Articles on Medical Diseases and Conditions

Month: December 2009

  • Thyroid Function Tests: Total serum thyroxine

    T4 can be measured directly by radioassay (or, more recently, by enzyme-linked assay). Radioassay involves competition of patient hormone and radioactive hormone for a hormone binder. In T4by radioimmunoassay (T4-RIA) the binder is anti-T4antibody; in T4 competitive binding (T4-CPB) or T4 displacement methods (T4-D) the binder is T4-binding serum protein. After patient T4 and radioactive T4 have reacted with the T4 binder, the bound complex is separated from the free (unbound) hormone and the radioactivity in either the bound or free fraction is counted. The amount of patient T4 determines the amount of radioactive T4 allowed to attach to the binder. There is general (but not unanimous) agreement that T4 values are not greatly changed in old age.

    Results in thyroid disease. The sensitivity of T4 assay is approximately 95% (literature range, 90%-100%) for hyperthyroidism, and approximately 92% (literature range, 54%-100%) for hypothyroidism. There is some difficulty in evaluating T4 data for hypothyroidism from the literature since patients with a temporary T4 decrease from thyroiditis or severe non thyroid illness may be included with patients having true primary hypothyroidism in some reports.

    Drawbacks. As noted previously, more than 99% of total serum T4 is protein bound, so that the contribution of free T4 to the test results is negligible. Therefore, serum T4 by any current method essentially measures protein-bound T4 and will be affected by alterations in T4-binding proteins. These alterations may be congenital, drug induced, or secondary to severe non thyroid illness. As a rule of thumb, estrogens from pregnancy or birth control medication increase T4 levels by increasing TBG levels, and amphetamine abuse is reported to increase T4 levels in some patients by increasing pituitary secretion of TSH. Most other drugs that affect T4 produce decreased T4 levels by decreasing TBG levels or T4 binding to TBG (or albumin). Medications that may affect T4 assay are listed in Table 37-14. The most commonly encountered medication problems, in my experience, are associated with administration of levothyroxine (Synthroid), estrogens, or phenytoin (Dilantin). Like phenytoin, valproic acid, furosemide, and some of the nonsteroidal anti inflammatory drugs can decrease T4 levels by displacing T4 from its binding proteins. However, these medications, especially furosemide, are often administered to patients who already have severe non thyroid illness, so that it may be difficult to separate the effect of the drug from the effect of the illness.

    Another condition producing false T4 increase is familial dysalbuminemic hyperthyroxinemia (FDH), which is uncommon but not rare. This is a congenital condition transmitted as an autosomal dominant trait, which results in production of an albumin variant that has an increased degree of T4 binding (albumin normally has only a weak affinity for T4). Therefore, in FDH more T4 binds to albumin, which raises serum total T4 values. Thyroid function is not affected and there apparently is no association with disease. Yet another cause for false T4 elevation is the very uncommon syndrome of peripheral resistance to T4. Peripheral tissue utilization of T4 is decreased to variable degree; whether symptoms develop depends to some extent on the degree of “resistance.” The pituitary response to T4 feedback may be decreased in some patients. Total T4, free T4, and total T3 are elevated; serum THBR (T3U), TSH, and TSH response in the TRH test are normal or elevated.

    With the possible exception of TBG alterations, the most frequent false abnormalities in T4 are produced by severe non thyroidal illness (see the box). Severe non thyroid illnesses or malnutrition of various etiologies may decrease T4 below the lower limits of the T4 reference range.

    Some Nonthyroid Illnesses that Can Affect Thyroid Tests

    Cirrhosis or severe hepatitis
    Renal failure
    Cancer
    Chemotherapy for cancer
    Severe infection or inflammation
    Trauma
    Postsurgical condition
    Extensive burns
    Starvation or malnutrition
    Acute psychiatric illness

    The incidence of decreased T4 is roughly proportional to the severity of illness. Therefore, the overall incidence of decreased T4 in non thyroid illness is low but in severe illness reports indicate decreased T4 levels in approximately 20%-30% of cases (literature range, 9%-59%). In fewer cases the free T4 index (TI) or even free T4 assay (especially analog methods) is reduced below reference limits. On the other hand, in the majority of patients, and in patients without alterations in albumin or TBG, the T4 remains within reference range (although possibly decreased from baseline values). In occasional patients (for poorly understood reasons) the T4 value may be mildly elevated. This has been called “sick euthyroid syndrome” by some investigators. The TSH value may decrease in severe non thyroid illness somewhat parallel to T4 but to a lesser extent, usually (but not always) remaining within reference range. In the recovery phase, TSH levels increase before or with T4 and could temporarily even become elevated. The THBR value in severe non thyroid illness is most often normal but may be mildly increased, reflecting decreased TBG levels. Occasionally the THBR is decreased, mainly in acute hepatitis virus hepatitis

    Cushing’s syndrome produces a mild or moderate T4 decrease below lower limit of reference range in two thirds or more of patients. Free T4 (FT4) levels are usually normal.

    Conditions producing a decrease in T4 are listed in the box and conditions producing an increase in T4 are listed in the box.

    One group of conditions involves certain iodine-containing substances. For many years it was thought that neither organic iodine nor inorganic iodide would interfere with T4 by immunoassay methods. However, it was subsequently found that a few x-ray contrast media such as ipodate (Oragrafin) and iopanoic acid (Telepaque) can elevate

    Causes for Decreased Thyroxine or Free Thyroxine Values

    Lab error
    Primary hypothyroidism
    Severe non thyroid illness;* many patients
    Lithium therapy; some patients
    Severe TBG decrease (congenital, disease, or drug-induced) or severe albumin decrease*
    Dilantin, Depakene, or high-dose salicylate drugs*
    Pituitary insufficiency
    Large doses of inorganic iodide (e.g., SSKI)
    Moderate or severe iodine deficiency
    Cushing’s syndrome
    High-dose glucocorticoid drugs; some patients
    Pregnancy, third trimester (low-normal or small decrease)
    Addison’s disease; some patients (30%)
    Heparin effect (a few FT4 kits)
    Desipramine or amiodarone drugs; some patients
    Acute psychiatric illness; a few patients
    ___________________________________________________________________
    *FT4 less affected than T4; two-step FT4 method affected less than analog FT4 method.

