Goiter, Simple, Nontoxic Diffuse

Goiter, Simple, Nontoxic Diffuse

No specific laboratory findings

Goiter, Single Or Multiple Nodular

• See Fig. 13-3.
• FNA biopsy produces a definitive diagnosis in 85% of cases of thyroid nodules.
• Isotope scanning of thyroid may show decreased ("cold") or increased ("hot") uptake.
• Functioning solitary adenoma may produce hyperthyroidism.
• In multinodular goiter, TSH is rarely increased; usually is in normal or low-normal range.
• T , T , TBG, thyroglobulin do not differ in benign and malignant cyst fluid.

Hyperthyroidism

See Table 13-3 and Fig. 13-4.

Thyrotoxicosis with Hyperthyroidism

• Due To
• Thyroid-stimulating immunoglobulins
• Diffuse toxic goiter (Graves' disease-autoimmune disorder due to antibody to TSH receptors, causing destruction of thyroid gland)
• Autonomous nodules in thyroid (serum TSH is low)
• Toxic adenoma
• Toxic multinodular goiter
• Neonatal thyrotoxicosis associated with maternal Graves' disease
• Thyrotropin-induced (TRH) hyperthyroidism (serum TSH is increased)
• With pituitary tumor
• Without pituitary tumor
• Secretion of nonpituitary TSH
• Trophoblastic tissues (neoplasms that secrete hCG which binds to TSH receptors), e.g.,
• Choriocarcinoma, hydatidiform mole
• Embryonal carcinoma of testis

Thyrotoxicosis without Hyperthyroidism

• Due To
• Thyroiditis
• Hashimoto's
• Lymphocytic (painless)
• Subacute granulomatous
• Iodide-induced (Jod-Basedow)
• Metastatic functioning thyroid carcinoma
• Struma ovarii with hyperthyroidism
• Factitious
• Drug effects (e.g., amiodarone)
• In neonate, is usually due to transplacental maternal TSH receptor-stimulating antibodies that mimic TSH action. May persist for several months.
• 2% of hospitalized elderly patients have unsuspected hyperthyroidism
• Serum TSH is decreased; is now used by most as initial screening test for thyrotoxicosis because it detects virtually all hyperthyroid patients except the very rare cases involving pituitary neoplasms that secrete TSH, ectopic secretion of TSH or TRH, resistance to thyroid hormone (pituitary, generalized), and artifact (e.g., autoantibodies to TSH, human antimouse antibodies).
• Serum total and free T are increased. With a typical clinical picture of hyperthyroidism, serum T >16 µg/dL confirms the diagnosis. Normal in ~10% of patients but TSH is low, suggesting use of both tests to confirm the diagnosis. Severity of hyperthyroidism does not correlate with thyroid hormone levels.

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• Serum T concentration on RIA and T resin uptake are increased in ≤85% of patients. T is usually elevated to a greater degree than T4. Ratio of T to T is >20:1 in T -dependent type of Graves' disease.
• FTI (serum T concentration × T resin uptake) is a useful initial screening test, because it is not affected by alterations in T -binding protein sites. Is increased in ~90% of hyperthyroid patients.
• TRH stimulation test.
• Serum TBG is normal.
• RAIU is increased. It is relatively more affected at 1, 2, or 6 hrs than at 24 hrs. It may be normal with recent iodine ingestion. RAIU is no longer used for diagnosis of hyperthyroidism but should be performed before administration of therapeutic dose of I.
• Salivary and urinary excretion of radioactive iodine are increased.
• ○ Technetium pertechnetate ( Tc) uptake parallels hormone production and may be useful when T and TSH results are discordant.
• ○ Microsomal antibodies are found in moderate to high titers in most patients with Graves' disease; may be helpful in confirming diagnosis in a hyperthyroid patient without ocular findings or a euthyroid patient with eye findings.
• ○ Other thyroid autoantibodies are thyroid-stimulating immunoglobulins and TSH-binding inhibitory immunoglobulins found only with Graves' disease; sometimes helpful in diagnosis and management. TSH-receptor antibody (formerly called LATS, long-acting thyroid stimulator) is present in 80-100% of untreated Graves' disease patients.
• Thyroid suppression test: T administration decreases RAIU in normal persons but not in hyperthyroid persons. Was replaced by TRH stimulation test.
• Serum cholesterol is decreased, and total lipids are usually decreased.
• Glucose tolerance is decreased with early high peak and early fall. Hyperglycemia and glycosuria are present.
• Liver function tests show impairment.
• Creatine excretion in urine and creatine tolerance are increased.
• Normal serum creatine almost excludes hyperthyroidism.
• Serum total and ionized calcium are increased in >10% of patients. Serum phosphorus is high-normal or increased. Parathormone level is decreased. Serum 1,25-dihydroxy-vitamin D is decreased. Urinary and fecal excretion of calcium are increased. Increased serum ALP in 75% of patients (liver and bone origin; only liver ALP in 919j913j 7%; only bone ALP in 15%). After successful treatment, may continue to increase and not become normal for up to 18 mos.
• Serum ferritin is increased.
• Hb and TIBC are decreased.
• Unusual laboratory manifestations of hyperthyroidism include hypoproteinemia, malabsorption.
• Serum ACE is increased.
• Laboratory findings due to complications of treatment
• Surgery-hypoparathyroidism (3% of cases), hypothyroidism (30-50% of cases)
• Drugs-agranulocytosis, hepatitis, vasculitis, drug-induced lupus
• T toxicosis-causes 5% of cases of hyperthyroidism
• Should be suspected in patients with clinical thyrotoxicosis in whom usual laboratory tests are normal (serum T , FTI, 24-hr RAIU, TBG, and T4-binding albumin), but serum T is increased.
• RAIU is autonomous (not suppressed by T administration).
• TSH may be increased.
• Abnormal TRH test (lack of TSH response to TRH)

