Diabetes Ketoacidosis

Renal Tubular Acidosis REF: Harrison’s Internal Medicine 17′ edition chapter 48 Table 48-4, http://en.wikipedia.org/ wiki/Anion_gap#High anion_ gap

Repeat from June 2009

All evaluations of acid-base disorders should include a simple calculation of the AG; it represents those unmeasured anions in plasma (normally 10 to 12 mmol/L) and is calculated as follows: AG = Na’ – (C1- + HCO₃-). When acid anions such as acetoacetate and lactate accumulate in extracellular fluid, the AG increases causing a high AG acidosis. An increase in the AG is most often due to an increase in unmeasured anions and less commonly is due to a decrease in unmeasured cations (calcium, magnesium, potassium).

CAUSES OF HIGH-ANION-GAP METABOLIC ACIDOSIS:

Renal Tub2ular Acidosis REF: Harrison’s Internal Medicine 17^th edition chapter 48 Table 48-4, http://en.wikipedia.org/ wiki/Anion_gap#High anion_gap

Repeat from December 2010

All evaluations of acid-base disorders should include a simple calculation of the AG; it represents those unmeasured anions in plasma (normally 10 to 12 mmol/L) and is calculated as follows: AG = Na’ – (C1- + HCO₃-). When acid anions such as acetoacetate and lactate accumulate in extracellular fluid, the AG increases causing a high AG acidosis. An increase in the AG is most often due to an increase in unmeasured anions and less commonly is due to a decrease in unmeasured cations (calcium, magnesium, potassium).

CAUSES OF HIGH-ANION-GAP METABOLIC ACIDOSIS

Lactic acidosis                              Toxins

Ketoacidosis                                  Ethylene glycol

Diabetic                                          Methanol

Alcoholic                                        Salicylates

Starvation                                       Propylene glycol Pyroglutamic acid Renal failure (acute and chronic)

Therapy of diabetic ketoacidosis requires more than insulin. Intravascular volume is often depleted, and initial fluids to restore volume should include isotonic saline or lactated Ringer’s solution.

If arterial blood pH is less than 7.1 or if severe hyperkalemia is present, bicarbonate supplementation should be used.

IV fluids containing 5-10% dextrose (glucose) should be used when the serum glucose levels fall to 200-300 mg/dL, since high doses of rapidly acting insulin can cause life-threatening hypoglycemia.

Additionally, the serum potassium concentration should be watched very carefully, since potassium is co transported into cells with glucose in the presence of insulin.

It is often the case that hyperkalemia is present initially, secondary to decreased cellular uptake of potassium with decreased cellular uptake of glucose. However, this can rapidly change when insulin drives glucose (with potassium) into cells, and a life-threatening hypokalemia can develop.

Therapy of diabetic ketoacidosis requires more than insulin. Intravascular volume is often depleted, and initial fluids to restore volume should include isotonic saline or lactated Ringer’s solution. If arterial blood pH is less than 7.1 or if severe hyperkalemia is present, bicarbonate supplementation should be used.

IV fluids containing 5-10% dextrose (glucose) should be used when the serum glucose levels fall to 200-300 mg/dL, since high doses of rapidly acting insulin can cause life-threatening hypoglycemia. Additionally, the serum potassium concentration should be watched very carefully, since potassium is co transported into cells with glucose in the presence of insulin.

It is often the case that hyperkalemia is present initially, secondary to decreased cellular uptake of potassium with decreased cellular uptake of glucose. However, this can rapidly change when insulin drives glucose (with potassium) into cells, and a life-threatening hypokalemia can develop.

Ketoacidosis is a high anion gap metabolic acidosis due to an excessive blood concentration of ketone bodies. Ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone) are released into the blood from the liver when hepatic lipid metabolism has changed to a state of increased ketogenesis.

The three major types of ketosis are:

• Starvation ketosis

• Alcoholic ketoacidosis

• Diabetic ketoacidosis
   

Starvation Ketoacidosis: Occurs secondary to starvation, is due to a diminished insulin secretion, that leads to an increase in lipolysis and ketogenesis. The acidosis even with prolonged fasting is only mild to moderate.

Diabetic ketoacidosis (DKA) is a state of absolute or relative insulin deficiency and is defined by the American Diabetes Association’s (ADA) diagnostic criteria of

• Hyperglycemia [blood glucose >250 mg/dl (13.9 mmol/l)],

• Acidosis (arterial pH

• Ketosis (moderate ketonuria or ketonemia)

The metabolic differences between diabetes and starvation include-

Insulin levels: The level of insulin is decreased in both diabetes and starvation.