    T4values above reference range in some patients and that the iodinated antiarrhythmic drug amiodarone can produce temporary hyperthyroidism in some patients and hypothyroidism in others. These compounds do not affect the T4 assay directly but can increase T4 values by certain metabolic actions (e.g., blocking of T4 deiodination) that are still being investigated. Effects of iodine on the thyroid will be discussed in detail later

  • Thyroid Function Tests: Thyroid hormone-binding ratio (THBR; T3 uptake)

    The THBR is a variant of what is commonly known as the T3 uptake, or T3U. T3U does not measure T3, as its name might imply, but instead estimates the amount of non occupier (unsaturated) thyroid hormone-binding sites on serum protein. Therefore, the American Thyroid Association has recommended that the name thyroid hormone-binding ratio replace the name T3 uptake. The T3U was originally used as a substitute for direct T4 measurement. Radioactive T3 placed into patient serum competes for binding sites both with patient serum proteins and with a special hormone-binding resin (or other added binding material). The number of T3 binding sites available on serum proteins depends primarily on the amount of T4 occupying the protein binding sites, since T4 molecules greatly outnumber T3 molecules. Radioactive T3 not able to bind to protein is forced onto the resin. Therefore, the greater the amount of T4 bound to protein, the fewer protein binding sites are available for radioactive T3, and the greater is the radioactive T3 uptake by the resin.

    Several modifications of the basic resin uptake procedure are sold by commercial companies. Although the various kits in general give similar results, in my experience there have been definite and significant differences between some of the kits. In particular, some may produce occasional and inexplicable mildly decreased results. There also is some confusion in the way that resin uptake results are reported. Most T3 uptake kits use a reference range expressed in percent of resin uptake. A few count radioactivity in the serum proteins, which produces opposite values to those derived from resin uptake. Some kits (including the THBR) report results as a ratio between resin uptake and a “normal” control.

    Results in thyroid disease. As a thyroid function test, THBR becomes an indirect estimate of T4 when the quantity of thyroxine-binding protein is normal, since the number of T3 binding sites is determined primarily by the amount of T4 and the amount of binding protein. There are rather widely variant opinions on diagnostic accuracy of THBR in thyroid disease. Some reports were highly favorable, although recent ones tend to be less so. There is reasonably good sensitivity for hyperthyroidism (approximately 80%, with a literature range of 46%-96%). The test is not affected by iodine. However, there is relatively poor separation of normal from hypothyroid conditions (sensitivity for hypothyroidism is approximately 50%-60%, with a literature range of 27%-92%).

    Drawbacks. Problems in diagnosis of hypothyroidism were mentioned previously. Also, since the test depends on the number of binding sites, changes in the amount of thyroxine-binding protein will affect results. Increased TBG decreases the THBR, and decreased TBG or medications (such as Dilantin) that bind to TBG increase THBR. TBG alterations may be congenital, drug induced, or produced by non thyroid illness (see the box). There is interference by a considerable number of medications, the majority of which also affect serum T4 assay (see Table 37-14). In addition, atrial fibrillation, severe acidosis, or hypoalbuminemia have been reported to sometimes falsely increase the THBR. Current use of the THBR is mainly as an adjunct to a T4 assay to provide a warning of alterations in T4-binding protein. The THBR can also be of some help in ruling out laboratory error as a cause for T4 elevation; if both the T4 and resin uptake levels are increased, the T4 elevation is probably genuine.

    Causes for Increased or Decreased Thyroxine-Binding Globulin

    I. Increased TBG
    A. Increased estrogens
    1. Pregnancy
    2. Oral contraceptives
    3. Estrogen therapy
    B. Other medications
    1. Perphenazine (Trilafon) occasionally
    2. Heroin and methadone (variable degree)
    C. Severe liver disease
    1. Severe acute hepatitis
    2. Severe cirrhosis (occasionally)
    D. Congenital
    E. Acute intermittent porphyria
    F. Human immunodeficiency virus (HIV) infection
    II. Decreased TBG
    A. Certain medications
    1. Androgens
    2. Drugs that compete with T4and T3 for binding sites on TBG or albumin (e.g., phenytoin, valproic acid, Ponstel, salicylate)
    B. Severe non thyroidal illness
    C. Congenital decrease
    D. Nephrotic syndrome or conditions leading to severe hypoalbuminemia

  • Thyroid Function Tests: Radioactive iodine uptake

    Radioactive iodine uptake is an indirect estimate of thyroid hormone production based on the need of the thyroid for iodine to make thyroid hormone, which, in turn, depends on the rate of thyroid hormone synthesis. A small dose of radioactive iodine is given, and a radiation detector measures the amount present in the gland at some standard time (usually 24 hours after the dose). The radioactive iodine uptake (RAIU) measurement is one of the oldest currently used thyroid function tests, but it has several drawbacks:

    Thyroid Function Tests*

    I. Thyroid uptake of iodine
    A. RAIU
    II. Thyroxine tests
    A. “Direct” measurement
    1. T4 by RIA or EIA
    2. Free T4assay
    B. “Indirect” measurement
    1. THBR (T3 uptake, or T3U)
    2. Free T4 index
    III. Triiodothyronine tests
    A. T3-RIA
    IV. Pituitary and hypothalamic function tests
    A. TSH assay
    B. TRH assay
    V. Other
    A. Stimulation and suppression tests
    B. Thyroid scan
    C. Thyroid autoantibody assay

    *RAIU = radioactive iodine uptake; = radioimmunoassay; EIA = enzyme immunoassay; THBR = thyroid hormone–binding ratio; TRH = thyrotropin-releasing hormone.

