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Hypocalcemia (Familial), Latent Tetany, and Calcification of Basal Ganglia Syndrome

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Hypocalcemia (Familial), Latent Tetany, and Calcification of Basal Ganglia Syndrome

  • (Rare clinical syndrome has features resembling those of pseudohypoparathyroidism, pseudopseudohypoparathyroidism, and basal cell nevus syndrome)
  • Hypocalcemia is not responsive to parathormone administration.
  • Parathormone administration produces a phosphate diuresis.

Hypocalcemia, Neonatal




  • Because pH affects ionized calcium values, obtain free-flowing sample anaerobically and seal in capillary tube until analysis
  • Age 1-4 wks: serum calcium <7 mg/dL or ionized calcium <4 mg/dL
  • Age 1-2 days-associated with
    • Prematurity and low birth weight occurs in ≤30% of infants
    • Maternal diabetes found in ≤25% of cases
    • Birth asphyxia occurs in ≤30% of infants

P.607

  • Age 5-10 days-associated with
    • Feeding of cow's milk (increased serum phosphorus and decreased serum calcium)
  • Rarely associated with
    • Maternal hypercalcemia or HP 313k1022d T
    • Congenital absence of parathyroid glands (see DiGeorge syndrome)
    • Hypoproteinemia (e.g., nephrosis, liver disease)
    • Maternal osteomalacia
    • Renal disease (primary rental tubular defect; decreased GFR causing phosphate retention)
    • Iatrogenic disorders (e.g., citrate administration during exchange transfusions)
  • When tetany syndrome is associated with a normal serum calcium level or is not relieved by administration of calcium, rule out decreased serum magnesium. Hypocalcemia associated with hypomagnesemia does not respond unless hypomagnesemia is treated.
  • Serum phosphorus is >8 mg/dL when neonatal hypocalcemia is due to high phosphate feeding. BUN is increased when neonatal hypocalcemia is due to severe renal disease.
  • Check serum calcium at the following intervals:
    • Infants of diabetic mothers: 6, 12, 24, 48 hrs
    • Infants with intrapartum asphyxia: 1, 3, 6, 12 hrs
    • Premature infants: 12, 24, 48 hrs

Hypocalciuric Hypercalcemia, Familial (Familial Benign Hypercalcemia)

  • (Rare familial autosomal dominant disorder of chronic lifelong, asymptomatic, nonprogressive, mild hypercalcemia due to resistance to action of extracellular calcium on parathyroid gland and kidney; onset before age 10 yrs without renal stones, kidney damage, peptic ulcer; no response to parathyroidectomy; parathyroid glands are histologically normal)
  • Has many of same biochemical findings as primary HPT, including
    • Mildly increased serum total and ionized calcium.
    • Inappropriately increased (although within normal range) PTH level for hypercalcemia.
    • Serum phosphorus is slightly decreased or normal.
    • Urinary cAMP is increased in about one-third of patients.
  • Urine calcium excretion is decreased or low normal despite hypercalcemia.
    • ≤200 mg/24 hrs in familial hypocalciuric hypercalcemia; calcium/creatinine clearance ratio is usually <0.01 (but usually >0.02 in primary HPT).
    • Up to 300 mg/24 hrs in normal adult males.
    • Increased (often >250 mg/24 hrs) in two-thirds of patients with HPT.
    • Increased (often >500 mg/24 hrs) in patients with malignancies.
  • Serum magnesium is mildly increased in 50% of patients; this is the only condition in which serum magnesium and calcium are both increased. Urine magnesium excretion is decreased also.
  • Renal function is maintained with normal creatinine clearance.
  • Serum 25-hydroxy-vitamin D is normal and 1,25-dihydroxy-vitamin D is proportional to PTH level.
  • Serum ALP is normal.
  • No dysfunction of other endocrine glands.
  • May be family history of hypercalcemia or failed parathyroidectomy attempts.

Hypoparathyroidism

  • (Rare disorder often detected in childhood; may be autoimmune disorder associated with Addison's disease, diabetes mellitus, hypothyroidism, PA, chronic hepatitis, moniliasis, malabsorption, or hypogonadism)
  • See Table 13-8 and Fig. 13-6.
  • Serum calcium is decreased (as low as 5 mg/dL) in presence of low or inappropriately low PTH and normal serum magnesium, which affects PTH secretion and action. Hypocalcemia stimulates PTH secretion in pseudohypoparathyroidism but not in hypoparathyroidism.

P.608

  • ○ Serum phosphorus is increased (usually 5-6 mg/dL; as high as 12 mg/dL).
  • Serum ALP is normal or slightly decreased.
  • Urine calcium is decreased.
  • Urine phosphorus is decreased. Phosphate clearance is decreased.
  • Serum PTH is decreased.
  • Renal resistance to PTH is shown by Ellsworth-Howard test
    • PTH challenge (IV administration of 200 IU of synthetic PTH) causes increased urine phosphate (>10×) and cAMP in normal persons and in primary hypoparathyroidism but little or no increase in urine phosphorus.
    • Increased urine phosphate (<2×) and cAMP in classical type I pseudohypoparathyroidism or pseudopseudohypoparathyroidism.
    • In type II pseudohypoparathyroidism cAMP increases without phosphaturia.
    • Decreased response may occur in basal cell nevus syndrome.
  • Alkalosis is present.
  • Serum uric acid is increased.
  • OGTT results are flat (due to poor absorption).
  • CSF is normal, even with mental or emotional symptoms or with calcification of basal ganglia.
  • ○ Hypoparathyroidism should be ruled out in presence of mental and emotional changes, cataracts, faulty dentition in children, associated changes in skin and nails (e.g., moniliasis is frequent). One-third of these patients may present as "epileptics."
  • Congenital absence may be associated with thymic aplasia (DiGeorge's syndrome).

