User:Alteripse/hypoglycemia workshop 2 diag w/u

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Hundreds of conditions can cause hypoglycemia (below, and Causes of hypoglycemia). While many other aspects of the medical history and physical examination may be informative, the two best guides to the cause of unexplained hypoglycemia are usually

1. the circumstances
2. a critical sample of blood obtained at the time of hypoglycemia, before it is reversed.

The circumstances include the age of the patient, time of day, time since last meal, previous episodes, nutritional status, physical and mental development, drugs or toxins (especially insulin or other diabetes drugs), diseases of other organ systems, physical abnormalities, family history, and response to treatment. When hypoglycemia occurs repeatedly, a record or "diary" of the spells over several months, noting the circumstances of each spell (time of day, relation to last meal, nature of last meal, response to carbohydrate, and so forth) may be very useful in determining the nature and cause of the hypoglyemia.

The following are the most relevant aspects of the history, but note that the specific diseases mentioned are examples rather than the only condition associated with each item.

• AGE: Factors contributing to hypoglycemia in the first day of life differ from common causes in older children. Even beyond the newborn period, causes vary by age. Young adults have a different range of probable causes than older adults. See below for common causes by age.

• TIME OF DAY & TIME SINCE LAST MEAL: Fasting hypoglycemia has different causes than postprandial. E.g., ketotic hypoglycemia is the most common hypoglycemia occurring before breakfast in young children past the first year of life.

• PREVIOUS EPISODES: If a truly low blood sugar has been discovered, a history of similar episodes increases the likelihood of significant organic disease and gives clues to the nature. E.g., ingestion or drug effect is less likely.

• NUTRITIONAL STATUS: Obesity or large size suggests hyperinsulinism. E.g., a large for gestational age newborn suggests maternal diabetes. Children with ketotic hypoglycemia are usually underweight for height. Adults with chronic hyperinsulinism due to a pancreatic tumor will usually have gained weight.

• PHYSICAL & MENTAL DEVELOPMENT: Growth failure with onset in the second 6 months of life suggests hypopituitarism or a significant inborn error of metabolism, such as glycogen storage disease. Developmental delay also points toward congenital metabolic diseases.

• DRUGS OR TOXINS: See Causes of hypoglycemia for a detailed list of drugs which may cause or predispose to hypoglycemia. A toddler with a sudden onset of hypoglycemia is at highest risk of this cause; alcohol and grandparent's diabetes pills are notorious. An older adult on multiple medications may well be suffering a drug interaction amplifying the hypoglycemic effect of one of the drugs.

• DISEASES OF OTHER ORGAN SYSTEMS: Advanced dysfunction of most of the major organ systems may cause or contribute to hypoglycemia. This is primarily an intensive care unit problem.

• FAMILY HISTORY: There are a few inherited diseases in which hypoglycemia is a major aspect {e.g., glycogen storage disease). There are others in which different family members may have different types of problems (e.g., polyglandular autoimmunity). Ethnic ancestry is occasionally a useful clue, as certain inherited diseases are more common in certain populations (e.g., K_{ATP channel hyperinsulinism in Ashkenazi Jews. For a newborn with hypoglycemia, maternal glucose status is an important piece of information, since maternal hyperglycemia (even unsuspected) is a common cause of hypoglycemia due to hyperinsulinism in the first two days of life.}