    1. The RAIU result is falsely normal in 50%-70% (literature range, 20%-80%) of patients with hyperthyroidism due to toxic nodules.
    2. The RAIU results are affected by a considerable number of medications (see Table 36-24) and may be elevated during the last trimester of pregnancy.
    3. Any condition that alters thyroid requirements for iodine will affect the RAIU response. Iodine deficiency goiter elevates RAIU results, and some reports indicate that elevation for similar reasons occurs in 25%-50% of patients with cirrhosis. Excess iodine in the blood contained in certain medicines (inorganic iodide) or in x-ray contrast media (organic iodine) competes with radioactive iodine for thyroid uptake, thereby preventing uptake of some radioactive iodine and falsely decreasing test results.
    4. The standard 24-hour uptake requires two patient visits and 2 days.
    5. Normal values are uncertain due to increasing environmental and foodstuff iodine content. Before 1960 the average 24-hour RAIU reference range was 15%-40%. Reports from 1960-1970 suggest a decrease of the range to 8%-30%. There have been little recent data on this subject, and most nuclear medicine departments are unable to obtain reference values for their own locality.
    6. Occasionally patients with hyperthyroidism have unusually fast synthesis and release (turnover) of T4 and T3. The RAIU measurement depends not only on uptake of radioactive iodine but also on retention of the radioactive iodine (incorporated into hormone) within the gland until the amount of radioactivity within the gland is measured. By 24 hours a significant amount of newly formed hormone may already be released, providing falsely lower thyroid radioactivity values compared with earlier (2-6 hours) uptake measurements.
    7. The RAIU provides relatively poor separation of normal from hypothyroid persons. Before 1960, approximate sensitivity of the RAIU was 90% for hyperthyroidism and 85% for hypothyroidism. Current RAIU sensitivity in thyroid disease is difficult to determine because of reference range problems. However, sensitivity is probably about 80% for hyperthyroidism and about 50%-60% for hypothyroidism. One study found that patients over age 65 may have a higher incidence of normal 24-hour RAIU than younger persons. The 24-hour RAIU was normal in 15% of hyperthyroid patients under age 65 and 41% of those over age 65. Various factors can decrease the RAIU besides severe destruction of thyroid tissue (see the box).
    8. The patient receives a certain small amount of radiation (especially if a scan is done), whereas thyroid hormone assays, even those using radioisotopes, are performed outside the patient’s body and therefore do not deliver any radiation to the patient.

    Etiologies of Decreased Radioactive Iodine Uptake Values

    Hypothyroidism, primary or secondary
    Technical error
    Excess organic iodine or inorganic iodide with euthyroidism
    Subacute thyroiditis
    Painless (silent) thyroiditis
    Postpartum transient toxicosis
    Chronic (Hashimoto’s) thyroiditis (some patients)
    Amiodarone-induced hyerthyroidism
    Self-administered (factitious) thyroid hormone intake
    Iodide-induced (Jod-Basedow) hyperthyroidism
    Struma ovarii

    These difficulties have precluded use of the RAIU measurement for screening purposes. However, RAIU in conjunction with the thyroid scan has definite value in patients when there is laboratory evidence of hyperthyroidism. As will be discussed later, the RAIU can help differentiate between primary hyperthyroidism and hyperthyroidism secondary to thyroiditis or self-administration of thyroid hormone; and the thyroid scan can differentiate Graves’ disease from Plummer’s disease.

  • Thyroid Function Tests

    The classic picture of hyperthyroidism or hypothyroidism is frequently not complete and may be totally absent. There may be only one noticeable symptom or sign, and even that may be vague or misleading or suggestive of some other disease. The physician must turn to the laboratory to confirm or exclude the diagnosis.

    There is a comparatively large group of laboratory procedures that measure one or more aspects of thyroid function (see the box). The multiplicity of these tests implies that none is infallible or invariably helpful. To get best results, one must have a thorough knowledge of each procedure, including what aspect of thyroid function is measured, sensitivity of the test in the detection of thyroid conditions, and the rate of false results caused by non thyroid conditions. In certain cases, a brief outline of the technique involved when the test is actually performed helps clarify some of these points.

  • Signs and Symptoms of Thyroid Disease

    Many persons have at least one sign or symptom that could suggest thyroid disease. Unfortunately, most of these signs and symptoms are not specific for thyroid dysfunction. Enumeration of the classic signs and symptoms of thyroid disease is the best way to emphasize these facts.

    Hyperthyroidism

    Thyrotoxicosis from excess secretion of thyroid hormone is usually caused by a diffusely hyperactive thyroid (Graves’ disease, about 75% of hyperthyroid cases) or by a hyperfunctioning thyroid nodule (Plummer’s disease, about 15% of hyperthyroid cases). A much less common cause is iodine-induced hyperthyroidism (Jod-Basedow disease), and rare causes include pituitary overproduction of TSH, ectopic production of thyroid hormone by the ovary (struma ovarii), high levels of chorionic gonadotropin (with some thyroid-stimulating activity) from trophoblastic tumors, and functioning metastic thyroid carcinoma. Thyroiditis (discussed later) may produce symptoms of thyrotoxicosis (comprising about 10% of hyperthyroid cases), but the symptoms are caused by leakage of thyroid hormones from damaged thyroid tissue rather than over secretion from intact tissue. Many hyperthyroid patients have eye signs such as exophthalmos, lid lag, or stare. Other symptoms include tachycardia; warm, moist skin; heat intolerance; nervous hyperactive appearance; loss of weight; and tremor of fingers. Less frequent symptoms are diarrhea, atrial fibrillation, and congestive heart failure. The hemoglobin level is usually normal; the white blood cell (WBC) count is normal or slightly decreased. There is sometimes an increase in the lymphocyte level. The serum alkaline phosphatase level is elevated in 42%-89% of patients. In elderly patients the clinical picture is said to be more frequently atypical, with a higher incidence of gastrointestinal symptoms, atrial fibrillation, and apathetic appearance.

