketotic acidosis ( HHS) = Hypperosmolar acidosis (HONK): Metabolic changes in DKA: HONK):
1. Diabetic Ketoacidosis (DKA) Diabetic Ketoacidosis (DKA) 1. 2. Hyperosmolar Hyperosmolar hyperglycaemic hyperglycaemic state (HHS)= state (HHS)= 2. Hypperosmolar Hypperosmolar non non- -ketotic ketotic acidosis (HONK) acidosis (HONK) 3. Hypoglycemia Hypoglycemia 3.
Triad of hyperglycemia, high anion gap Triad of hyperglycemia, high anion gap metabolic acidosis, and metabolic acidosis, and ketonemia ketonemia Characteristically associated with T Characteristically associated with T1 1DM DM It has become increasingly common in T It has become increasingly common in T2 2DM DM DKA may be the first presentation of T DKA may be the first presentation of T1 1DM DM
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 urine). In uncontrolled DM the rate of ketogenesis is > the rate of ketolysis urine). ketonemia ketonemia ( ( [KB] in blood) [KB] in blood) ketonuria ketonuria ( ( [KB] in [KB] in Manifestations of DKA: Fruity odor on the breath (acetone) Acidosis (low pH of blood because KBs are acids) Dehydration (due to Manifestations of DKA: Fruity odor on the breath (acetone) Acidosis (low pH of blood because KBs are acids) Dehydration (due to glucosuria 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 Manifestations: Characterized by: 1. see details later 2. 3. administration of glucose Common complication of treatment with insulin or oral hypoglycaemics More common in patients with T1 1DM Manifestations: Characterized by: 1.CNS Symptoms (confusion, aberrant behavior, or coma): DM CNS Symptoms (confusion, aberrant behavior, or coma): 2.Low blood [Glucose] 3.Symptoms resolved within minutes following the administration of glucose 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 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 Glucagon & adrenaline response to hypoglycemia becomes impaired later in the course of DM
Clinical presentation: Symptoms of sympathetic [glucose] < tremors, sweating & palpitation Symptoms of < <2.6 drowziness or seizures Clinical presentation: Symptoms of sympathetic overactivity [glucose] <3.6 tremors, sweating & palpitation Symptoms of neuroglycopenia 2.6 mmol drowziness and ultimately loss of consciousness or seizures (at plasma [glucose] < overactivity ( (plasma /L, abrupt fall): anxiety, plasma anxiety, 3.6 mmol mmol/L, abrupt fall): neuroglycopenia ( (plasma [glucose] mmol/L, gradual fall): and ultimately loss of consciousness (at plasma [glucose] <1.5 plasma [glucose] headache, confusion, /L, gradual fall): headache, confusion, 1.5 mmol mmol/L) /L)
i.e. < i.e. <2.22 2.22 mmol mmol/L /L Hormonal mechanisms to prevent or correct hypoglycemia: Hormonal mechanisms to prevent or correct hypoglycemia: Production of insulin Production of insulin production of: - Epinephrine & glucagon - Growth hormone - Cortisol
mmol/L /L Blood glucose, mmol 5.6 5.6 Blood glucose, 4.4 4.4 Glycemic thresholds for the various responses to hypoglycemia: 3.3 3.3 2.2 2.2 1.1 1.1
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 ++++ 3.9- -5.6 (trace) 22- -30 3.9 (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 serum water) Hematocrit Plasma analytes PCO2 Anion gap ( mmol/L) Urea nitrogen (mmol Creatinine ( ( mol/L) Albumin (g/L) Osmolality ( (mOsm serum water) Hematocrit analytes 2 ( (kPa gap (mmol /L) Patient 2.7 35.5 5.5 15 200 50 325 Patient s results 2.7 35.5 5.5 15 200 50 325 s results Normal levels 4.3 7 7- -16 3.5 2.5 44 41 275 Normal levels 4.3- -6.0 16 3.5- -5.0 2.5- -7.1 44- -80 41- -53 275- -295 kPa) ) 6.0 mmol/L) /L) 5.0 7.1 80 53 295 mmol/L) mol/L) /L) mOsm/kg /kg 0.500 0.500 0.354 0.354- -0.444 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. 3. 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. Dehydration 3. 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 Dehydration 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 lipolysis fatty acid oxidation production of Ketone bodies metabolism lipolysis 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
Acute complications of DM include: DKA, HHS, and hypoglycemia DKA is a triad of hyperglycemia, ketonemia and high anion gap metabolic acidosis, and can be precipitated by several stressful factors. Ketone bodies (KB) are synthesized in the liver (HMG CoA synthase is the rate limiting enzyme) and utilized by peripheral organs and not the liver (liver lacks thiophorase enzyme) KB can serve as energy source (this is important for the brain in case of hypoglycemia)
In DKA there is excessive ketogenesis (more than ketolysis) (details of the mechanisms and consequences are required) HHS is a serious condition, usually occurs in elderly with T2DM, and has high mortality rate. Hypoglycemia is a medical emergency that might be caused by DM treatment (intensive) and impaired protective mechanisms against hypoglycemia. Its clinical manifestations are due to sympathetic overactivity and neuroglycopenia. Case presentation, examination of DKA can provide provisional diagnosis, and should be confirmed by comprehensive blood and urine lab investigation including measuring blood glucose, KB, pH, pCO2, electrolytes, osmolality, protein, and kidney function test; anion gap calculation; hematocrit; and urine glucose and KB.