• _{RESPONSE TO TREATMENT: When 15-30 grams of sugar or starch are given by mouth, a low blood glucose will usually rise by 18-36 mg/dl (1-2 mmol/l) within 5-10 minutes, relieving hypoglycemic symptoms within 10 minutes. It may take longer to recover from severe hypoglycemia with unconsciousness or seizure even after restoration of normal blood glucose. When a person has not been unconscious, failure of carbohydrate to reverse the symptoms in 10-15 minutes increases the likelihood that hypoglycemia was not the cause of the symptoms. When severe hypoglycemia has persisted in a hospitalized patient, the amount of glucose required to maintain satisfactory blood glucose levels becomes an important clue to the underlying etiology. Glucose requirements above 10 mg/kg/minute in infants, or 6 mg/kg/minute in children and adults are strong evidence for hyperinsulinism. In this context it is referred to as the glucose infusion rate (GIR). Finally, the blood glucose response to glucagon given when the glucose is low can also help distinguish among various types of hypoglycemia. A rise of blood glucose by more than 30 mg/dl (1.7 mmol/l) suggests insulin excess as the probable cause of the hypoglycemia.}

_{Rarely, PHYSICAL ABNORMALITIES apparent to examination provide clues to the cause of hypoglycemia: E.g., omphalocele (Beckwith-Wiedemann syndrome), hepatomegaly (glycogen storage disease), micropenis (hypopituitarism).}

_{The critical sample is the other important clue to the cause of hypoglycemia. Hormone and metabolite levels obtained at the time of hypoglycemia, before it is reversed, can provide information that would otherwise require a several-thousand-dollar hospital admission and unpleasant starvation testing. For severe hypoglycemia of unknown cause, the serum should be used for as many as possible of the following tests, roughly in order of importance.}

• _{Glucose is needed to confirm that the problem is hypoglycemia, and for interpretation of most of the other levels.}

• _{Insulin levels range from undetectable to several hundred μU/ml and over a few minutes can change as rapidly as glucose. It is usually the highest priority test, but is of no value if not obtained simultaneously with a low blood sugar. Insulin levels above 1 μU/ml at the time of hypoglycemia implicate hyperinsulinism as the probable cause of hypoglycemia.}

• _{Cortisol should rise above 10 μg/dl in response to hypoglycemia at any age. Lower levels suggest adrenal failure or hypopituitarism.}

• _{Growth hormone should rise above 10 ng/ml in response to hypoglycemia at any age. Low levels suggest possible growth hormone deficiency or hypopituitarism.}

• _{Urine and serum ketones (acetone, acetoacetate, and β-hydroxybutyrate) normally rise as insulin levels fall (e.g., prolonged fasting and most types of hypoglycemia). Absence of ketosis at the time of hypoglycemia usually indicates hyperinsulinism or defective ketogenesis (as in certain mitochondrial fatty acid oxidation disorders).}

• _{Electrolytes should be part of the initial tests for an ill-appearing patient. Various patterns of abnormality may reflect major organ system dysfunction, poisoning, severe ketosis, or disorders of gluconeogenesis.}

_{The following tests also must be obtained at the time of hypoglycemia to be interpretable, and may be essential for certain diagnoses. Because they require larger amounts of blood or special tubes, or are useful in only a few circumstances, they are used more selectively.}

• _{Lactic acid (or lactate) is most likely to be useful in severely ill patients with vomiting, hepatomegaly, or prior episodes. Lactic acidosis occurs with (a) circulatory failure and (b) many metabolic disorders, especially those involving gluconeogenesis (e.g., type I glycogenosis).}

• _{Free fatty acids (or non-esterified fatty acids) rise during fasting as a result of lipolysis. Typical FFA levels after overnight fasting are 0.5-1.5 mmol/l in infants and young children, slightly lower in older children and adults, and rise with prolonged fasting. Inappropriately low levels at the time of hypoglycemia suggest hyperinsulinism.}

• _{Beta-hydroxybutyrate is one of the ketone bodies described above. βOHB, or BOHB, is typically less than 1 mmol/l after an overnight fast in infants, and less than 0.5 in older children and young adults. Levels rise 3- to 4-fold with more prolonged starvation. Postprandial levels should be nearly undetectable. Low levels during hypoglycemia suggest hyperinsulinism.}

• _{Alanine is the principal amino acid substrate for gluconeogenesis. Because alanine values vary by age, dietary protein, time since meal, and laboratory, they must be interpreted with caution and consideration of other evidence.}