Hypophosphatasia

  • (Rare [1 in 100,000 live births] autosomal recessive disease of bone mineralization with radiographic changes and at least three different clinical syndromes found in infants [most severe], children, and adults [least severe])
  • Serum ALP is decreased to ~25% of normal (may vary from 0 ≤ 40% of normal); is not correlated with severity of disease. Due to bone and sometimes liver isoenzymes; normal ALP in intestine and placenta. Is decreased in heterozygotes but the level cannot distinguish patients from carriers.
  • Serum calcium may be increased in severe cases in newborns.
  • Serum phosphorus is normal.
  • Serum and urine levels of phosphoethanolamine are increased (may be increased in asymptomatic heterozygotes and useful for detection).
  • Treatment with corticosteroids usually causes an increase in serum ALP (but it never attains normal level) with a marked fall in serum calcium; phosphoethanolamine excretion in urine continues to be high.
  • Prenatal diagnosis by measurement of ALP in cultured amniocytes, but activity in amniotic fluid is unreliable.
  • Urine hydroxyproline is low; in contrast, it is high in vitamin D-resistant rickets or hyperphosphatasia.

Hypophosphatemia, Primary

  • (Familial but occasionally sporadic condition of intrinsic renal tubular defect in phosphate resorption)
  • Serum phosphorus is always decreased in the untreated patient.
  • Serum calcium is usually normal.
  • Serum ALP is often increased.
  • Bone biopsy shows a characteristic pattern of demineralization around osteocyte lacunae.

Milk-Alkali (Burnett's) Syndrome

  • Increased serum calcium (without hypercalciuria)
  • Increased serum phosphorus
  • Mild alkalosis

P.609

  • ○ The previous section should suggest the diagnosis in a patient with peptic ulcer.
  • Normal serum ALP
  • Renal insufficiency with azotemia (increased BUN)
  • Metastatic calcinosis

Pseudohypoparathyroidism

  • (Heterogeneous group of inherited disorders with renal resistance to PTH action. Patients may be short, stocky with round face, short metacarpals and metatarsals, calvarial thickening, mental retardation.)
  • Serum calcium, phosphorus, and ALP are the same as in hypoparathyroidism but cannot be corrected by (or respond poorly to) administration of PTH (see description of Ellsworth-Howard test,).
  • Serum PTH level is normal or elevated.
  • Renal resistance to PTH is shown by Ellsworth-Howard test (see previous section).

Pseudopseudohypoparathyroidism

  • (Clinical anomalies are the same as in pseudohypoparathyroidism.)
  • Serum and urine calcium, phosphorus, and ALP are normal.
  • Ellsworth-Howard test (see Hypoparathyroidism).

Pseudohypophosphatasia

  • (Clinical syndrome resembling hypophosphatasia)
  • Serum ALP is normal.

Tetany With Decreased Tissue Calcium

  • Tetany associated with normal serum calcium, magnesium, potassium, and carbon dioxide, responds to vitamin D therapy.
  • Special radioactive calcium studies show decreased tissue calcium pool that returns toward normal with therapy.

Tetany Syndrome Due To Magnesium Deficiency

  • Serum magnesium is decreased (usually <1 mEq/L).
  • Serum calcium is normal (slightly decreased in some patients)
  • Blood pH is normal.
  • Tetany responds to administration of magnesium but not of calcium.

Tests for Diagnosis of Diabetes Mellitus and Hypoglycemia

C-Peptide, Serum

  • C-peptide is formed during conversion of proinsulin to insulin; C-peptide serum levels correlate with insulin levels in blood, except in patients with islet cell tumors and possibly in obese patients.

Use

  • Estimation of insulin levels in the presence of antibodies to exogenous insulin.
  • Diagnosis of factitious hypoglycemia due to surreptitious administration of insulin, in which high serum insulin levels occur with low C-peptide levels.

Increased In

  • Insulinoma
  • Type II diabetes mellitus

P.610

Decreased In

  • Exogenous insulin administration (e.g., factitious hypoglycemia)
  • Type I diabetes mellitus

Fructosamine, Serum

  • Measures concentration of nonlabile glycated serum proteins, giving a reliable estimate of mean blood glucose levels during preceding 1-3 wks.
  • Should primarily be compared with previous values in same patient rather than with reference range.
  • Reference range in nondiabetic persons: fructosamine = 2.4-3.4 mmol/L; fructosamine:albumin ratio = 54-86 µmol/gm.

Use

To monitor treatment of diabetic patients

Interpretation

Correlates with HbA1c but is not affected by abnormal hemoglobins, HbF, or increased RBC turnover and shows changed glucose levels earlier; is cheaper, faster, less subjective than HbA1c

Interferences

  • Changes in fructosamine values correlate with significant changes in serum albumin or protein concentrations. Abnormal values also occur during abnormal protein turnover (e.g., thyroid disease) even though patients are normoglycemic. Obviated by using fructose/albumin ratio.
  • Dysproteinemias
  • Increased serum bilirubin may interfere.
  • Possibly uremia, lipemia, hemolysis, ascorbate.