    Hypothyroidism

    Myxedema develops from thyroid hormone deficiency. Most common signs and symptoms include nonpitting edema of eyelids, face, and extremities; loss of hair in the outer third of the eyebrows; large tongue; cold, dry skin; cold intolerance; mood depression; lethargic appearance; and slow mental activity. Cardiac shadow enlargement on chest x-ray film is common, with normal or slow heart rate. Anorexia and constipation are frequent. Laboratory tests show anemia in 50% or more of myxedema patients, with a macrocytic but non- megaloblastic type in approximately 25%. The WBC count is usually normal. The cerebrospinal fluid (CSF) usually has an elevated protein level with normal cell counts, for unknown reasons. Serum creatine kinase (CK) is elevated in about 80% (range, 20%-100%) of patients; aspartate aminotransferase (AST; formerly SGOT) is elevated in about 40%-50%; and serum cholesterol is frequently over 250 mg/dl in overt cases.

    Hypothyroidism in the infant is known as “cretinism.” Conditions that superficially resemble or simulate cretinism include mongolism and Hurler’s disease (because of mental defect, facial appearance, and short stature); various types of dwarfism, including achondroplasia (because of short stature and retarded bone age); and nephrosis (because of edema, high cholesterol levels, and low T4 levels). Myxedema in older children and adults may be simulated by the nephrotic syndrome, mental deficiency (because of mental slowness), simple obesity, and psychiatric depression.

  • Thyroid Hormone Production

    Thyroid hormone production and utilization involve several steps (Fig. 29-1). Thyroid gland activity is under the control of thyroid-stimulating hormone (TSH, space or thyrotropin), produced by the anterior pituitary. Pituitary TSH secretion is regulated by space thyrotropin-releasing hormone (TRH, thyroliberin, protirelin) from the hypothalamus. The main space raw material of thyroid hormone is inorganic iodide provided by food. Thyroid hormone synthesis space begins when inorganic iodide is extracted from the blood by the thyroid. Within the thyroid, space in organic iodide is converted to organic iodine, and one iodine atom is incorporated into a space tyrosine nucleus to form monoiodotyrosine. An additional iodine atom is then attached to form space diiodotyrosine. Two diiodotyrosine molecules are combined to form tetraiodothyronine (thyroxine, T4), or one monoiodotyrosine molecule can be combined with one diiodotyrosine molecule to form triiodothyronine (T3). Thyroid hormone is stored in the thyroid acini as thyroglobulin, to be reconstituted and released when needed. Under normal conditions the greater part of thyroid hormone secretion is T4, with only about 7% being T3. In the blood, more than 99% of both T4and T3 is bound to serum proteins. About 80%-85% of T4attaches to T4-binding globulin (TBG), an alpha-1 globulin; about 10%-15% to pre albumin; and about 5% to albumin. Parenthetically, although only a small percentage binds to albumin, there is a large quantity of albumin, so that large changes in serum albumin (usually a decrease) may significantly affect the amount of T4 bound to protein. About 70% of T3 is bound to TBG and most of the remainder to albumin. Protein-bound hormone is metabolically inactive, as though it were in a warehouse for storage. The unbound (“free”) T4and T3 are metabolically active in body cells. Within body cells, particularly the liver, about 80% of daily T3 production takes place by conversion of free T4 to T3. Thyroxine is also converted into a compound known as “reverse T3,” which is not biologically active. Finally, there is a feedback system of control over thyroid hormone production and release. Decreased serum levels of free T4 and T3 stimulate TRH production, whereas increased levels of free T4 and T3 directly inhibit pituitary secretion of TSH as well as inhibit TRH production.

    29-1

    Fig. 29-1 Iodine and thyroid hormone metabolism.

    Certain drugs affect aspects of thyroid hormone production. Perchlorate and cyanate inhibit iodide trapping by the thyroid. The thionalide compounds propylthiouracil (PTU) and methimazole (Tapazole) inhibit thyroid hormone synthesis within the gland from iodine and tyrosine. In addition, PTU inhibits liver conversion of T4 to T3. Iodine in large amounts tends to decrease thyroid vascularity and acinar hyperplasia and to have some inhibitory effect on thyroid hormone release in Graves’ disease. Cortisol has some inhibitory effect on pituitary TSH secretion.

  • Neonatal and Childhood Hypoglycemia

    Neonatal and childhood hypoglycemia will be considered together, although some are of the fasting type and some are postprandial.

    Idiopathic hypoglycemia of infancy. It has been reported that as many as 10% of all neonates have at least one low blood glucose value. Neonatal reference values are lower than the adult reference range, and there is disagreement as to what level should be considered hypoglycemic. Values considered hypoglycemic in the literature range from 20-40 mg/100 ml (1.10-2.20 mmol/L). The most widely quoted reference value lower limits are 20 mg/100 ml for premature or low-birth-weight newborns and 30mg/100 ml for term normal-weight newborns during the first day of life. These values were originally derived from whole blood assay. Conversion to serum or plasma glucose assay values (15% higher than whole blood) would bring the premature lower limit on serum specimens to about 25 mg/100 ml (1.38 mmol/L) and the mature infant lower limit on serum to about 35 mg/100 ml (1.93 mmol/L). The other frequently used reference range consists of premature infant serum lower limit of 30 mg/100 ml (1.65 mmol/L) and mature infant serum lower limit of 40 mg/100 ml (2.20 mmol/L) during the first day of life. Use of these reference values results in at least 10% more diagnoses of hypoglycemia than use of the lower reference limits. Since a substantial number of these infants are asymptomatic, the lower values are more commonly used. In both systems, the serum glucose lower limit after the first day of life is 40 mg/100 ml. Idiopathic neonatal hypoglycemia is more common in male infants with low birth weight for age and in premature infants. In some cases the condition is aggravated by delay in beginning milk feeding. Clinical symptoms occur within 72 hours of birth and include some combination of tremors, twitching, cyanosis, respiratory difficulties, high-pitched or weak cry, refusal to eat, limpness, apnea, and convulsions. These symptoms are nonspecific and could be due to a wide variety of serious or life-threatening neonatal illnesses.