Factitious Hyperthyroidism

• (Self-induced hyperthyroidism by ingestion of T or Cytomel [T
• Increased total and free serum T or T , depending on which drug is ingested. T may be absent if T is ingested.
• Serum Tg is depressed to low-normal level or undetectable unless patient is taking desiccated thyroid extract of Tg; therefore may be useful to distinguish from early or recovery phases of subacute thyroiditis and most causes of hyperthyroidism, in which it is increased.
• RAIU is low when all other thyroid function tests indicate hyperthyroidism.
• Augmented RAIU after TSH administration, whereas patients with subacute and painless thyroiditis usually do not have any response to TSH administration.

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Thyroid Storm

• (Occurs in operative/perioperative period; fever, symptoms of CNS, GI, and cardiovascular systems)
• Thyroid function test values may be somewhat higher than in uncomplicated thyrotoxicosis but are useless for differentiation.
• Transient hyperglycemia is common.
• Abnormal liver function tests are common.

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• Abnormal serum electrolytes (especially decreased potassium, mild to moderate hypercalcemia) and decreased arterial pCO are common.
• Laboratory findings due to associated conditions, especially bacterial infection (increased WBC, shift to left; bacteria in urine, sputum, etc.), pulmonary or arterial embolism

Hypothyroidism

See Table 13-6, Fig. 13-1 and Fig. 13-5.

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Due To

• Treatment of preceding hyperthyroidism (surgery, drugs, radioiodine)
• Irradiation (e.g., treatment of head and neck cancer)
• Autoimmune disease, thyroiditis
• Pituitary disease (e.g., tumors, granulomas, cysts, vascular disorders)
• Hypothalamic disease (e.g., granulomas, TRH deficiency, pituitary-stalk section)
• Iodine deficiency
• Drugs (e.g., iodides, propylthiouracil, methimazole, phenylbutazone, amiodarone, lithium)
• Congenital developmental defects
• Organification defect (diagnosis by perchlorate washout test)