Glycohemoglobin (Glycated Hemoglobin)

  • May be reported as HbA1c or as total of A1b, A1a, A1c
  • Values may not be comparable using different methodologies and even from different laboratories using same methodology.
  • Glucose combines with Hb continuously and nearly irreversibly during life span of RBC (120 days); thus glycated Hb is proportional to mean plasma glucose level during previous 6-12 wks.
  • Glycated Hb predicts risk of progression of diabetic complications.
  • Glycosylated albumin (half life ~14 days) has been used for monitoring degree of hyperglycemia during previous 1-2 wks when glycated Hb cannot be used. Not yet shown to be related to risk of progression of diabetic complications.

Use

  • Monitor diabetic patients' compliance with therapeutic regimen and long-term blood glucose level control
  • In known diabetics:
    • 7% indicates good diabetic control.
    • 10% indicates fair diabetic control.
    • 13-20% indicates poor diabetic control.
    • When mean annual HbA1c is <1.1× ULN, renal and retinal complications are rare, but complications occur in >70% of cases when HbA1c is >1.7 ULN.
  • Not presently recommended for diagnosis of diabetes mellitus although ~85% sensitivity and specificity each for screening.

Interpretation



  • Dietary preparation or fasting not required.
  • Low sensitivity but high specificity compared to OGTT, which has high sensitivity but low specificity in diagnosis of diabetes mellitus.

P.611

  • Increase almost certainly means diabetes mellitus if other factors (see below) are absent (>3 SD above the mean has 99% specificity and ~48% sensitivity), but a normal value does not rule out impaired glucose tolerance. Values less than normal mean are not seen in untreated diabetes.
  • May rise within 1 wk after rise in blood glucose when therapy is stopped but may not fall for 2-4 wks after blood glucose decrease when therapy is resumed.
  • Mean blood glucose in first 30 days (days 0-30) before sampling glycated Hb contributes ~50% to final glycated Hb value, whereas mean blood glucose in days 90-120 contributes only ~10%. Time to reach a new steady state is 30-35 days.
  • When fasting blood glucose = <110 mg/dL, HbA1c is normal in >96% of cases.2
  • When fasting blood glucose = 110-125 mg/dL, HbA1c is normal in >80% of cases.2
  • When fasting blood glucose = >126 mg/dL, HbA1c is normal in >60% of cases.2

Normal (A1a, A1b, A1c

  • For level of 4-20%, this formula may estimate daily average plasma glucose: Mean daily plasma glucose (mg/dL) = 10 × (glycohemoglobin level + 4)
  • 1% increase in glycohemoglobin is related to ~30 mg/dL increase in glucose.

Increased In

  • HbF above normal or 0.5% (e.g., heterozygous or homozygous persistence of HbF, fetomaternal transfusion during pregnancy)
  • Chronic renal failure with or without hemodialysis
  • Iron-deficiency anemia
  • Splenectomy
  • Increased serum triglycerides
  • Alcohol
  • Lead and opiate toxicity
  • Salicylate treatment

Decreased In

  • Shortened RBC life span
    • Presence of HbS, HbC, HbD
    • Hemolytic anemias (e.g., congenital spherocytosis)
    • Acute or chronic blood loss
  • After transfusions
  • Pregnancy
  • Ingestion of large amounts (>1 gm/day) of vitamin C or E

Insulin, Plasma

Use

  • Diagnosis of insulinoma
  • Not clinically useful for diagnosis of diabetes mellitus

Increased In

  • Insulinoma. Fasting blood insulin level >50 µU/mL in presence of low or normal blood glucose level. IV tolbutamide or administration of leucine causes rapid rise of blood insulin to very high levels within a few minutes with rapid return to normal.
  • Factitious hypoglycemia
  • Insulin autoimmune syndrome
  • Untreated obese patients with mild diabetes. The fasting level is often increased.
  • Patients with acromegaly (especially with active disease) after ingestion of glucose
  • Reactive hypoglycemia after glucose ingestion, particularly when diabetic type of glucose tolerance curve is present

P.612

Absent In

Severe diabetes mellitus with ketosis and weight loss. In less severe cases, insulin is frequently present but only at lower glucose concentrations.

Normal In

  • Hypoglycemia associated with nonpancreatic tumors
  • Idiopathic hypoglycemia of childhood, except after administration of leucine

Insulin/C-Peptide Ratio

Use

To differentiate insulinoma from factitious hypoglycemia due to insulin

Interpretation

  • <1.0 in molarity units (or >47.17 µg/ng in conventional units)
    • Increased endogenous insulin secretion (e.g., insulinoma, sulfonylurea administration)
    • Renal failure
  • >1.0 in molarity units (or <47.17 µg/ng in conventional units)
    • Exogenous insulin administration
    • Cirrhosis

Proinsulin

Proinsulin level is normally ≤20% of total insulin. Proinsulin is included in the immunoassay of total insulin, and separation requires special technique.

Increased In

  • Insulinoma. Proinsulin >30% of serum insulin after overnight fast suggests insulinoma.
  • Factitious hypoglycemia due to sulfonylurea use (see Table 13-14).
  • Familial hyperproinsulinemia-heterozygous mutation affecting cleavage of proinsulin, leading to secretion of excess amounts of proinsulin.
  • Non-insulin dependent diabetes mellitus

Interferences

May also be increased in renal disease.

Tolerance Test, Insulin

Administer 0.1 U insulin/kg body weight IV. Use smaller dose if hypopituitarism is suspected. Always keep IV glucose available to prevent severe reaction.

Normal

Blood glucose falls to 50% of fasting level within 20-30 mins; returns to fasting level within 90-120 mins.