    Neonatal hypoglycemia is thought to be caused at least in part by low hepatic glycogen levels. The condition is usually transient and is treated by oral milk and glucose (if mild) or by parenteral glucose (if severe). If the infant does not develop a clinical problem until after milk feeding is begun and the problem continues, the possibility of leucine sensitivity should be considered.

    Leucine sensitivity. Symptoms of leucine sensitivity usually begin within the first 2 years of life and spontaneously disappear by age 5-6 years. Intake of foods that are rich in the amino acid leucine (e.g., cow’s milk) apparently stimulate the pancreatic beta cells to overproduce insulin, rather similar to the effect of tolbutamide. The patients typically have a low FBG level and demonstrate marked hypoglycemia after leucine administration. Diagnosis is made by a leucine tolerance test, similar to the OGTT but using oral leucine. Since leucine also stimulates 50%-70% of insulinomas, the possibility of insulin-producing tumor or nesidioblastosis must also be considered.

    Nesidioblastosis. Occasionally children with hypoglycemia have diffuse pancreatic islet cell hyperplasia known as nesidioblastosis. Insulinomas also occur but are rare. Diagnosis is the same as for insulinomas and is based on demonstrating inappropriate elevation of insulin when blood glucose levels are low.

    Galactosemia. Galactosemia is an inborn error of metabolism produced by deficiency of an enzyme necessary to metabolize galactose to glucose. Galactose is produced by metabolism of lactose, which is present in milk. Some of these patients develop hypoglycemic episodes, presumably due to abnormality of liver production of glucose from glycogen. A more complete summary of this condition, including laboratory diagnosis, is found in Chapter 34.

    Ketosis. Ketosis said to be the most common etiology of hypoglycemia in childhood. Onset is usually between age 1.5 and 5 years, and the condition usually disappears by age 10 years. It is more common in males of lower than normal birth weight. Episodes of hypoglycemia tend to be precipitated by prolonged lack of food intake or by a low-calorie, low-carbohydrate diet. The cause is thought to be at least partially due to depletion of hepatic glycogen. The child is normal between episodes. Hypoglycemic attacks are usually associated with readily detectable plasma ketone bodies and frequently with urine ketonuria. Blood glucose levels and plasma insulin values are both low.

    Other. Hypoglycemia may be associated with maternal toxemia of pregnancy, poorly controlled diabetes mellitus, neonatal severe hypoxia, or neonatal sepsis. Diagnosis would be based on recognition that these conditions are present.

  • Postprandial Hypoglycemia

    Some of the most common etiologies of postprandial hypoglycemia (which is also known as “reactive hypoglycemia”) include the following eiologies

    Alimentary. Postprandial Hypoglycemia of gastrointestinal tract origin (sometimes called the “dumping syndrome”) most often occurs after gastric surgery and results from unusually swift or complete gastric emptying of ingested carbohydrate into the duodenum, resulting in abnormally high blood glucose levels and temporary hypoglycemia after hastily produced insulin has overcome the initial hyperglycemia. Initial blood glucose elevation is definitely greater than that of a normal person.

    Diabetic. Some persons with subclinical or early diabetes mellitus of the NDDG type II (noninsulin-dependent) category may develop mild and transitory hypoglycemia 3-5 hours after eating. This seems to be an early manifestation of their disease, which often disappears as the disease progresses. The exact incidence in diabetics is unclear but is probably low. However, because of the large number of diabetic persons, it may be a relatively frequent cause of postprandial hypoglycemia. Initial elevation of blood glucose values may or may not be higher than in normal persons, but the 2-hour postprandial value is elevated. The rise in plasma insulin after eating tends to be delayed, and the insulin peak (when finally achieved) may be somewhat elevated, resulting in the hypoglycemic episode.

    Functional. Some patients develop symptoms of hypoglycemia after eating without known cause. This most often occurs 3-4 hours postprandially (range, 1-5 hours). In some cases symptoms can be correlated with acceptably low blood glucose values, in which case many physicians make a diagnosis of functional hypoglycemia (although there is controversy on this point, to be discussed later with the 5-hour OGTT). In other cases, probably the majority, symptoms cannot be adequately correlated with acceptably low blood glucose values. Either the OGTT serum glucose value is low but no symptoms occur, or (less commonly) symptoms occur at a relatively normal glucose level. In these cases some have used the diagnosis of “idiopathic postprandial syndrome.” Perhaps a better term would be “pseudohypoglycemia.” The peak blood glucose elevation after eating is not higher than in a normal person, and the 2-hour value is also normal.

    Other. A few patients with insulinoma or alcoholism may develop postprandial hypoglycemia, although fasting hypoglycemia is much more common.

    Laboratory tests

    The first consideration is to rule out a fasting hypoglycemia, especially when hypoglycemic symptoms occur several hours after food intake. Self-administered hypoglycemic agents are also possible, although for some reason this is not often mentioned when associated with postprandial symptoms. The best test would be a blood glucose measurement drawn at the same time that symptoms were present. Because symptoms in daily life usually occur at times when blood specimens cannot be obtained, the traditional laboratory procedure in postprandial hypoglycemia has been the 5-hour OGTT. In alimentary hypoglycemia the classic OGTT pattern is a peak value within 1 hour that is above OGTT reference limits, followed by a swift fall to hypoglycemic levels (usually between 1 and 3 hours after glucose). In diabetic hypoglycemia, there is an elevated 2-hour postprandial value, followed by hypoglycemia during the 3-5 hours postglucose time interval. In functional hypoglycemia, there is a normal OGTT peak and 2-hour level, followed by hypoglycemia during the 2 to 4-hour postglucose time interval (Fig.).

