HYPOGLYCEMIA

MA. MELISSA MONICA L. TURAO MD

Hypoglycemia
most commonly caused by: drugs used to treat diabetes mellitus exposure to other drugs (including alcohol)

Hypoglycemia
 May be caused by disorders
Insulinoma critical organ failure sepsis and inanition hormone deficiencies non- beta cell tumors inherited metabolic disorders prior gastric surgery

Causes of Hypoglycemia in Adults

Ill or Medicated Individual Drugs Causes of Hypoglycemia in Adults Insulin or insulin secretagogues Alcohol

Critical Illness

Hepatic, renal or cardiac failure Sepsis Inanition Cortisol Glucagon and epinephrine (IDDM)

Hormone Deficiency Non-islet cell tumor

Causes of Hypoglycemia in Adults

Seemingly well individual Endogenous hyperinsulinism Insulinoma Functional beta cell disorders (nesidioblastosis) -Non-insulinoma pancreatogenous hypoglycemia - Post-gastric bypass hypoglycemia Insulin autoimmune hypoglycemia - Antibody to insulin - Antibody to insulin receptor Insulin secretagogue

Accidental, sureptitious or malicious hypoglycemia

Hypoglycemia
Whipple's triad: (1) symptoms consistent with hypoglycemia (2) a low plasma glucose concentration measured with a precise method (not a glucose monitor) (3) relief of those symptoms after the plasma glucose level is raised

 lower limit of the fasting plasma glucose

concentration is normally approximately 70 mg/dL (3.9 mmol/L)

 Glucose levels <55 mg/dL (3.0 mmol/L)

with symptoms that are relieved promptly after the glucose level is raised document hypoglycemia.

 It should be considered in any patient with

episodes of:
confusion altered level of consciousness seizure

Systemic Glucose Balance and Glucose Counterregulation

 Glucose
obligate metabolic fuel for the brain under physiologic conditions brain cannot synthesize glucose or store more than a few minutes' supply as glycogen and therefore requires a continuous supply of glucose from the arterial circulation

 As the arterial plasma glucose concentration

falls below the physiologic range, blood-to-brain glucose transport becomes insufficient to support brain energy metabolism and function.  However, redundant glucose counterregulatory mechanisms normally prevent or rapidly correct hypoglycemia.

 Plasma glucose concentrations are normally

maintained within a relatively narrow range

70 110 mg/dL (3.9 6.1 mmol/L) in the fasting state with transient higher excursions after a meal wide variations in exogenous glucose delivery from meals endogenous glucose utilization by, for example, exercising muscle

 Between meals and during fasting, plasma

glucose levels are maintained by endogenous glucose production, hepatic glycogenolysis, and hepatic (and renal) gluconeogenesis

 Hepatic glycogen stores

usually sufficient to maintain plasma glucose levels for approximately 8 hours this time period can be shorter if glucose demand is increased by exercise or if glycogen stores are depleted by illness or starvation

 Gluconeogenesis requires a coordinated

supply of precursors from muscle and adipose tissue to the liver (and kidneys).  Muscle provides lactate, pyruvate, alanine, glutamine, and other amino acids.

 Triglycerides in adipose tissue are broken

down into fatty acids and glycerol, which is a gluconeogenic precursor.  Fatty acids provide an alternative oxidative fuel to tissues other than the brain (which requires glucose).

Systemic glucose balance

 maintenance of the normal plasma glucose

concentration is accomplished by a network of hormones, neural signals, and substrate effects that regulate endogenous glucose production and glucose utilization by tissues other than the brain  Among the regulatory factors, insulin plays a dominant role

 As plasma glucose levels decline within the

physiologic range in the fasting state, pancreatic cell insulin secretion decreases, thereby increasing hepatic glycogenolysis and hepatic (and renal) gluconeogenesis.

 Low insulin levels also reduce glucose

utilization in peripheral tissues, inducing lipolysis and proteolysis, thereby releasing gluconeogenic precursors.  Thus, a decrease in insulin secretion is the first defense against hypoglycemia.

Physiology of Glucose Counterregulation

Physiologic Responses to Decreasing Plasma Glucose Concentrations

 As plasma glucose levels decline just below

the physiologic range, glucose counterregulatory (plasma glucose raising) hormones are released  Among these, pancreatic cell glucagon, which stimulates hepatic glycogenolysis, plays a primary role.