Increased Tolerance In

  • Blood glucose falls <25% and returns rapidly to fasting level.
  • Hypothyroidism
  • Acromegaly
  • Cushing's syndrome
  • Diabetes mellitus (some patients; especially older, obese ones)

Decreased Tolerance In

  • Increased sensitivity to insulin (excessive fall of blood glucose)
  • Hypoglycemic irresponsiveness (lack of response by glycogenolysis)
    • Pancreatic islet cell tumor

P.613

Fig. 13-8. Sample oral glucose tolerance test curves in various conditions.

    • Adrenocortical insufficiency
    • Adrenocortical insufficiency secondary to hypopituitarism
    • Hypothyroidism
    • von Gierke's disease (some patients)
    • Starvation (depletion of liver glycogen)

Tolerance Test, Insulin Glucose

  • Administer simultaneously 0.1 U insulin/kg body weight IV and 0.8 gm glucose/kg body weight orally.
  • Insulin-sensitive diabetics show little change in blood sugar.
  • Insulin-resistant diabetics show a diabetic glucose tolerance curve.
  • Other changes parallel those in the insulin tolerance test.

Tolerance Test, Oral Glucose (Ogtt)

  • See Fig. 13-8.
  • Standards for OGTT: Prior diet of >150 gm of carbohydrate daily, no alcohol, and unrestricted activity for 3 days before test. Test in morning after 10-16 hrs of fasting. No medication, smoking, or exercise (remain seated) during test. Not to be done during recovery from acute illness, emotional stress, surgery, trauma, pregnancy, inactivity due to chronic illness; therefore is of limited or no value in hospitalized patients. Certain drugs should be stopped several weeks before the test (e.g., oral diuretics, oral contraceptives, phenytoin). Loading dose of glucose consumed within 5 mins: for adults = 75 gm, for children = 1.75 gm/kg (of ideal body weight in obese children but never >75 gm), for pregnant women = 100 gm. Draw blood at fasting, 30, 60, 90, 120 mins; 30-min sample offers little additional information but can confirm adequate gastric absorption when patient is nauseous.

P.614

Use

  • OGTT should be reserved principally for patients with "borderline" fasting plasma glucose levels (i.e., fasting range 110-140 mg/dL).
  • All pregnant women should be tested for gestational diabetes with a 50-gm dose at 24-28 wks of pregnancy; if result is abnormal, OGTT should be performed after pregnancy.
  • OGTT is not indicated in
    • Persistent fasting hyperglycemia (>140 mg/dL).
    • Persistent fasting normoglycemia (<110 mg/dL).
    • Patients with typical clinical findings of diabetes mellitus and random plasma glucose >200 mg/dL.
    • Suspected gestational diabetes.
    • Secondary diabetes (e.g., genetic hyperglycemic syndromes, after administration of certain hormones).
    • Should never be performed to evaluate reactive hypoglycemia.
    • Test is of limited value for diagnosis of diabetes mellitus in children and is rarely indicated for that purpose.

Interpretation

For diagnosis of diabetes mellitus in nonpregnant adults, at least two values of OGTT should be increased (or fasting serum glucose ≥140 mg/dL on more than one occasion) and other causes of transient glucose intolerance must be ruled out. See Classification of Diabetes Mellitus and Other Hyperglycemic Disorders, Diabetes Mellitus, Gestational.

Decreased Tolerance In

  • Excessive peak
    • Increased absorption (normal IV GTT curve) with normal return to fasting level
    • Mechanical causes (e.g., gastrectomy, gastroenterostomy)
    • Hyperthyroidism
    • Excess intake of glucose
  • Decreased utilization with slow fall to fasting level
    • Diabetes mellitus
    • Hyperlipidemia, types III, IV, V
    • Hemochromatosis
    • Steroid effect (Cushing's disease, administration of ACTH or steroids)
    • CNS lesions
  • Decreased formation of glycogen with low fasting levels and subsequent hypoglycemia
    • von Gierke's disease
    • Severe liver damage
    • Hyperthyroidism (normal return to fasting level)
    • Increased epinephrine (stress, pheochromocytoma) (normal return to fasting level)
    • Pregnancy (normal return to fasting level)
  • Drugs that may cause increased serum glucose and/or impaired glucose tolerance
    • Hormones (e.g., oral contraceptives, thyroid hormone, ACTH or steroids, progestins)
    • Antiinflammatory agents (e.g., indomethacin)
    • Diuretic and antihypertensive drugs (e.g., thiazides, furosemide, clonidine)
    • Neuroactive drugs (e.g., phenothiazines, tricyclics, lithium carbonate, haloperidol, adrenergic agonists)
    • Others (e.g., isoniazid, heparin, cimetidine, nicotinic acid)

Increased Tolerance In

  • Flat peak
    • Pancreatic islet cell hyperplasia or tumor
    • Poor absorption from GI tract (normal IV GTT curve)
    • Intestinal diseases (e.g., steatorrhea, sprue, celiac disease, Whipple's disease)
    • Hypothyroidism
    • Addison's disease
    • Hypoparathyroidism
  • Late hypoglycemia
    • Pancreatic islet cell hyperplasia or tumor

P.615

    • Hypopituitarism
    • Liver disease
  • See Glucose, for effect of drugs.
  • Difficulty in interpretation has caused abandonment of other GTTs, such as IV GTT, cortisone GTT.

Tolerance Test, Tolbutamide



Administer 1 gm sodium tolbutamide IV within 2 mins. Always keep IV glucose available to prevent severe reaction.

Use

Most useful for diagnosis of insulinoma and to rule out functional hyperinsulinism.

