Hypoglycemia

hypoglycemia and its management

1. HYPOGLYCEMIA Dr. Anup Bhatta Dhulikhel Hospital

2. DEFINITION Glucose levels <55mg/ dL (<3.0mmol/L) with symptoms that are relieved promptly after the glucose level is raised document hypoglycemia.

3. DEFINITION Hypoglycemia is most convincingly documented by, Whipple’s triad, i.e : Symptoms consistent with hypoglycemia Low plasma glucose concentration (measured with a precise method) Relief of symptoms when plasma glucose concentration is increased.

4. Glucose levels <3.5mmol/L (63mg/ dL ).

5. SYSTEMIC GLUCOSE BALANCE AND GLUCOSE COUNTERREGULATION

6. PHYSIOLOGIC RESPONSES TO DECREASING PlASMA GLUCOSE CONCENTRATIONS RESPONSE GLYCEMIC THRESHOLD (mg/dl) PHYSIOLOGIC EFFECTS ROLE IN GLUCOSE REGULATION ↓ Insulin 80-85 ↑ Ra ( ↓ Rd) 1 st line of defense (Primary glucose regulatory factor) ↑ Glucagon 65-70 ↑ Ra 2 nd line of defense (Primary glucose counterreg. factor) ↑ Epinephrine 65-70 ↑ Ra ↓ Rc 3 rd line of defense (critical when glucagon ↓ ) ↑ Cortisol & GH 65-70 ↑ Ra ↓ Rc Defense against prolonged hypoglycemia, not critical Symptoms 50-55 Recognition of hypoglycemia Prompt behavioral defense(food ingestion) ↓ Cognition < 50 ----- Compromises behavioral defense against hypoglycemia

7. However, these thresholds are dynamic. They shift to higher-than normal glucose levels in people with poorly controlled diabetes, who can experience symptoms of hypoglycemia when their glucose levels decline toward the normal range ( pseudohypoglycemia ). On the other hand, thresholds shift to lower-than-normal glucose levels in people with recurrent hypoglycemia;

8. Causes of Hypoglycemia in Adults Ill or medicated individual    1. Drugs       Insulin or insulin secretagogue      Alcohol  others  2. Critical illness      Hepatic, renal or cardiac failure      Sepsis    3. Hormone deficiency       Cortisol      Glucagon and epinephrine (in insulin-deficient diabetes) 4. Non–islet cell tumor

9.      Seemingly well individual    5. Endogenous hyperinsulinism        Insulinoma      Functional beta-cell disorders ( nesidioblastosis )          Noninsulinoma pancreatogenous hypoglycemia         Post–gastric bypass hypoglycemia       Insulin autoimmune hypoglycemia          Antibody to insulin          Antibody to insulin receptor       Insulin secretagogue          6. Accidental, surreptitious or malicious hypoglycemia

10. Clinical manifestations COMMON SYMPTOMS OF HYPOGLYCAEMIA Autonomic Sweating Trembling Pounding heart Hunger Anxiety Neuroglycopenic confusion Drowsiness Speech difficulty Inability to concentrate Incoordination Non-specific Nausea Tiredness Headache

11. signs Pallor Diaphoresis ↑ Heart rate ↑ systolic BP ( But may not be raised in an individual who has experienced repeated, recent episodes of hypoglycemia.)

12. HYPOGLYCEMIA IN DIABETES Hypoglycemia is most commonly a result of the treatment of diabetes. it is the limiting factor in the glycemic management of diabetes mellitus it causes recurrent morbidity in most people with type 1 diabetes (T1DM) and in many with advanced type 2 diabetes (T2DM), and it is sometimes fatal. it causes a vicious cycle of recurrent hypoglycemia by producing hypoglycemia-associated autonomic failure —i.e., the clinical syndromes of defective glucose counterregulation and of hypoglycemia unawareness

13. Epidemiology They suffer an average of two episodes of symptomatic hypoglycemia per week , thousands of such episodes over a lifetime of diabetes, and one episode of severe, at least temporarily disabling hypoglycemia per year . An estimated 6–10% of people with T1DM die as a result of hypoglycemia.

14. Conventional Risk Factors Relative or absolute insulin excess is the sole determinant of risk.it occurs when: (1) insulin (or insulin secretagogue ) doses are excessive, ill-timed, or of the wrong type (2) the influx of exogenous glucose is reduced (3) insulin-independent glucose utilization is increased (e.g., during exercise); (4) sensitivity to insulin is increased (5) endogenous glucose production is reduced ( following alcohol ingestion) (6) insulin clearance is reduced (e.g., in renal failure).

15. Nocturnal hypoglycaemia : Nocturnal hypoglycaemia in patients with type 1 diabetes is probably common and under- recognised . As hypoglycaemia does not usually waken a person who is asleep and the usual warning symptoms are not perceived, it is often undetected. However, on direct questioning, patients may admit to poor quality of sleep, morning headaches, ‘hangover’, chronic fatigue and vivid dreams or nightmares. Sometimes a partner may observe profuse sweating, restlessness, twitching or even seizures. The only reliable way to identify this problem is to measure the blood glucose during the night.

16. Exercise-induced hypoglycaemia Exercise-induced hypoglycaemia occurs in people with well-controlled, insulin-treated diabetes because of hyperinsulinaemia and the absence of the capacity to suppress secretion of endogenous insulin, a key factor in the normal adaptation to exercise.