 Glucagon is the second defense against

hypoglycemia.  Adrenomedullary epinephrine, which stimulates hepatic glycogenolysis and gluconeogenesis (and renal gluconeogenesis), is not normally critical.

 However, it becomes critical when glucagon is

deficient.  Epinephrine is the third defense against hypoglycemia.  When hypoglycemia is prolonged, cortisol and growth hormone also support glucose production and limit glucose utilization.

 As plasma glucose levels fall to lower

levels, symptoms prompt the behavioral defense against hypoglycemia, including the ingestion of food

 On the other hand, they shift to lower-

than-normal glucose levels in people with recurrent hypoglycemia, e.g., those with aggressively treated diabetes or an insulinoma. Such patients have symptoms at glucose levels lower than those that cause symptoms in healthy individuals.

Clinical Manifestations
 NEUROGLYCOPENIC SYMPTOMS
direct result of central nervous system (CNS) glucose deprivation

behavioral changes confusion fatigue seizure loss of consciousness if severe and prolonged, death

Clinical Manifestations
 NEUROGENIC (AUTONOMIC)

SYMPTOMS
perception of physiologic changes caused by the CNS-mediated sympathoadrenal discharge triggered by hypoglycemia Adrenergic symptoms
mediated largely by norepinephrine released from sympathetic postganglionic neurons but perhaps also by epinephrine released from the adrenal medullae such as palpitations, tremor and anxiety

Clinical Manifestations
 NEUROGENIC (AUTONOMIC)

SYMPTOMS
Cholinergic symptoms (mediated by acetylcholine released from sympathetic postganglionic neurons) Presents as: Sweating Hunger Paresthesias

Nonspecific symptoms
 Common signs of hypoglycemia include:
Diaphoresis pallor Increase in heart rate and systolic blood pressure but NOT in patients who has experienced repeated, recent episodes of hypoglycemia Transient neurologic focal deficits

 Heart rate and systolic blood pressure are

typically raised, but these findings may not be prominent.  Neuroglycopenic manifestations are often observable.  Transient focal neurologic deficits occur occasionally.  Permanent neurologic deficits are rare.

Etiology and Pathophysiology

 Hypoglycemia is most commonly a result of the treatment of diabetes

Hypoglycemia in Diabetes
 Impact and Frequency  Hypoglycemia is the limiting factor in the

glycemic management of diabetes.  First, it causes recurrent morbidity in most people with type 1 diabetes (T1DM) and many with type 2 diabetes (T2DM) and is sometimes fatal.

 Second, it precludes maintenance of euglycemia

over a lifetime of diabetes and thus full realization of the well-established benefits of glycemic control.

 Third, it causes a vicious cycle of recurrent

hypoglycemia by producing hypoglycemia-associated autonomic failure the clinical syndromes of defective glucose counterregulation and of hypoglycemia unawareness.

 Hypoglycemia is a fact of life for people with T1DM.  They suffer an average of two episodes of symptomatic hypoglycemia per week and at least one episode of severe, at least temporarily disabling, hypoglycemia each year.  An estimated 2 4% of people with T1DM die as a result of hypoglycemia.

 hypoglycemia is less frequent in T2DM.  Metformin, thiazolidinediones, -

glucosidase inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists or analogues, and dipeptidyl peptidase-IV (DPP-IV) inhibitors should not cause hypoglycemia.

 However, they increase the risk when

combined with an insulin secretagogue, such as one of the sulfonylureas, or with insulin.  Notably, the frequency of hypoglycemia approaches that in T1DM as persons with T2DM develop insulin deficiency and require treatment with insulin

Conventional Risk Factors

 for hypoglycemia in diabetes are based on

the premise that relative/absolute insulin excess is the sole determinant of risk.

Relative or absolute insulin excess occurs when:

insulin doses are excessive, ill-timed, or of the wrong type influx of exogenous glucose is reduced (during an overnight fast or following missed meals or snacks) insulin-independent glucose utilization is increased (during exercise)

Relative or absolute insulin excess occurs when:

sensitivity to insulin is increased (with improved glycemic control, in the middle of the night, late after exercise, or with increased fitness or weight loss) endogenous glucose production is reduced (following alcohol ingestion) insulin clearance is reduced (renal failure)

Conventional Risk Factors

(5) endogenous glucose production is reduced (following alcohol ingestion) (6) insulin clearance is reduced (renal failure). However, these conventional risk factors alone explain a minority of episodes; other factors are typically involved.