Interpretation

  • In healthy persons, glucose is a more potent stimulus for insulin release than tolbutamide, but the opposite is true in insulinoma, which shows an exaggerated early insulin peak (3-5 mins after injection) with a sustained elevation of insulin and depression of glucose at 150 mins.
  • The fall in blood sugar is usually more marked in insulinoma than in functional hypoglycemia; more importantly, the blood sugar fails to recover even after 2-3 hrs. A mean serum glucose at 120, 150, and 180 mins after tolbutamide of ≤55 mg/dL in lean patients and 62 mg/dL in obese patients has a 95% specificity and >95% sensitivity for insulinoma; this is the most useful test.4 Other calculations of glucose and insulin levels are less useful.
  • In functional hypoglycemia, return of blood sugar to normal is usually complete by 90 mins.
  • Adrenal insufficiency-normal or low curve
  • Severe liver disease-low curve

Diabetes Mellitus and Other Hyperglycemic and Hypoglycemic Disorders

Beckwith-Wiedemann Syndrome

  • (Inherited syndrome characterized by various abnormalities [e.g., macroglossia, umbilical hernia, gigantism that may be unilateral, abnormal ear lobe grooves, microcephaly])
  • Symptomatic hypoglycemia in ≤ 50% of patients, usually within first day, but may occur up to 3 days later; may be severe, difficult to control, and lasts for several months.
  • Hypocalcemia may occur.
  • Polycythemia may occur.
  • Cytogenetic studies are normal.

Classification of Diabetes Mellitus and Other Hyperglycemic Disorders

  • Type I: immune-mediated beta cell destruction diabetes mellitus (formerly called insulin-dependent, juvenile-onset, ketosis-prone, or brittle diabetes mellitus); represents 10-20% of diabetic patients. Autoantibodies are present in 85-90% of cases. Insulin secretion is virtually absent. Plasma C-peptide low or undetectable. Other autoimmune disorders may be present (e.g., Graves' disease, Hashimoto's thyroiditis, Addison's disease, PA). No autoantibodies in 10-15% of cases; strongly inherited.

P.616

  • Type 2 (formerly called non-insulin-dependent or adult-onset diabetes mellitus); represents 80-90% of diabetic patients. Varies from predominantly insulin resistance with relative deficiency to predominantly insulin secretory defect with insulin resistance. Relative rather than absolute insulin deficiency. Not due to autoimmunity or other disorders listed below. Plasma insulin may be normal or increased but expected to be higher relative to blood glucose concentration. Ketosis occurs with stress (e.g., infection) but seldom spontaneously. Associated with dyslipidemia, obesity, increasing age, hypertension, family history.
  • Other specific types, e.g.,
    • Genetic defects of beta cell function (e.g., chromosome 12, 7, 20). Formerly referred to as maturity-onset diabetes of the young. Onset of mild hyperglycemia, usually before age 25 yrs, and impaired insulin secretion. Autosomal dominant inheritance.
    • Genetic defects in insulin resistance (e.g., leprechaunism, type A insulin resistance, Rabson-Mendenhall syndrome, lipoatrophic diabetes)
    • Diseases of exocrine pancreas (e.g., pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis)
    • Endocrine disorders (e.g., Cushing's syndrome, acromegaly, pheochromocytoma, aldosteronoma, hyperthyroidism, glucagonoma)
    • Drug/chemical induced (e.g., glucocorticoids, phenytoin, beta-adrenergic agonists, pentamidine, thiazides, interferon-alpha)
    • Infections (e.g., CMV infection, congenital rubella)
    • Uncommon forms of immune-mediated diabetes (e.g., anti-insulin receptor antibodies, stiff-man syndrome)
    • Other genetic syndromes that may be associated with diabetes mellitus (e.g., Down syndrome, Klinefelter's syndrome, Turner's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome, porphyria, Prader-Willi syndrome)
    • Gestational diabetes mellitus (see below)

Criteria for Diagnosis

  • Diabetes Mellitus
    • Random glucose >200 mg/dL when classical symptoms are seen or
    • Fasting (>8 hrs) serum glucose ≥126 mg/dL or
    • 2-hr glucose >200 mg/dL after 75-gm glucose load. OGTT not recommended for routine use.
    • Must be confirmed on another day by any of the previous tests.
    • Fasting blood glucose ≥126 mg/dL = provisional diagnosis of diabetes mellitus; must be confirmed as noted previously.
    • Diagnosis of "acute metabolic decompensation with hyperglycemia" need not be confirmed on a subsequent day.
  • Impaired Glucose Tolerance
    • Fasting glucose ≥110 mg/dL but <126 mg/dL in nonpregnant adult.
    • With OGTT, 2-hr value ≥140 and <200 mg/dL. Replaces terms latent and chemical diabetes.
  • Impaired Fasting Glucose
    • Fasting glucose ≥110 mg/dL but <126 mg/dL or
    • With OGTT, 2-hr value ≥140 but <200 mg/dL.
  • In absence of pregnancy, impaired glucose tolerance and impaired fasting glucose are risk factors for future diabetes mellitus and cardiovascular disease; not clinical entities.
  • Other causes of transient glucose intolerance must be ruled out before an unequivocal diagnosis of diabetes mellitus is made
  • Test asymptomatic undiagnosed individuals every 3 yrs over age 45.
  • Test at younger age if
    • HDL cholesterol is ≤35 mg/dL or triglyceride is ≥250 mg/dL.
    • Previous impaired glucose tolerance or impaired fasting glucose.
    • Obese.
    • Has first-degree relative with diabetes mellitus.
    • Member of high-risk ethnic population (e.g., black, Native American, Hispanic).
    • Delivered baby weighing >9 pounds.
  • See sections on diabetic nephrosclerosis, papillary necrosis, GU tract infection, serum lipoproteins, etc.