17. MORBIDITY OF SEVERE HYPOGLYCAEMIA IN DIABETIC PATIENTS CNS Impaired cognitive function Coma Convulsions Transient ischaemic attack, stroke Intellectual decline Brain damage (rare) Focal neurological lesions (rare) Heart Cardiac arrhythmias Myocardial ischaemia

18. Eye Vitreous haemorrhage ? Worsening of retinopathy Other Hypothermia Accidents (including road traffic accidents) with injury

19. HYPOGLYCEMIA ASSOCIATED AUTONOMIC FAILURE The concept of HAAF in diabetes posits that recent antecedent iatrogenic hypoglycemia (or sleep or prior exercise) causes both defective glucose counterregulation and hypoglycemia unawareness . Defective glucose counterregulation compromises physiologic defense, and hypoglycemia unawareness compromises behavioral defense.

20. DEFECTIVE GLUCOSE COUNTERREGULATION Fa i lure of All 3 lines of defense. Result of antecedent iatrogenic hypoglycemia Glycemic threshold is shifted to lower plasma glucose concentrations. 25x or more risk of sever iatrogenic hypoglycemia during aggressive glycemic therapy . ↓ Glucose No ↓ Insulin No ↑ Glucagon No ↑ Epinephrine ↑ Glucose

21. HYPOGLYCEMIA UNAWARENESS Caused by the reduced sympathoadrenal response (largely the ↓ sympathetic neural response) to hypoglycemia. Characterised by the loss of warning adrenergic & cholinergic symptoms that previously allowed the patient to recognise developing hypoglycemia and therefore abort the episode by ingesting carbohydrates. 6x increased risk of severe iatrogenic hypoglycemia during aggressive treatment .

22. These impaired responses create a vicious cycle of recurrent iatrogenic hypoglycemia.

23. HYPOGLYCEMIA WITHOUT DIABETES

24. Drugs Insulin Sulfonylureas Quinine Pentamidine Salicylates Sulfonamides indomethacin Ethanol Haloperidol ACE inhibitors others

25. Critical illness renal, hepatic, or cardiac failure, sepsis. are second only to drugs as causes of hypoglycemia.

26. Hormone deficiencies hypoglycemia can occur with prolonged fasting in patients with primary adrenocortical failure (Addison's disease) or hypopituitarism . Growth hormone deficiency can cause hypoglycemia in young children.

27. Non–Beta-Cell Tumors occurs occasionally in patients with large mesenchymal or epithelial tumors (e.g., hepatomas , adrenocortical carcinomas, carcinoids )

28. Endogenous Hyperinsulinism Hypoglycemia due to endogenous hyperinsulinism can be caused by (1) a primary β- cell disorder—typically a β- cell tumor ( insulinoma ), sometimes multiple insulinomas , or a functional β- cell disorder with β- cell hypertrophy or hyperplasia (2) an antibody to insulin or to the insulin receptor; (3) a β- cell secretagogue such as a sulfonylurea; (4) ectopic insulin secretion,

29. INBORN ERRORS OF METABOLISM CAUSING HYPOGLYCEMIA those resulting in- 1.Fasting Hypoglycemia: disorders of glycogenolysis . These disorders include glycogen storage disease (GSD) of types 0, I, III, and IV and Fanconi -Bickel syndrome Defects in fatty acid oxidation also result in fasting hypoglycemia. These defects can include (1) defects in the carnitine cycle (2) fatty-acid β- oxidation disorders; (3) electron transfer disturbances; and (4) ketogenesis disorders

30. 2.Postprandial Hypoglycemia: These errors include (1) glucokinase and potassium channel mutations; (2) congenital disorders of glycosylation ; and (3) inherited fructose intolerance. 3. Exercise-Induced Hypoglycemia: It results in hyperinsulinemia caused by increased activity of monocarboxylate transporter 1 in β cells.

31. Approach to the patient with Hypoglycemia RECOGNITION AND DOCUMENTATION Symptoms and signs Whipple’s triad

32. DIAGNOSIS OF THE HYPOGLYCEMIC MECHANISM history, physical examination, investigation

33. Laboratory tests Glucose CBC Insulin C-peptide Beta- hydroxybutyrate Proinsulin Antibodies for insulin and its receptors Sulfonylurea and meglitinide screen Electrolytes, BUN/Cr, UA liver function tests, cortisol and thyroid levels , growth hormone level Other tests: CT and MRI

34. Urgent Treatment Oral treatment with glucose tablets or glucose containing fluids, candy or food is appropriate if the patient is able & willing to take these. Initial dose = 20 g of glucose Unable to take oral foods  parenteral therapy IV glucose 25 g bolus followed by infusion guided by serial plasma glucose measurements. Or, Inj.Glucagon 1.0 mg sc/ im can be used esp in T1DM. (it has no role in alcohol induced hypoglycemia)

35. The somatostatin analogue octreotide can be used to suppress insulin secretion in sulfonylurea-induced hypoglycemia. These treatments raise plasma glucose concentrations only transiently, and patients should therefore be urged to eat as soon as is practical to replete glycogen stores.

36. Non-diabetic hypoglycemia definitive management depends on the underlying etiology. Offending drugs can be discontinued or their doses reduced. Underlying critical illnesses should be treated. Cortisol and growth hormone can be replaced if levels are deficient. Surgical, radiotherapeutic , or chemotherapeutic reduction of a non–islet cell tumor . Surgical resection of an insulinoma is curative; medical therapy with diazoxide or octreotide can be used if resection is not possible and in patients with a nontumor β-cell disorder.

37. PREVENTION OF HYPOGLYCEMIA Identifying & addressing the cause Encouraging Self-monitoring of blood glucose by patient Education & empowerment of patient Flexible insulin or Oral anti-diabetic regimens Rational, individual glycemic goals Ongoing professional guidance & support

38. References; Harrison's Principles of Internal Medicine, 18th Ed Davidson's Principles & Practice of Medicine 21th ed ,

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