It is more decreased in case of diabetes (virtually absent in type I diabetes). There is relative excess of glucagon in both the cases. Glucagon acts through elevation in CAMP level.

Blood glucose levels: Diabetics exhibit a characteristic hyperglycemia where as in starvation the individual maintain a blood glucose level that is near to normal

Ketosis: The mobilization of fatty acids from adipose tissue and hepatic ketogencsis are greater in diabetes than in starvation. As a result the ketoacidosis observed in diabetes in much more severe than that observed during starvation.

Ref: Lippincott’s illustrated reviews Biochemistry, 2nd Edition, Page 297.

High-anion gap metabolic acidosis is caused by ? Lactic acidosis ? Ketoacidosis (Diabetic, Alcoholic, Starvation) ? Toxins – Ethylene glycol, Methanol, Salicylates, Propylene glycol and Pyroglutamic acid and ? Renal failure (acute and chronic). COPD is not associated with high anion gap metabolic acidosis.

Metabolic acidosis results from an imbalance between the plasma concentration of H+ and HCO3– and is defined as a decrease in [HCO3–] to below 22meq/l with a decrease in pH below 7.36. High anion gap metabolic acidosis result from excess accumulation of fixed acid. If its level is increased to 30mmol/L or more, a high anion gap metabolic acidosis is present regardless of pH and HCO3. Anion gap is calculated by the formula, anion gap= Na+ – (CL- + HCO-3). Normal value is  8- 12 mmol/l.

Ref: Harrison’s Principle of Internal Medicine, 18th Edition, Page 366, Table 47-4; CURRENT Diagnosis and Treatment Emergency Medicine, 7th Edition, Chapter 44

Typical of DKA:

1.    Hyperglycemia >250mg/dl

2.    Acidosis with blood pH < 7.3

3.    Sodium Bicarbonate < 15 mEq/L

4.    Serum positive for ketones

Ref: CMDT 2008 Edition, Page 1062.

A i.e. Increase in glucagons/ insulin ratio, increased C- AMP & increased blood sugar.

In diabetes little glucose is oxidized as fuel, except by the brain. The rest of tissues burn a large amount of fat, particularly the liver where the amount of acetyl COA formed from fatty acids exceeds the capacity of the tricarboxylic acid cycle to oxidize it. The excess acetyl COA is converted to ketone bodies l/t ketonemia, ketonuria & ketoacidosis

Diabetics not only have a defect in the tissue utilization of glucose but also appears to be metabolically poised to produce maximum amount of glucose from amino acids (gluconeogenesis) and to prevent glucose from being utilized to to form fat. (fat synthesis)

Insulin is decreased & glucagons is increased 1/t Dglucagon/ insulin ratioQ. Glucagon acts via elevation in C- AMPQ

B i.e. Blood transfusion

Ans. is ‘d’ i.e., Diabetic ketoacidosis

Note – Orbital mucormycosis occurs secondary to paranasal sinus mucormycosis.

• Predisposing factors for paranasal sinus mucormycosis

– Diabetes mellitus                                                           – Long term deferoxamine therapy

–  Hematological malignancies                                      – Organ transplantation

.  Predisposing factors for G.I. mucormycosis

– Uremia                                                                           – Diarrheal diseases

–   Severe malnutrition

Ans. is `a’ i.e., Esophageal varices; ‘b’ i.e., Diabetic ketoacidosis

o Uses of somatostatin

i)           Bleeding esophageal varices

Somatostatin constricts blood vessels.

ii)         Bleeding peptic ulcers

iii)        Pancreatic, biliary or intestinal fistula —> Somatostatin has antisecretory action.

iv)       Diabetic ketoacidosis —> inhibiting glucagon & GH release.(These counter regulatory hormones are increased in DKA)

Answer is A & C (Family history is present in 90% cases and Time of onset is usually predictable):

Family history is present in about 15% of patients with type I DM and time of onset is not predictable.

Type I Diabetes often occurs in children (Oxford textbook)

‘Type I Diabetes is the most severe form of diabetes with acute onset often in children’ – Oxford Textbook of Medicine Median age of diagnosis of Type I DM is 12 years

As many as 25% of cases are now diagnosed under the age of 5 years.

Family History is present in about 15% of cases of Type I DM (Harrison 17th)

‘Most individuals with type I DM do not have a first degree relative with this disorder’ – Harrison 17th/2280 The risk of developing type I D.M. is 3–9% if the parent has type I DM.