• _{Glucagon plays a crucial role in promoting glycogenolysis, and should rise above 120 pg/ml in any type of hypoglycemia. However, because it requires a larger serum sample in a special tube, and because clinically significant deficiency is rare, this test is seldom obtained.}

• _{Epinephrine (adrenaline) is an important mediator of both glycogenolysis and lipolysis in response to hypoglycemia of any type, usually rising above 100 pg/ml. Although it may be measured in suspected autonomic failure, it provides little additional information when prominent adrenergic symptoms and signs are present.}

• _{C-peptide is released as a byproduct when insulin is released from the pancreas or a tumor of the pancreas. Because C-peptide is not present in animal or synthetic human insulin products, measurement during hypoglycemia can help distinguish endogenous from exogenous hyperinsulinism. Levels of 1-2 ng/ml occur with significant endogenous insulin secretion. A significant insulin level with undetectable C-peptide indicates exogenous hyperinsulinism (insulin-dependent diabetes, malicious or factitious insulin injection).}

• _{Proinsulin is cleaved to produce C-peptide and insulin in beta cells and is normally present in the circulation in amounts under 20% of the insulin level. Disproportionate levels in hypoglycemic patients with endogenous hyperinsulinism indicate an insulinoma.}

• _{Ethanol (alcohol) ingestion can cause severe hypoglycemia and metabolic acidosis in a previously healthy toddler, although it rarely causes severe hypoglycemia in adolescents and adults.}

_{The following tests can be useful even when the glucose is not low.}

• _{Uric acid rises (to 5-12 mg/dl, typically) in several types of congenital metabolic disease (e.g., type I glycogenosis), especially those involving lactic acidosis. Similar levels can occur in diarrheal dehydration or acute renal failure.}

• _{Thyroxine (T4) and triiodothyronine (T3) are worth checking if hypopituitarism is suspected.}

• _{Ammonia is elevated in congenital hyperinsulinism due to glutamic acid dehydrogenase mutations, in Reye's syndrome, and in advanced liver failure.}

• _{Liver enzymes and ammonia rise with Reye's syndrome, sepsis, hepatitis, and some metabolic diseases.}

• _{Carnitine should be measured when a mitochondrial fatty acid oxidation disorder is suspected. Free carnitine levels in young, fasting children are usually above 30 μmol/L, but normal ranges vary by laboratory.}

• _{IGF-1 (insulin-like growth factor 1) is a good screen for growth hormone deficiency after early infancy. Low levels (especially under 20 ng/ml) are consistent with growth hormone deficiency, but also with undernutrition.}

• _{IGF-2 (insulin-like growth factor 2 or II) is useful in only two suspected diagnoses. Levels are low in severe growth hormone deficiency (usually below 200 ng/ml). Mild elevations of IGF-2 (above 300) have been found in a few cases of solid tumor hypoglycemia, mainly in adults; it was suspected that IGF-2 was cross-reacting with insulin receptors.}

• _{Urine organic acids are abnormal in a variety of congenital metabolic diseases. Dicarboxylic acids is suggestive of mitochondrial oxidation defects, whereas ketoacids occur with ordinary ketotic hypoglycemia as well as other conditions involving poor food intake and stress. Urine amino acids are rarely useful in the work-up of hypoglycemia.}

• _{Toxic screen or drug screen for oral hypoglycemic agents (especially sulfonylureas), salicylate, acetominophen, methanol and other alcohols, etc., is most likely to yield useful information in the young child with no previous history of hypoglycemia, or an obtunded older adult.}

• _{Insulin antibodies (of several types) occur mainly in three situations: in the prodromal phase and for several years after diagnosis of type 1 diabetes; after repeated injection of exogenous insulin; and in the rare syndrome of insulin autoimmunity, in which the antibodies alter endogenous insulin kinetics, causing sporadic episodes of insulin-induced hypoglycemia.}