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• 2% of hospitalized elderly patients and 0.5% of patients admitted to psychiatric hospitals or units have unsuspected hypothyroidism
• Serum TSH is increased in proportion to degree of hypofunction; is at least 2× and often 10× normal value. A single determination is usually sufficient to establish the diagnosis. Because increased serum TSH is earliest evidence of hypothyroidism, it should be measured to document subclinical hypothyroidism and begin early therapy in patients with Graves' disease treated with radioactive iodine or surgery or with chronic thyroiditis. TSH is especially useful in cases in which T and FTI are not diagnostic and is essential when the diagnosis of hypothyroidism must be confirmed. Serum TSH should always be measured before treatment for all patients with hypothyroidism to distinguish primary from secondary (pituitary) or tertiary (hypothalamic) types, because the latter two are often associated with secondary adrenal insufficiency, which could be lethal if unrecognized.
• Increased TSH and decreased FT establishes diagnosis of primary hypothyroidism.
• Increased TSH and normal FT indicates early stage of primary hypothyroidism.
• Normal or decreased TSH and decreased FT suggests hypothyroidism secondary to decreased TSH secretion (hypopituitarism).
• TSH is undetectable or inappropriately low in relation to degree of thyroid hormone deficiency in secondary or tertiary hypothyroidism.
• Serum T and FT concentration are decreased; T >7 µg/dL almost certainly excludes hypothyroidism. Measurement of serum FT and TSH together is diagnostic method of choice.
• Serum T concentration is decreased (may be normal in 20-30% of hypothyroid patients), and serum T resin uptake is decreased (may be normal in ≤50% of hypothyroid patients). T has little role in this diagnosis.
• FTI is decreased
• Serum T /T ratio is increased.
• RAIU is usually decreased; is not helpful in diagnosis. Salivary and urinary excretion of radioactive iodine are decreased.
• TSH stimulation (20 U/day for 3 days) increases RAIU to approximately normal (20%) in secondary but not in primary hypothyroidism. Diagnosis of primary hypothyroidism is unlikely if RAIU increases substantially after administration of TSH. Replaced by serum TSH.
• A TRH-provocative test shows a normal or delayed TSH response in tertiary, no response in secondary, and exaggerated and prolonged response in primary hypothyroidism. (See Fig. 13-2.)
• Serum TBG is normal.
• Serum cholesterol is increased (may be useful to follow effect of therapy, especially in children).
• Serum myoglobin is significantly increased in 90% of untreated patients with long-term hypothyroidism; inversely proportional to serum T and T . Gradual decrease after T therapy begins with return to normal before TSH becomes normal.
• Serum total CK and CK-MM are increased.
• Increase in serum CK (10-15×), AST (2-6×), LD (2-3×) above upper reference limit in 40-90% of cases.
• Glucose tolerance is increased (OGTT results are flat; IV GTT results are normal); fasting blood sugar level is decreased.
• Serum calcium is sometimes increased.
• Serum ALP is decreased.
• Serum carotene is increased.
• Normocytic normochromic anemia may occur.
• Serum iron and TIBC may be decreased.
• Serum sodium is decreased in ~50% of cases.
• CSF protein is elevated (100-340 mg/dL) in 25% of cases of myxedema.
• Urine 17-KS and 17-OHKS may be increased.
• Proteinuria in ~8% of cases.
• Adequate levothyroxine treatment results in normal serum T and TSH. When hypothyroidism is due to thyroid failure, the dose is gradually increased, and adequate therapy is indicated when serum T increases to normal and TSH decreases to normal (may take several months). TSH response to TRH also returns to normal if originally abnormal, but this test is generally not necessary. When hypothyroidism

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is secondary or tertiary, TSH is not useful and serum T is used to judge adequacy of therapy. When levothyroxine is used for TSH suppression in patients with thyroid cancer, nodular disease, or chronic thyroiditis, the decreased TSH cannot be distinguished from normal levels; therefore levothyroxine dose is increased until serum T is normal and TSH is undetectable, or an abbreviated TRH test is performed with a single TSH measurement 15 mins after injection of TRH-if TSH is undetectable, then TSH secretion is considered adequately suppressed.

• Laboratory findings indicative of other autoimmune diseases (e.g., PA and primary adrenocortical insufficiency occur with increased frequency in primary hypothyroidism)
• Thyroid hormone status should be reassessed at least yearly in treatment of hypothyroidism.
• Laboratory findings due to involvement of other organs (e.g., muscle, heart, ileus, CNS, etc.)

Myxedema Coma

• Hypoglycemia, hyponatremia, and findings due to adrenocortical insufficiency may be found.
• Serum creatinine may be increased.
• Arterial pCO may be increased and pO2 decreased.
• Increased WBC and shift to left may occur.

Hypothyroidism, Neonatal

• ~2-4% of cases of infantile hypothyroidism are not detected on neonatal screening.
• Estimated cost of finding one case of congenital hypothyroidism is ~$10,000. Estimated cost of institutionalization and special education of mental retardation due to late or no therapy is $105,000.
• Neonatal screening is usually performed on same filter paper specimen of blood used for PKU screening on third to fifth day of life. Do not do T or TSH during first few days of life when levels may surge; e.g., mean cord T of 11-12 µg/dL may increase to 16 µg/dL by 24-36 hrs and then fall. T rises more rapidly. TSH peaks 30 mins after birth. Changes in T , T , and TSH are less marked in premature infants.
• RAIU ( I) scan should be performed on infants with confirmed hypothyroidism to differentiate thyroid agenesis/dysgenesis from dyshormonogenesis.
• If mother has autoimmune thyroid disease, infant should be checked for TSH receptor-blocking antibodies, because this type of hypothyroidism cannot be distinguished clinically from thyroid agenesis/dysgenesis and RAIU may be absent. Hypothyroidism is transient.