P.617

Table 13-11. Differential Diagnosis of Diabetic Coma

Coma, Nonketotic, Hyperosmolar Hyperglycemic

  • (Due to combination of severe dehydration caused by inadequate fluid intake and insulin deficiency; occurs predominantly in type II diabetes mellitus)
  • See Table 13-11 and .
  • Blood glucose is very high, often 600-2000 mg/dL, but contrary to expectation in diabetic coma, acidosis and ketosis are minimal and plasma acetone is not found.
  • Serum osmolality is very high (normal = 280-300 mOsm/L). In mildly drowsy patients, mean is 320 mOsm/L. At level of 350 mOsm/L, some confusion or some stupor is seen. At level >350 mOsm/L, many patients are in coma. At 400 mOsm/L, most patients are obtunded. State of consciousness does not correlate with height of acidemia.
  • ○ Serum sodium may be increased, normal, or decreased but is disproportionately decreased for degree of dehydration due to marked hyperglycemia (artifactual decrease 1.6 mEq/L for every 100 mg/dL increase of serum glucose).
    • Increased sodium with marked hyperglycemia indicates severe dehydration.
  • Serum potassium may be increased (due to hyperosmolality), low (due to osmotic diuresis with urinary loss), or normal depending on balance of factors.
  • BUN is increased (70-90 mg/dL) more than in diabetic ketoacidosis.
  • Laboratory findings due to complications or precipitating factors
    • Renal insufficiency in 90% of cases
    • Infection (e.g., pneumonia)
    • Drugs (e.g., steroids, phenytoin, potassium-wasting diuretics such as thiazides and furosemide, others [propranolol, diazoxide, azathioprine])
    • Other medical conditions (e.g., cerebrovascular or cardiovascular accident, subdural hematoma, severe burns, acute pancreatitis, thyrotoxicosis, Cushing's syndrome)
    • Glucose overloading or use of concentrated glucose solutions (e.g., hyperalimentation, dialysis, IV infusions in treatment of burns)
    • Spontaneous in 5-7% of cases
    • Preexisting mild diabetes mellitus type II
    • Dehydration
  • Clinical picture: A middle-aged or older person with diabetes of recent onset or unrecognized diabetes, who shows neurologic symptoms (e.g., convulsions or hemiplegia) and then becomes stuporous or comatose

Diabetes Mellitus, Gestational

  • Hyperglycemia that develops for the first time during pregnancy; affects ~4% of pregnant women; most have return to normal glucose tolerance after delivery. 60% become diabetic in next 16 yrs.

P.618

Table 13-12. Comparison of Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic Nonketotic Coma

P.619

  • Diagnosis is necessary for short-term identification of increased risk of fetal morbidity (stillbirth, macrosomia, birth trauma, hypoglycemia, hyperbilirubinemia, hypocalcemia, polycythemia).
  • Screening of all pregnant women should include
    • Random (need not be fasting) venous blood glucose 1 hr after ingestion of 50 gm of glucose at 24-28 wks' gestation. Values >140 mg/dL are indication for 3-hr GTT with 100 gm glucose. 1-hr, 50-gm test is abnormal in ~15% of pregnant women, ~14% of whom have abnormal 3-hr OGTT. Sensitivity is ~79%, specificity is ~87%.

Diagnostic Criteria

  • At least two of the following glucose plasma levels are found on OGTT with 100-gm glucose loading dose:
  • Fasting ≥105 mg/dL
  • 1 hr ≥190 mg/dL
  • 2 hrs ≥165 mg/dL
  • 3 hrs ≥145 mg/dL
  • If abnormal results during pregnancy, repeat GTT at first postpartum visit; if GTT is normal, diagnose as diabetes mellitus only during pregnancy, but blood glucose should be tested at every subsequent visit because of increased risk (30% during next 5-10 yrs) of developing diabetes mellitus. If postpartum GTT is abnormal, classify as impaired glucose tolerance, impaired fasting glucose, or diabetes mellitus using above criteria.
  • Glycosylated Hb and fructosamine are not recommended tests for detection of gestational diabetes.
  • For management of diabetes mellitus during pregnancy, goal is fasting plasma glucose of 60-110 mg/dL and postprandial levels of <150 mg/dL. Measure serum or 24-hr urine estriol for fetal surveillance. Amniotic fluid lecithin/sphingomyelin ratio, phosphatidylglycerol, shake test, or fluorescence polarization to evaluate fetal pulmonary maturity.
  • During labor, keep maternal glucose at 80-100 mg/dL; beware of markedly increased insulin sensitivity in immediate postpartum period.

Laboratory Evaluation of Fetus

  • During third trimester, urinary estriol level is used as indicator of fetoplacental integrity.
    • Placental function is also indicated by hCG, human placental lactogen, estradiol, and progesterone levels. Lecithin/sphingomyelin ratio measured on amniotic fluid is used to predict pulmonary maturity.
  • At time of cesarean section, before opening amniotic sac, obtain sterile sample of amniotic fluid for culture, Gram stain, lecithin/sphingomyelin ratio.

Diabetes Mellitus, Neonatal

  • Blood glucose is often between 245 and 2300 mg/dL.
  • Metabolic acidosis of some degree is usually present.
  • Ketonuria is variable.
  • Laboratory findings due to dehydration
  • Laboratory findings due to infection or CNS lesions, which are present in one-third of patients
  • Has been detected as early as fourth day. Usually is transient.
  • Increased association with postmaturity, low birth weight, neonatal hypoglycemia, steroid therapy early in neonatal period.