Hypoglycemia-Associated Autonomic Failure

 Iatrogenic hypoglycemia in diabetes is typically

the result of the interplay of relative or absolute insulin excess and compromised physiologic and behavioral defenses against falling plasma glucose concentrations

 Defective glucose counterregulation

compromises physiologic defense, and hypoglycemia unawareness compromises behavioral defense.

Defective Glucose Counterregulation

 In the setting of endogenous insulin deficiency,

insulin levels do not decrease as plasma glucose levels fall; the first defense against hypoglycemia is lost

Defective Glucose Counterregulation

 Glucagon levels do not increase as plasma

glucose levels fall further; the second defense against hypoglycemia is lost  Finally, the increase in epinephrine levels, the third defense against hypoglycemia, in response to a given level of hypoglycemia is typically attenuated

Defective Glucose Counterregulation

 The glycemic threshold for the

sympathoadrenal (adrenomedullary epinephrine and sympathetic neural norepinephrine) response is shifted to lower plasma glucose concentrations. That is typically the result of recent antecedent iatrogenic hypoglycemia.

Defective Glucose Counterregulation

 The attenuated increment in epinephrine causes

the clinical syndrome of defective glucose counterregulation

 Affected patients are at 25-fold or greater

increased risk of severe iatrogenic hypoglycemia during aggressive glycemic therapy of their diabetes compared with those with normal epinephrine responses.

Hypoglycemia Unawareness
 The attenuated sympathoadrenal response

causes the clinical syndrome of hypoglycemia unawareness  Affected patients are at a sixfold increased risk of severe iatrogenic hypoglycemia during aggressive glycemic therapy of their diabetes.

Hypoglycemia-Associated Autonomic Failure

 Recent antecedent iatrogenic hypoglycemia

(sleep or prior exercise) causes both defective glucose counterregulation and hypoglycemia unawareness.

additional risk factors in diabetes

1) insulin deficiency that indicates that insulin

levels will not decrease and glucagon levels will not increase as plasma glucose levels fall 2) history of severe hypoglycemia or of hypoglycemia unawareness 3) lower HgbA1C levels or lower glycemic goals all other factors being equal

Hypoglycemia Risk Factor Reduction

1. application of the principles of aggressive glycemic therapy 2. patient education and empowerment, frequent self-monitoring of blood glucose, flexible insulin and other drug regimens including the use of insulin analogues, individualized glycemic goals

Hypoglycemia Risk Factor Reduction

3. ongoing professional guidance and support and consideration of both the conventional risk factors and those indicative of compromised glucose counterregulation. In a history of hypoglycemia unawareness, a 2- to 3-week period of scrupulous avoidance of hypoglycemia is indicated.

Hypoglycemia without Diabetes

 Drugs  Critical Illness  Hormone Deficiencies  Non-Beta Cell Tumors  Endogenous Hyperinsulinism

Drugs
 Insulin and insulin secretagogues suppress

glucose production and stimulate glucose utilization  Ethanol blocks gluconeogenesis but not glycogenolysis  Alcohol-induced hypoglycemia typically occurs after a several-day ethanol binge during which the person eats little food, thereby causing glycogen depletion

Drugs
 Salicylates in large doses can cause

hypoglycemia by inhibiting glucose production

Drugs
 Sulfonamides also rarely cause

hypoglycemia by stimulating insulin secretion

Drugs
 Pentamidine is toxic to pancreatic cells. It

causes insulin release initially, with hypoglycemia in about 10% of treated patients, and can cause diabetes later

Drugs
 Quinine also stimulates insulin secretion.

However, the relative contribution of hyperinsulinemia to the pathogenesis of hypoglycemia in critically ill patients with malaria treated with quinine is debated.

Drugs
 Quinolone antibiotics, particularly

gatifloxacin, have been reported to cause hypoglycemia, often in the setting of drugtreated diabetes. Among the antiarrhythmic drugs, quinidine, disopyramide, and cibenzoline have been reported to cause hypoglycemia.