Due To

Primary Hypothyroidism (Incidence 1 in 3600 to 1 in 4800)

• Aplasia and hypoplasia  63%
• Ectopic gland   23%
• Inborn errors of thyroid hormone synthesis or metabolism 14%
• Increased serum TSH is most sensitive test for primary hypothyroidism.
• Decreased serum T
• Normal or decreased serum T
• Normal serum TBG.
• Increased serum CK.

Deficiency of TBG (Incidence 1 in 8000 to 1 in 12,000)

• Hereditary
• Drug effect
• Hypoproteinemia
• Decreased serum T (e.g., 3.2 µg/dL)
• Normal serum TSH

Secondary Hypothyroidism (Incidence 1 in 50,000 to 1 in 70,000)

• Pituitary aplasia, septo-optic dysplasia
• Idiopathic hypopituitarism
• Hypothalamic disease
• Serum TSH is low or not detectable.
• Decreased serum T
• TSH response to TRH differentiates pituitary from hypothalamic cause of hypothyroidism
• Normal serum TBG

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Transient

• Prematurity
• Euthyroid sick syndrome
• Small size for gestational age
• Maternal ingestion of iodides or antithyroid drugs
• Idiopathic
• Treatment of neonatal hypothyroidism is based on frequent T4, TSH tests. For example, T should be kept >10 µg/dL during first year, >8 µg/dL during second year, >7 µg/dL after that. 10% of congenital hypothyroidism patients may need T of 14-15 µg/dL to achieve normal TSH levels.

Pregnancy and Thyroid Function Tests

• See Table 13-3.
• Thyroid function test values are very different in normal pregnancy.
• Serum TBG is increased.
• Serum T rises from nonpregnant level of 4-8 µg/dL to 10-12 µg/dL from 12th week of gestation until 6 wks postpartum.
• Serum free T and free T are normal.
• T uptake is decreased; FTI remains normal.
• Increased serum T , rT
• TSH is slightly increased by 16th week.
• RAIU is increased but the test is contraindicated.
• In hyperthyroidism, both serum T uptake and T are increased, but in the pregnant euthyroid patient or euthyroid patient taking birth control pills or estrogens, T is increased and T uptake is decreased. Hyperthyroidism may be indicated by the failure of T uptake to decrease during pregnancy.
• T uptake gradually decreases (as early as 3-6 wks after conception) until the end of the first trimester and then remains relatively constant. It returns to normal 12-13 wks postpartum. Failure to decrease by the eighth to tenth week of pregnancy may indicate threatened abortion (the patient's normal nonpregnancy level should be known).
• Maternal hypothyroidism is relatively uncommon because of spontaneous abortion and menstrual irregularities. Most often is iatrogenic or due to Hashimoto's disease. Serum T in the normal nonpregnancy range of 4-8 µg/dL should suggest hypothyroidism.
• Maternal hyperthyroidism: Serum T is increased above the normal range for pregnancy (>12 µg/dL) with T uptake increased to normal nonpregnancy range.

Thyroid Hormone, Generalized Tissue Resistance

• (Genetic syndrome)
• Serum thyroid hormone levels are elevated in presence of nonsuppressed serum TSH with isolated pituitary resistance and show variable degree of thyrotoxicosis. In generalized tissue resistance involving pituitary and peripheral tissues, serum TSH and total and free T show variable increases with or without clinical hypothyroidism.
• Elevated thyroid hormone levels are not due to drugs, intercurrent illness or alterations in thyroid hormone transport proteins.
• Full replacement doses of thyroid hormone fail to produce expected suppression of TSH and fail to induce appropriate peripheral tissue responses.
• Few clinical manifestations; goiter is most common in adults, growth and mental retardation in children. No clinical evidence of hypo- or hyperthyroidism.

Thyroiditis

Hashimoto's Thyroiditis (Chronic Lymphocytic Thyroiditis)

• Thyroid function may be normal; occasionally a patient passes through a hyperthyroid stage. 15-20% of patients develop hypothyroidism, but Hashimoto's disease is a very unlikely cause of hypothyroidism in the absence of thyroglobulin and microsomal antibodies.
• Test for antimicrosomal antibodies is 99% sensitive and 90% specific. Test for antithyroglobulin antibodies is 36% sensitive and 98% specific and is seldom positive if

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microsomal antibodies are negative. Thus antimicrosomal antibody alone is sufficient for diagnosis. High titers are pathognomonic.