Laboratory Evaluation of Infant

  • 47% risk of hypoglycemia  Check blood glucose at 1, 2, 3, 6, 12, 24, 36, 48 hrs
  • 22% risk of hypocalcemia  Check blood calcium at 6, 12, 24, 48 hrs
  • 34% risk of polycythemia  Check Hct at 1, 24 hrs
  • 19% risk of hyperbilirubinemia Check serum bilirubin at 24, 48 hrs
  • Sixfold increased risk of hyaline membrane disease During first hour of life, examine gastric aspirate with Gram stain for bacteria and PMNs and perform shake test for lecithin/sphingomyelin

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Fig. 13-9. Algorithm for neonatal hypoglycemia. (GSD = glycogen storage disease.)

  • 9% risk of major congenital anomalies (e.g., cardiac, renal) and other problems (e.g., renal vein thrombosis, excess mucus)  Check blood gases for evaluation of ear, nose, and throat, umbilicus, rectum, urine, blood, CSF, gastric aspirate

Glucagonoma

  • (Arise from alpha cells of pancreatic islets. 60% are malignant.)
  • Diabetes mellitus
  • Anemia
  • Increased serum insulin level is characteristic
  • Increased serum level of glucagon. Serum proglucagon is also increased occasionally.
  • ○ Clinical clue is association of dermatitis (necrolytic migratory erythema) with insulin-requiring diabetes.

Hyperglycemia, With Heterogeneous Genetic Diseases



  • Alström's syndrome
  • Ataxia-telangiectasia
  • Diabetes mellitus
  • Friedreich's ataxia
  • Hemochromatosis
  • Herrmann's syndrome
  • Hyperlipoproteinemias (three different types)
  • Isolated growth hormone (GH) deficiency
  • Laurence-Moon-Bardet-Biedl syndrome
  • Lipoatrophic diabetes
  • Myotonic dystrophy
  • Optic atrophy

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  • Prader-Willi syndrome
  • Refsum's syndrome
  • Schmidt's syndrome
  • Werner's syndrome

Hypoglycemia, Classification

  • See Table 13-13.
  • Diagnosis requires triad of low blood glucose at the time of spontaneous hypoglycemic symptoms and alleviation by administration of glucose that corrects hypoglycemia. (Glucose concentration is 15% lower in whole blood than in serum or plasma.)
  • Reactive (i.e., after eating)
    • Alimentary (rapid gastric emptying, e.g., after subtotal gastrectomy, vagotomy)
    • Impaired glucose tolerance as in diabetes mellitus (mild maturity onset)
    • Functional (idiopathic)
    • Rare conditions (e.g., hereditary fructose intolerance, galactosemia, familial fructose and galactose intolerance)
  • Fasting (spontaneous)-almost always indicates organic disease
    • Liver-severe parenchymal disease (including sepsis, congestive heart failure, Reye's syndrome) or enzyme defect (e.g., glycogen storage diseases, galactosemia)
    • Chronic renal insufficiency
    • Pancreatic
      • Insulinoma (pancreatic islet cell tumor)
      • MEN type I
      • Pancreatic hyperplasia
    • Deficiency of hormones that oppose insulin (e.g., decreased function of thyroid, anterior pituitary, or adrenal cortex)
    • Postoperative removal of pheochromocytoma
    • Large extrapancreatic tumors (65% are intra- or retroperitoneal fibromas or sarcomas)
    • Certain epithelial tumors (e.g., hepatoma, carcinoid, Wilms' tumor)
    • Drugs (including factitious use)
      • Insulin
      • Sulfonylureas
      • Alcohol
      • Salicylates
      • Pentamidine
      • Quinine
      • Propranolol (rare)
      • Others may potentiate effect of sulfonylurea (e.g., sulfonamides, butazones, coumarins, clofibrate)
    • Artifactual (high WBC or RBC count, e.g., leukemia or polycythemia)
    • Starvation, anorexia nervosa, lactic acidosis, intense exercise
    • Insulin antibodies or insulin receptor antibodies
  • Combined reactive and fasting types
    • Insulinoma
    • Adrenal insufficiency
    • Insulin antibodies or insulin receptor antibodies

Infants

  • See Fig. 13-9.
  • Transient (<14 days)
  • Symptomatic or asymptomatic; occurs in 1-3 in 1000 full-term infants
    • Maternal (e.g., diabetes, toxemia, complicated labor or delivery)
    • Infant, e.g.,
      • Prematurity, small size for gestational age
      • Intrauterine malnutrition
      • Erythroblastosis
      • Secondary, e.g., sepsis, asphyxia, anoxia, cerebral or subdural hemorrhage
      • Congenital anomalies
      • Iatrogenic, e.g., postoperative complications, abrupt cessation of glucose infusion, after exchange transfusion, cold injury

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Table 13-13. Laboratory Interpretation of 72-Hr Fast for Hypoglycemia

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    • Persistent
    • Hyperinsulinism
      • Beta cell hyperplasia
      • Nesidioblastosis
      • Beckwith-Wiedemann syndrome (children also have Wilms' and other embryonal tumors, visceromegaly, macroglossia)
      • Beta cell tumor
      • Teratoma
    • Endocrine disorder
      • Hypothyroidism
      • Congenital adrenal hyperplasia (CAH)
      • Anterior pituitary hypofunction
      • Decreased glucagon
    • Hepatic enzyme deficiencies
      • Glycogen storage disease types I, III, VI, 0
      • Congenital fructose intolerance
      • Galactose 1-phosphate deficiency
    • Maple syrup urine disease
    • Galactosemia
    • Hereditary tyrosinemia
    • Methylmalonic acidemia
    • Propionicacidemia

Hypoglycemia, Factitious

  • See Table 13-13, and Fig. 13-10.