Drugs
 Hypoglycemia has been attributed to many other

drugs, including the nonselective -adrenergic antagonist propanolol.  Glycemic actions of epinephrine and the adrenergic symptoms of hypoglycemia (but not the cholinergic symptoms such as sweating) are mediated by 2adrenergic receptors, it is reasonable to use a relatively selective 1-adrenergic antagonist (atenolol or metoprolol) in a setting in which hypoglycemia might occur.

Critical Illness
 Among hospitalized patients

renal, hepatic, or cardiac failure, sepsis, and inanition are second only to drugs as causes of hypoglycemia.

Critical Illness
 Rapid and extensive hepatic destruction (toxic

hepatitis) causes fasting hypoglycemia because the liver is the major site of endogenous glucose production.

Critical Illness
 The mechanism of hypoglycemia in patients

with cardiac failure is unknown. It may involve hepatic congestion and hypoxia.

Critical Illness
 Although the kidneys are a source of glucose

production, hypoglycemia in patients with renal failure is also caused by the reduced clearance of insulin and reduced mobilization of gluconeogenic precursors in renal failure.

Critical Illness
 Sepsis is a relatively

common cause of hypoglycemia. Increased glucose utilization is induced by cytokine production in macrophage-rich tissues such as the liver, spleen, and lung. Hypoglycemia develops if glucose production fails to keep pace.

Critical Illness
 Cytokine-induced inhibition of gluconeogenesis in the

setting of nutritional glycogen depletion, in combination with hepatic and renal hypoperfusion.

Critical Illness
 Hypoglycemia can be seen with starvation, perhaps

because of loss of whole-body fat stores and subsequent depletion of gluconeogenic precursors (amino acids), necessitating increased glucose utilization.

Hormone Deficiencies
 Neither cortisol nor growth hormone is critical to

the prevention of hypoglycemia, at least in adults. Nonetheless, hypoglycemia can occur with prolonged fasting in patients with primary adrenocortical failure or hypopituitarism.

Hormone Deficiencies
 Anorexia and weight loss are typical features of

chronic cortisol deficiency

result in glycogen depletion

Hormone Deficiencies
 Cortisol deficiency is associated with impaired

gluconeogenesis and low levels of gluconeogenic precursors

suggests that substrate-limited gluconeogenesis, in the setting of glycogen depletion, is the cause of hypoglycemia.

Hormone Deficiencies
 Growth hormone deficiency can cause

hypoglycemia in young children

Hormone Deficiencies
 High rates of glucose utilization (during

exercise or in pregnancy) or low rates of glucose production (following alcohol ingestion) can precipitate hypoglycemia in adults with previously unrecognized hypopituitarism

Endogenous Hyperinsulinism
 Caused by:

a primary cell disorder Insulinoma or a functional cell disorder with cell hypertrophy or hyperplasia

Endogenous Hyperinsulinism
 Caused by:

cell secretagogue such as a sulfonylurea autoantibody to insulin ectopic insulin secretion more likely in an overtly healthy individual without clues to other potential causes of hypoglycemia Accidental, surreptitious, or even malicious administration of an insulin secretagogue or insulin

Reactive Hypoglycemia
 postprandial hypoglycemia occurs

exclusively after meals. Its diagnosis requires documentation of Whipple's triad after a mixed meal.  The diagnosis should not be made on the basis of seemingly low venous plasma glucose concentrations after an oral glucose load.

Reactive Hypoglycemia
 It can occur following gastrectomy

alimentary hypoglycemia result of early hyperinsulinemia caused by rapid increments in plasma glucose enhanced secretion of the gut incretin GLP-1 coupled with suppression of glucagon secretion by GLP-1

 Administration of

-glucosidase inhibitor (acarbose or miglitol) is a conceptually attractive treatment, although controlled clinical trials documenting its efficacy are lacking.

Reactive hypoglycemia
 occurs in patients with autoantibodies to insulin and in the noninsulinoma pancreatogenous hypoglycemia syndrome  Affected patients have symptomatic hyperinsulinemic postprandial hypoglycemia (but negative 72-h fasts) that remits following partial pancreatectomy

 Histologic findings include cell hypertrophy with or without hyperplasia

 similar syndrome following Roux-en-Y gastric

bypass surgery for obesity has been described

 In any event, caution should be exercised before labeling a person with a diagnosis of hypoglycemia.  Frequent feedings, avoidance of simple sugars, and high-protein diets are commonly recommended to patients thought to have idiopathic reactive hypoglycemia.  The efficacy of these approaches has not been established by controlled clinical trials.