• ○ Serum TSH is earliest indicator of hypothyroidism; is increased in one-third of persons who are clinically euthyroid and in those with clinical hypothyroidism, many of whom have normal T , T , and T
• Abnormal iodide-perchlorate discharge test exceeding 10% of gland radioactive iodine in 60-80% of cases (indicates an underlying organification defect)
• Response to TSH distinguishes primary and secondary hypothyroidism. If thyroid uptake for each lobe is measured separately after TSH, a difference between the lobes may demonstrate lobar thyroiditis when total uptake is apparently normal.
• Radioactive iodine scan may show involvement of only a single lobe (more common in younger patients); "salt and pepper" pattern is classical.
• RAIU is variable; may be higher than expected in hypothyroidism.
• Biopsy of thyroid may be diagnostic

Lymphocytic (Painless) Thyroiditis; Silent Thyroiditis

• This form of hyperthyroidism comprises ≤25% of all cases of hyperthyroidism; resolves spontaneously in several weeks to months and is often followed by a transient hypothyroidism during recovery period; common in postpartum period; multiple episodes may occur. Pathologic changes are less severe than in Hashimoto's thyroiditis, but the latter cannot be ruled out in biopsy specimens.
• Hyperthyroid phase is briefer in postpartum type (≤3 mos) than in sporadic type (≤12 mos).
• Increased serum T , T , T resin uptake, FTI. T /T ratio is <20:1. Become normal in 10 days with prednisone therapy.
• RAIU is very low (<3%); not increased after TSH administration.
• Serum TSH is low and fails to respond to TRH.
• Antithyroglobulin antibodies are increased in most patients; antimicrosomal antibodies are increased in ~60% of patients. High titers are rarely in the very high ranges seen in Hashimoto's thyroiditis.
• Nonspecific markers of inflammation are generally normal in contrast to granulomatous thyroiditis. ESR increased in 50% of patients to range of 20-40 mm/hr. WBC and serum proteins are normal.
• Urine iodide level is 2-5× higher than normal (due to leakage of iodinated material from thyroid).
• Recovery phase is complete in ~50%.
• Serum T and T fall into normal range, but RAIU and TSH response to TRH remain suppressed.
• Hypothyroid phase (occurs in 20-30% of patients; lasts 1-8 mos; most recover completely but a few develop permanent hypothyroidism; recurs in >10% of cases of sporadic type and more often in postpartum type)
• Antithyroid antibody titers are highest during this phase (especially in postpartum patients). Gradually decrease with time; 50% become negative within 6 mos.
• Serum TSH, T , and T gradually return to normal.
• RAIU, TRH test begin to normalize toward the end of this phase, and urinary iodide falls to normal levels (50-200 µg/day).

Subacute Granulomatous (de Quervain's) Thyroiditis

• (Probably of viral origin)
• Biopsy of thyroid confirms diagnosis.
• Antithyroglobulin antibodies may be present for up to several months, but the titer is never as high as in Hashimoto's thyroiditis. The level falls with recovery.
• ESR is increased.
• WBC is normal or decreased.
• Four sequential phases may be identified: hyperthyroid, euthyroid, hypothyroid, recovery.
• Hyperthyroid phase lasts 1-2 mos.
• Decreased RAIU is the characteristic finding and differentiates it from acute thyroiditis; may be <5% with bilateral involvement; is not increased by TSH administration. It may be >50% for several weeks after recovery.
• Increased total and free T ; T may be only mildly increased; T /T ratio is <20:1.
• Serum TSH is very low and does not respond to TRH.
• ESR is markedly increased.

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• Euthyroid phase lasts 1-2 wks.
• RAIU remains low.
• Hypothyroid phase lasts 2-6 mos.
• TSH increases.
• Recovery
• Return of radioactive iodine trapping is the first indication.
• 24-hr RAIU may rise above normal.
• Thyroid hormone levels rise to normal.
• TSH and RAIU fall to normal.
• Relapses occur in up to 47% of patients, usually in first year.

Suppurative Thyroiditis, Acute

• WBC and PMNs are increased in 75% of cases; absence may indicate anaerobic infection.
• ESR is increased.
• 24-hr RAIU is decreased in <50% of cases.
• Thyroid function tests are normal in 80% of cases.
• Staphylococcus causes one-third of cases; other organisms include Streptococcus pyogenes, Streptococcus pneumoniae, Enterobacteriaceae, Haemophilus influenzae, Pseudomonas aeruginosa, anaerobes. Fungi are rare and principally occur in immunocompromised patientsx.