The risk of developing type I D.M. is 5-15% if a sibling has type I DM

Percent of cases with positive family history in Type I DM 10-15%

Percent of cases with positive family history in Type II DM 90%

Type I DM is associated with auto immune destruction of Beta cells

Pathogenesis of type 1 DM involves autoimmune destruction of Beta cells mediated by T cells and humoral mediators, resulting in absolute insulin deficiency — Robbins 7th/1204

Diabetic Ketoacidosis is dependant on Insulin

Diabetic ketoacidosis is a serious complication of Type I DM and requires insulin for reversal. ‘Diabetic ketoacidosis cannot be reverted without insulin’ — Harrison

Answer is A (Family history is present in 90% of cases):

A strong family history (.90%) is a feature of type II DM and not type I DM. Family history may he present in only about 15% cases of type I DM.

Answer is D (Regular Insulin):

The drug of choice for managing hyperglycemia in diabetic ketoacidosis is regular insulin

The drug of choice for managing hyperglycemia in diabetic ketoacidosis is regular insulin because of its rapid but short- duration actions. Regular (fast-acting) insulin is the primary insulin preparation used in the management of Diabetic Ketoacidosis (DKA) and is the only insulin that should be given intravenously or intramuscularly.

Lente insulin is a longer-acting form of insulin than regular and should not be used. Oral Hypoglycaemic agents are never used for initial management of Diabetic Ketoacidosis.

Answer is A (Regular insulin):

The drug of choice for managing hyperglycemia in diabetic ketoacidosis is regular insulin

The drug of choice for managing hyperglycemia in diabetic ketoacidosis is regular insulin because of its rapid but short- duration actions. Regular (fast-acting) insulin is the primary insulin preparation used in the management of Diabetic Ketoacidosis (DKA) and is the only insulin that should be given intravenously or intramuscularly. Lente insulin is a longer-acting form of insulin than regular and should not be used. Oral Hypoglycaemic agents are never used_, for initial management of Diabetic Ketoacidosis.

Answer is D (Serum Bicarbonate > 15 meq/I):

Serum Bicarbonate levels in Diabetic Ketoacidosis (DKA) are typically less than 15 meq/l.

Diabetic Ketoacidosis is an acute complication typically seen in patients with Type –I or Insulin Dependent Diabetes Mellitus characterized by High Anion Gap Metabolic acidosis (PH < 7.4) and Bicarbonate levels < 15meq/I.

Answer is A (Diarrhea):

The differential diagnosis of normal anion gap acidosis :

• Hyperalimentation
• Acetazolamide and other carbonic anhydrase inhibitors
• Renal tubular acidosis
• Diarrhea: due to a loss of bicarbonate.
• Ureteroenteric fistula
• Pancreaticoduodenal fistula
• Spironolactone

Answer is B (Diarrhea)

Diarrhea is a cause of normal anion gap metabolic acidosis produced as a result of increased gastrointestinal bicarbonate loss.

The differential diagnosis of normal anion gap acidosis :

• Hyperalimentation
• Acetazolamide and other carbonic anhydrase inhibitors
• Renal tubular acidosis
• Diarrhea: due to a loss of bicarbonate.
• Ureteroenteric fistula
• Pancreaticoduodenal fistula
• Spironolactone

When food intake ceases, the body’s glycogen stores are used up in about 24 hours.

The level of insulin in circulation is low and the level of glucagon is very high.

The main means of energy production is lipolysis.

Gluconeogenesis converts glycerol into glucose and the Cori cycle converts lactate into usable glucose.

The high demand for glucose by the fetus, and for lactose synthesis in lactation, can lead to ketosis. This may be seen as mild ketosis with hypoglycemia in human beings.

Two systems of energy enter the gluconeogenesis: proteolysis provides alanine and lactate produced from pyrivate, while acetyl CoA produces dissolved nutrients (ketone bodies), which can be detected in urine and are used by the brain as a source of energy.

In uncontrolled diabetes, the ketosis may be severe enough to result in pronounced acidosis (Ketoacidosis).

Ans. D: Insulin

Insulin increases peripheral glucose utilization and decreases hepatic glucose production, thereby lowering blood glucose concentration. In addition, insulin therapy inhibits the release of FFAs from adipose tissue and decreases ketogenesis, both of which lead to the reversal of ketogenesis.

In critically ill and mentally obtunded patients, regular insulin given intravenously by continuous infusion is the treatment of choice

Ans. Renal tubular acidosis

Ans. is ‘a’ i.e., Cerebral edema

• High blood sugar will cross the blood brain barrier and simultaneously will draw water inside leading to cerebral edema. Cerebral edema accounts for 60-90% of all DKA related deaths in children.
• Infection is a precipitator for development of DKA.
• Other precipitating factor can be tissue ischemia, inadequate insulin administration, drugs (cocaine) and pregnancy.