    Representative oral glucose tolerance curves.
    Representative oral glucose tolerance curves.

    Unfortunately, diagnosis has not been as simple as the classic OGTT findings just mentioned would imply. Many investigators have found disturbing variability in OGTT curves, which often change when testing is repeated over a period of time and may change when testing is repeated on a day-to-day basis. In some cases this is related to factors known to influence the OGTT, such as inadequate carbohydrate preparation, but in other cases there is no obvious cause for OGTT discrepancies. Another major problem is disagreement regarding what postprandial blood glucose value to accept as indicative of hypoglycemia. Most investigators use 50 mg/100 ml (2.76 mmol/L) of plasma glucose as the dividing line. However, there is considerable controversy in the literature on this point. In some cases it is not clear whether serum or whole blood was assayed (reference values for whole blood are 15% less than those for serum or plasma). An additional problem involves the concept of chemical hypoglycemia versus clinical hypoglycemia. A number of studies have shown that a certain percentage of clinically normal persons may have OGTT curves compatible with functional hypoglycemia without developing any symptoms. In some instances asymptomatic OGTT serum levels as low as 30 mg/100 ml (1.65 mmol/L) were observed. Moreover, in some studies continuous blood glucose monitoring systems disclosed hypoglycemic dips not evident in standard OGTT specimens. On the other hand, some persons with symptoms compatible with hypoglycemia do not develop OGTT values below reference limits. To make matters more confusing, some studies have found that when the 5-hour OGTT was repeated after it had initially displayed a hypoglycemic dip, a substantial number of the repeat OGTT results became normal (about 65% of cases in one report). Finally, several studies have indicated that hypoglycemic values found during an OGTT usually disappear when an ordinary meal is substituted for the carbohydrate dose. Since actual patients do not usually ingest pure carbohydrate meals, this casts doubt on the reliability and usefulness of the OGTT in the diagnosis of functional hypoglycemia. One study found that patients with symptoms of functional hypoglycemia had an increase in the plasma epinephrine level of at least 250 pg/ml over baseline at the time of the OGTT lowest (“nadir”) serum glucose level, regardless of the actual value, whereas those who did not develop symptoms had an epinephrine increase at the time of the glucose nadir that was less than 250 pg/ml.

    In summary, the diagnosis of postprandial hypoglycemia is clouded by controversy, especially the category of functional hypoglycemia. Probably the least debatable diagnosis would be one established by a serum glucose level less than 50 mg/100 ml obtained less than 5 hours after a regular meal while the patient is having hypoglycemic symptoms. A 5-hour OGTT could be done with a regular meal instead of the pure glucose dose. This would also help to exclude alimentary or diabetic etiologies.

  • Fasting Hypoglycemia

    Of the two clinical categories, fasting hypoglycemia is by far the more straightforward. The two chief mechanisms are insulin excess (either absolute or relative) and effects of carbohydrate deprivation. Conditions acting through these mechanisms are the following:

    1. The most well-known etiology of insulin excess is the beta-cell insulin-producing pancreatic islet cell tumor (insulinoma). About 80% of these tumors are single adenomas, about 10% are multiple adenomas, and about 10% are carcinomas. About 10% of patients with insulinoma also have the MEN type II syndrome (Chapter 33), and of these patients, about 80% have multiple insulinomas. Although insulinomas typically are associated with fasting hypoglycemia, one study reported that nearly 50% of their insulinoma patients developed symptoms less than 6 hours postprandially, which would clinically suggest a postprandial (reactive) etiology.
    2. Overdose of insulin in a diabetic person. Since the patient may be found in coma without any history available, insulin overdose must be a major consideration in any emergency room comatose patient.
    3. Hypoglycemia may be associated with deficiency of hormones that normally counteract the hypoglycemic effect of insulin. This group includes pituitary insufficiency (deficiency of growth hormone and cortisol) and adrenal insufficiency (cortisol). Glucagon and thyroxine also have a hyperglycemic effect, but hypoglycemia due to a deficiency of these hormones is rare.
    4. Prolonged carbohydrate deprivation, even when total calories are relatively adequate, has been reported to predispose to hypoglycemia. Occasionally patients with severe liver disease develop hypoglycemia, but this is uncommon.
    5. Certain nonpancreatic tumors have occasionally been reported to cause hypoglycemia, presumably either by glucose utilization or by production of an insulin-like substance. The great majority have been neoplasms of large size described as fibrosarcomas or spindle cell sarcomas, usually located in the abdomen (in one study, about two thirds occurred in the abdomen and one third occurred in the thorax). Hepatoma is next most frequent.
    6. Alcoholic hypoglycemia may occur in either chronic alcoholics or occasional drinkers. Malnutrition, chronic or temporary, is an important predisposing factor. In those persons who develop hypoglycemia, fasting for 12-24 hours precedes alcohol intake. Symptoms may occur immediately but most often follow 6-34 hours later. Therefore, alcohol-related hypoglycemia is most often a fasting type but occasionally may appear to be reactive.

    Laboratory tests

    The major consideration in these patients is to discover a pancreatic islet cell tumor or eliminate its possibility. Diagnosis of islet cell tumor is important since the condition is surgically correctable, but accurate diagnosis is a necessity to avoid unnecessary operation.