Due to Insulin

  • During hypoglycemic episode, high insulin and low C-peptide levels in serum confirm diagnosis of exogenous insulin administration (diagnostic triad). (Increased endogenous insulin secretion is always associated with increased secretion of C-peptide, which is the part of the proinsulin molecule cleaved off when insulin is secreted and therefore is produced in equimolar amounts with insulin.)
  • Insulin/glucose ratio >0.3 in serum (normal is <0.3). Increased ratio is also seen in autonomous production due to insulinoma.
  • Extreme elevations of serum insulin (e.g., >1000 µU/mL) suggest factitious hypoglycemia (fasting levels in patients with insulinoma are rarely >200 µU/mL).
  • Insulin antibodies appear in 90% of persons injected with beef or pork insulin and 50% of those injected with human insulin for more than a few weeks but are almost never present in persons not taking insulin (rarely occur on an autoimmune basis), although this indicator may be less useful with the future use of more purified and human insulin.

Due to Sulfonylureas

  • Biochemically indistinguishable from insulinoma (increased serum C-peptide and insulin levels with insulin/C-peptide molar ratio <1.0).
  • Specific chemical assay can identify the agent in serum or urine.

Due to Tolbutamide

Acidification of urine causes a white precipitate due to formation of carboxytolbutamide.

Hypoglycemia, Leucine-Induced

  • Symptoms within 30 mins of consumption of high-protein meal or after prolonged fast. May be neonatal or appear later in first year; symptoms become increasingly severe; tends to improve spontaneously by 4-6 yrs of age.
  • Blood glucose falls >50% within 20-45 mins after oral administration of L-leucine. Same result in 70% of patients with insulinoma.

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Table 13-14. Comparison of Laboratory Findings in Causes of Hypoglycemia

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Fig. 13-10. Algorithm for diagnosis of suspected insulinoma. (CT = computed tomography.)

Hypoglycemia, Neonatal

Diagnostic Criteria

  • Plasma glucose <25 mg/dL in low-birth-weight infants.
  • Plasma glucose <35 mg/dL in normal-birth-weight infants in first 72 hrs. Plasma glucose <45 mg/dL in normal-birth-weight infants after 72 hrs.
  • Make diagnosis on basis of two abnormal glucose values, e.g., two plasma levels, one plasma and one CSF level.
    • Plasma glucose values are 14% higher than whole blood values.
    • Capillary blood samples should be taken from warm heel and transported to laboratory on ice (at room temperature, blood glucose level decreases by 18 mg/dL/hr).
    • Determination by measurement of reducing substances may give falsely elevated levels for glucose because in blood of newborns, non-glucose-reducing substances

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may range up to 60 mg/dL. Therefore use techniques that measure glucose specifically, e.g., glucose oxidase.

    • Bedside glucose monitor utilizing dipsticks should not be used for this diagnosis-is not reliable in the low glucose range.

Due To

  • Transient symptomatic or asymptomatic hypoglycemia may be associated with delayed feeding, toxemia, perinatal asphyxia, twin birth, hypothermia, or low birth weight, or may be idiopathic. Occurs in 1-3 in 1000 full-term infants.
  • Hyperinsulinism (e.g., maternal diabetes, erythroblastosis, Beckwith-Wiedemann syndrome, insulinoma, maternal drug therapy or starvation)
  • Hormone deficiencies (e.g., hypothyroidism, pituitary hypofunction, adrenal insufficiency or unresponsiveness)
  • Hereditary metabolic disorders
    • Galactosemia
    • Type I glycogen storage disease
    • Amino acid disorders (e.g., tyrosinemia type I)
    • Organic acid disorders (e.g., methylmalonicacidemia, propionicacidemia)
    • Carnitine deficiency disorders (e.g., carnitine palmityl transferase deficiency)
    • Disorders of fat oxidation (e.g., medium-chain acyl-CoA dehydrogenase deficiency)
    • Disorders of gluconeogenesis (e.g., pyruvate carboxylase deficiency)
  • Others
    • Iatrogenic (e.g., after exchange transfusion)
    • Miscellaneous (e.g., sepsis diarrheal illness, CNS abnormalities, congenital heart disease)

Infants of Diabetic Mothers

  • Blood glucose is <30 mg/dL in ≤50% of infants of diabetic mothers; usually asymptomatic; usually within first hours after birth. Hypocalcemia is common in these cases and occurs at 24-36 hrs after birth.
  • Glucose levels should be checked every hour for first 6 hrs of life.

Insulin Autoimmune Syndrome

  • (Cause is unknown but patients may be receiving drugs containing a sulfhydryl group [e.g., pyritinol]. Associated with other autoimmune syndromes [e.g., hyperthyroidism, autoimmune thrombocytopenia with primary biliary cirrhosis]. Appears to be a self-limiting condition.)
  • Fasting hypoglycemia.
  • ○ Elevated serum insulin and C-peptide levels that are discordant (insulin/C-peptide molar ratio >1.0) indicates the possible presence of these antibodies. These elevations are artifactual due to effect of antibody on assay method.
  • May be difficult to distinguish from factitious hypoglycemia.
  • Extremely high levels of antiinsulin antibodies that rapidly decrease.
    • Never any prior exposure to exogenous insulin.









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