Factitious and Artifactual Hypoglycemia

 Factitious hypoglycemia,
 caused by surreptitious or even malicious

administration of insulin or an insulin secretagogue  shares many clinical and laboratory features with insulinoma

Factitious and Artifactual Hypoglycemia

 most common among health care workers, patients with diabetes or their relatives, and people with a history of other factitious illnesses.  should be considered in all patients being evaluated for hypoglycemia of obscure cause  Accidental ingestion of an insulin secretagogue (the result of a pharmacy error) also occurs

 Analytical error in the measurement of plasma

glucose concentrations is rare  Even with a quantitative method, low measured glucose concentrations can be artifactual the result of continued glucose metabolism by the formed elements of the blood ex vivo particularly in the presence of leukocytosis, erythrocytosis, or thrombocytosis, or if separation of the serum from the formed elements is delayed (pseudohypoglycemia)

Approach to the Patient

 In addition to recognition and documentation

of hypoglycemia, and often urgent treatment, diagnosis of the hypoglycemic mechanism is critical for choosing a treatment that prevents, or at least minimizes, recurrent hypoglycemia

Recognition and Documentation

 Hypoglycemia is suspected in patients with typical symptoms 1. presence of confusion 2. altered level of consciousness or a seizure 3. a clinical setting in which hypoglycemia is known to occur

 URGENT TREATMENT is often necessary in

patients with suspected hypoglycemia  Blood should be drawn, whenever possible, before the administration of glucose to allow DOCUMENTATION of a low plasma glucose concentration  Convincing documentation of hypoglycemia requires the fulfillment of Whipple's triad

 Ideal time to measure the plasma glucose level is

during a symptomatic episode  A normal glucose level excludes hypoglycemia as the cause of the symptoms

 A low glucose level confirms that hypoglycemia is the cause of the symptoms, provided the latter resolve after the glucose level is raised

 When the cause of the hypoglycemic episode is obscure, additional measurements, while the glucose level is low and before treatment, should include:
plasma insulin C-peptide ethanol concentrations levels of insulin secretagogues

 A distinctly low plasma glucose concentration measured in a patient without corresponding symptoms raises the possibility of an artifact (pseudohypoglycemia)

Diagnosis of the Hypoglycemic Mechanism

 DRUGS, particularly those used to treat diabetes or

alcohol, should be the first consideration, even in the absence of known use of a relevant drug, given the possibility of surreptitious, accidental, or malicious drug administration.

Urgent Treatment
Oral treatment with glucose tablets or glucosecontaining fluids, candy, or food  A reasonable initial dose is 20 g of glucose. If the patient is unable or unwilling (because of neuroglycopenia) to take carbohydrates orally, parenteral therapy is necessary.


Urgent Treatment
 Intravenous glucose (25 g) should be given and followed by a glucose infusion guided by serial plasma glucose measurements

 If intravenous therapy is not practical, subcutaneous or

intramuscular glucagon (1.0 mg in adults) can be used, particularly in patients with T1DM.
acts by stimulating glycogenolysis glucagon is ineffective in glycogen-depleted individuals (those with alcohol-induced hypoglycemia) stimulates insulin secretion and is therefore less useful in T2DM

 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.

Prevention of Recurrent Hypoglycemia

 Reduction or discontinuation of offending drugs  Treatment of underlying critical illnesses

Prevention of Recurrent Hypoglycemia

 Replacement of cortisol and growth hormone if they are deficient  Surgical, radiotherapeutic, or chemotherapeutic reduction of a non islet cell tumor can alleviate hypoglycemia even if the tumor cannot be cured;  Glucocorticoid or growth hormone administration

Prevention of Recurrent Hypoglycemia

 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 cell disorder  Partial pancreatectomy may be necessary

Prevention of Recurrent Hypoglycemia

 Frequent feedings  Avoidance of fasting

 Treatment of autoimmune hypoglycemia (with a glucocorticoid or immunosuppressive drugs) is problematic, but the disorders are often selflimited  Administration of uncooked cornstarch at bedtime or even an overnight intragastric infusion of glucose may be necessary in some patients

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