    Whipple’s triad. Whipple’s triad remains the basic screening procedure for insulinoma:

    1. Symptoms compatible with hypoglycemia while fasting.
    2. A FBG level of 10 mg/100 ml (0.55 mmol/L) or more below FBG normal lower limits at some time. This is most reliable when the specimen is obtained while the patient is having symptoms.
    3. Relief of symptoms by glucose.
    4. In addition, most endocrinologists would require an elevated serum insulin value during the hypoglycemia.

    Plasma (or serum) insulin/glucose ratio. In functioning insulinomas, one would expect serum insulin levels to be elevated. In some patients with serum glucose within glucose reference range, serum insulin may be elevated not only with insulinoma but also with Cushing’s syndrome, chronic renal failure, growth hormone overproduction, cortisol-type steroids, obesity, and estrogen therapy. On the other hand, about 10% (range, 0%-20%) of patients with insulinoma have been reported to show serum insulin levels in the upper 75% of insulin reference range during hypoglycemia. However, some of these patients with apparently normal insulin levels can be shown to have insulin values that are disproportionately high in relation to the glucose value. Therefore, some investigators consider the ratio of immunoreactive insulin to glucose (IRI/G ratio) to be more sensitive and reliable than blood levels or either glucose alone or insulin alone. Normally, the IRI/G ratio should be less than 0.3 (the immunoreactive insulin is measured in microunits per milliliter, the glucose in milligrams per 100 ml). The ratio is abnormal if it is greater than 0.3 in nonobese persons and greater than 0.3 in obese persons with serum glucose values less than 60mg/100 ml. Hyperinsulinism due to insulinoma results in serum insulin levels inappropriately high in relation to the low serum glucose values. In some institutions a G/IRI ratio is used instead of an IRI/G ratio.

    Amended insulin/glucose ratio for diagnosis of insulinoma. Some investigators have proposed variants of the IRI/G ratio to increase sensitivity or specificity for insulinoma. The most commonly used variant is the “amended ratio” of Turner, whose formula is:

    Serum insulin level x 100 / Serum glucose – 30 mg/100 ml

    when serum insulin is reported in µU/ml and serum glucose in mg/100 ml. A ratio over 50 suggests insulinoma, while a ratio less than 50 is evidence against insulinoma. The serum levels of glucose and insulin are obtained after fasting, which may have to be long-term. The amended IRI/G ratio is reported to be a little more sensitive than the standard IRI/G ratio in some reports, but in other reports there were 20%-35% false negative or nondiagnostic results in patients with insulinoma.

    Prolonged fasting. A considerable number of patients do not display symptoms or laboratory evidence of insulinoma after overnight fasting. When this occurs, the most useful procedure is prolonged fasting for a time period up to 72 hours long, with periodic insulin plus glucose measurements, or such measurements if symptoms develop. After an overnight fast, approximately 50% of insulinomas are revealed by the FBG level alone and about 66% by the IRI/G ratio. After a 48-hour fast, the blood glucose value uncovers about 66% of tumors and the IRI/G ratio about 85%. In 72 hours, the blood glucose level alone detects about 70% of patients and the IRI/G ratio is abnormal in more than 95%. In the Mayo Clinic series, Whipple’s triad appeared within 24 hours in 71% of insulinoma patients, within 36 hours in 79%, within 48 hours in 92%, and within 72 hours in 98%. Serum insulin assay alone reveals about the same percentage of patients with elevated values as the blood glucose level does with low values.

    Tolbutamide tolerance test. Tolbutamide (Orinase) is a sulfonylurea drug that has the ability to stimulate insulin production from pancreatic islet cells. The drug has been used to treat diabetics who produce insulin but not in sufficient quantity. In the tolbutamide test, a special water-soluble form of tolbutamide (not the therapeutic oral form) is given intravenously. In normal persons there is a prompt fall in blood glucose levels to a minimum at 30-45 minutes, followed by a return to normal values between 1.5 and 3 hours. In patients with insulinoma the fall in the blood glucose level is greater than that of most normal persons, declining to 40%-65% of baseline, whereas normal persons usually do not fall as low as 50% of baseline [Mayo Clinic recent criteria report sensitivity and specificity of 95% when the average of the 120-, 150-, and 180-minute plasma glucose specimens is less than 55 mg/100 ml (3.05 mmol/L) in lean persons and 62 mg/100 ml (3.44 mmol/L) in obese persons].

    Since there is occasional overlap between normal persons and those with insulinoma, of greater significance is the fact that hypoglycemia from insulinoma persists for more than 3 hours, whereas in most normal individuals the blood glucose level has returned to fasting values by 3 hours. In a few normal individuals and in those with functional hypoglycemia, values return to at least 80% of FBG levels by 3 hours. Adrenal insufficiency also returns to at least 80% of FBG levels by 3 hours, although the initial decrease may be as great as that for insulinoma. Some patients with severe liver disease have curves similar to those of insulin-producing tumor. However, this is not frequent and usually is not a real diagnostic problem. The tolbutamide test is definitely more sensitive than the OGTT for the diagnosis of islet cell tumor but has the disadvantage that the characteristic responses of diabetic or alimentary hypoglycemia to the OGTT cannot be demonstrated.

    The major drawback to the tolbutamide test is the necessity in some patients to stop the test prematurely because of severe hypoglycemic symptoms. Patients must be closely watched during the test. Sensitivity of the test for insulinoma seems to be approximately 80%-85% using the extended 3-hour time period (literature range, 75%-97%). A major advantage of the test is the short time required to obtain an answer. The tolbutamide test is usually not performed if the FBG value is already in the hypoglycemic range.

