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 AdultsIll or Medicated Individual

Drugs Causes of Hypoglycemia in Adults

Insulin or insulin secretagoguesAlcohol

Critical Illness Hepatic, renal or cardiac failureSepsisInanition

Hormone Deficiency CortisolGlucagon and epinephrine (IDDM)

Non-islet cell tumor

Causes of Hypoglycemia in Adults

Seemingly well individual

Endogenous hyperinsulinism InsulinomaFunctional beta cell disorders (nesidioblastosis) -Non-insulinoma pancreatogenous hypoglycemia - Post-gastric bypass hypoglycemiaInsulin autoimmune hypoglycemia - Antibody to insulin - Antibody to insulin receptorInsulin 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 changesconfusion fatigueseizure 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 post-ganglionic 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 PathophysiologyHypoglycemia 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 Reduction1. application of the principles of

aggressive glycemic therapy2. 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 Reduction3. 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 drug-treated 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 β -adrenergic antagonist propanolol.

Glycemic actions of epinephrine and the adrenergic symptoms of hypoglycemia (but not the cholinergic symptoms such as sweating) are mediated by β2-adrenergic receptors, it is reasonable to use a relatively selective β1-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 α-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 confusion2.altered level of consciousness or a

seizure3.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

glucose-containing 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

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

Prevention of Recurrent Hypoglycemia

Treatment of autoimmune hypoglycemia (with a glucocorticoid or immunosuppressive drugs) is problematic, but the disorders are often self-limited

Administration of uncooked cornstarch at bedtime or even an overnight intragastric infusion of glucose may be necessary in some patients

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