    Proinsulin. Insulin is derived from a precursor called proinsulin, which is synthesized in the pancreas, is metabolically inactive, and is larger in size (“big insulin”). Proinsulin consists of an alpha and a beta chain connected by an area called “connecting peptide” (C-peptide). Proinsulin is enzymatically cleaved within beta cells into equal quantities of insulin and C-peptide. Radioimmunoassay measurement of insulin includes both proinsulin and regular insulin. Normally, about 5%-15% of immunoreactive insulin (that substance measured by immunoassay) is proinsulin. In many (but not all) patients with insulinomas, the amount of circulating proinsulin is increased relative to total insulin. In diabetics with insulin deficiency who are being treated with insulin, the proinsulin fraction of the individual’s own immunoreactive insulin values may be increased. Measurement of proinsulin necessitates special procedures such as Sephadex column chromatography and is not widely available. Sensitivity of proinsulin assay for detection of insulinoma is reported to be about 80%.

    Serum connecting peptide (C-peptide) measurement. As noted previously, C-peptide is a by-product of insulin production. Although it is released in quantities equal to insulin, serum C-peptide levels do not exactly parallel those of insulin, due to differences in serum half-life and catabolic rate. Nevertheless, C-peptide values correlate well with insulin values in terms of the position of each in relation to its own normal range (i.e., if one is decreased, the other likewise is decreased). Therefore, C-peptide can be used as an indicator of insulin secretion.

    Some insulin is derived from animal pancreas (synthetic human insulin is available but not yet exclusively used). Use of this foreign substance may lead to antiinsulin antibody production. Pork insulin is less antigenic than beef insulin. Insulin antibodies falsely increase insulin assay values in most commercial kits (although in a few systems the values are decreased instead). C-peptide assay kits do not react with animal-origin insulin and therefore reflect only actual patient insulin production without being affected by the presence of insulin antibodies.

    C-peptide assay has been used in several ways: (1) most commonly, to detect or prove factitious (self-medication) insulin-induced hypoglycemia, (2) to detect insulinoma in diabetic patients requiring insulin therapy, (3) to evaluate pancreatectomy status, and (4) to evaluate insulin reserve or production in diabetics who have taken or are taking insulin.

    Occasionally patients become hypoglycemic by self-administration of insulin. Since insulin assay cannot differentiate between exogenous insulin and that produced by insulinoma, C-peptide assay should be performed on the same specimen that showed elevated insulin levels. In hyperinsulinism from islet cell tumor, C-peptide levels are elevated; in that due to exogenous (self-administered) insulin, C-peptide levels are low. Another cause of low C-peptide levels is a type I diabetic who cannot produce insulin; but the insulin assay value would be low. An elevation of the C-peptide level classically suggests insulinoma but may also be seen after taking oral hypoglycemic agents (since these agents stimulate the production of insulin).

    Connecting peptide assay has been used after pancreatectomy to evaluate the possibility of residual pancreatic islet tissue.

    Some investigators have used C-peptide assay in diabetics previously treated with insulin to see how much insulin production is possible. Those who have substantial capability for insulin production are treated differently from those who do not. This method can help diagnose the syndrome of peripheral insulin resistance. Also, if the diabetic patient has significant capability for insulin production, frequent and severe episodes of diabetic ketoacidosis may suggest some factor other than insulin deficiency. There is still controversy over criteria dividing type I and type II diabetics based on insulin or C-peptide assay and what therapeutic changes, if any, should be made based on the amount of insulin production using insulin or C-peptide information.

    Other tests. The 5-hour OGTT after overnight fasting was widely used in the past for detection of insulinoma. Patients characteristically had a low or low-normal FBG level and a normal sharp rise after glucose administration (the peak remaining within normal OGTT limits), then a slower fall to hypoglycemic levels that did not rapidly return to the reference range. However, the OGTT has been virtually abandoned for diagnosis of insulinoma because a considerable minority of insulinomas are reported to demonstrate a flat curve or sometimes even a diabetic-type curve, or the curve may be normal. The 5-hour OGTT, however, is sometimes used in patients with the postprandial type of hypoglycemia. Leucine and glucagon provocative tests for insulinoma have been reported. However, these are rarely used since they are somewhat less sensitive than tolbutamide and substantially less sensitive than the IRI/G ratio after prolonged fasting.

    Current status of tests for insulinoma

    At present, most investigators use Whipple’s triad and prolonged fasting (with insulin assay or the IRI/G ratio) as the primary screening tests for insulinoma, with the tolbutamide test available in equivocal or problem cases. The differential diagnosis of decreased glucose and elevated insulin includes insulinoma, factitious hypoglycemia, and antiinsulin antibodies. Insulinoma has increased C-peptide levels and the other two have normal or decreased C-peptide levels.

  • Hypoglycemia

    Hypoglycemia is a topic that has generated a great deal of confusion. Although the word means “low blood glucose,” the diagnosis of hypoglycemia is controversial, because it is sometimes defined strictly on the basis of an arbitrary blood glucose level (chemical hypoglycemia), sometimes in terms of symptoms (clinical hypoglycemia), and sometimes as a combination of glucose level and symptoms. The most readily accepted aspect of hypoglycemia is division into two clinical categories: one in which symptoms occur after fasting (fasting hypoglycemia) and one in which symptoms occur after eating (postprandial hypoglycemia). If the blood glucose level drops rapidly, symptoms tend to be similar to those associated with release of epinephrine (adrenergic) and include anxiety, sweating, palpitation, tremor, and hunger. If hypoglycemia persists, CNS glucose deprivation occurs (neuroglycopenia) and symptoms resemble those of cerebral hypoxia, such as lethargy, headache, confusion, bizarre behavior, visual disturbances, syncope, convulsions, and coma. Symptoms associated with fasting hypoglycemia tend to be one or more of those associated with CNS neuroglycopenia, and those associated with postprandial hypoglycemia tend to be adrenergic. However, there is some overlap in symptoms between the two groups. In general, symptoms due to fasting hypoglycemia have a much higher incidence of visual disturbances, bizarre behavior or personality changes, convulsions, and loss of consciousness, especially prolonged loss of consciousness. Postprandial hypoglycemia tends to be more abrupt in onset and is usually self-limited.