Riedel's Chronic Thyroiditis

• Biopsy of thyroid confirms diagnosis
• Hypothyroidism when complete thyroid involvement occurs; otherwise normal laboratory findings.

Tests of Parathyroid Function and Calcium/Phosphate Metabolism

Calcitriol (1,25-Dihydroxy-Vitamin D), Serum

Interpretation

• Suppressed during hypercalcemia unless an autonomous source of PTH exists as in hyperparathyroidism. (Normal range <42 pg/mL in hypercalcemic and <76 pg/mL in normocalcemic patients.) Failure to suppress indicates extrarenal production as it is normally secreted only by kidney.

Increased In

• Sarcoidosis (synthesized by macrophages within granulomas)
• Non-Hodgkin's lymphoma (~15% of cases). Returns to normal after therapy.

Not Increased In

• Hyperparathyroidism
• Humoral hypercalcemia of malignancy (HHM)

Calcium, Ionized Serum

Calcium, Total Serum

Parathyroid Hormone (Pth), Serum

• See Fig. 13-6.

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Use

• Differential diagnosis of hyper- and hypoparathyroidism.
• Very sensitive in detecting PTH suppression by 1,25-dihydroxy-vitamin D; therefore used for monitoring that treatment of chronic renal failure.

Interpretation

• Serum calcium should always be measured at same time as PTH.
• Immunochemiluminescent method is PTH assay of choice; detects intact PTH and active N-terminal PTH. Sensitivity >90% for hyperparathyroidism. PTH is suppressed (<1 pmol/L) in 95% of cases of HHM unless coexisting parathyroid adenoma is found, which occurs in 4% of HHM cases (especially breast or gastric cancer). Normal in chronic renal failure in which almost all patients have increased C-terminal PTH (inactive) values. PTH >25% above ULN occurs only in hyperparathyroidism (primary or tertiary), post-acute tubular necrosis, or posttransplant hypercalcemia.

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Some laboratories may assay different parts of PTH molecule. PTH shows diurnal variation with low in morning and peak around midnight (Table 13-7).

Parathyroid Hormone-Related Protein (Pthrp), Serum

Increased (>1.5 pmol/L) In

• >90% of cases of HHM
• 75% of breast cancer patients with hypercalcemia
• Some patients with hypercalcemia and hematologic cancers
• ~10% of cases of cancers without hypercalcemia
• Becomes normal when hypercalcemia is corrected by treatment of cancer.
• C-terminal PTHrP is increased in renal insufficiency.
• May be increased in nonmalignant pheochromocytoma.
• Normal lactation
• Rarely may be increased in mammary hypertrophy or lymphedema.
• ~20% of cancer patients with hypercalcemia have only local osteolytic changes but not increased PTHrP.

Not Increased In

• Other causes of hypercalcemia (e.g., sarcoidosis, vitamin D intoxication).

Phosphate Clearance

• After a diet of 800 mg phosphate/day, determine serum phosphorus and BUN and 12-hr urine phosphorus.
• Normal: 6-17 mL/min
• Hyperparathyroidism: higher (even with renal dysfunction)
• Hypoparathyroidism: lower (e.g., <6 mL/min), even when hypocalcemia has been corrected

Phosphate Deprivation Test

• Low-phosphate diet (430 mg phosphate and 700 mg calcium for 3-6 days) causes low serum phosphate and increased serum calcium in persons with hyperparathyroidism but not in normal persons. Formerly used when blood chemistry tests were borderline.

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Phosphate, Tubular Reabsorption (TRP)

Use

• Diagnosis of hyperparathyroidism. Largely superseded by PTH assay.
• After a constant dietary intake of moderate calcium and phosphorus for 3 days, phosphorus and creatinine are determined in fasting blood and 4-hr urine specimens to calculate tubular reabsorption.
• 
• Normal: TRP is >78% on normal diet; higher on low-phosphate diet (430 mg/day).
• Hyperparathyroidism: TRP is <74% on normal diet; <85% on low-phosphate diet.

Interferences

• False-positive result may occur in uremia, renal tubular disease (some patients), osteomalacia, sarcoidosis.

Phosphorus, Serum

Diseases of Parathyroid Glands and Calcium, Phosphorus, and Alkaline Phosphatase Metabolism

Humoral Hypercalcemia of Malignancy (HHM)

• See Tables 13-8 and and Figs. 13-6 and .
• Hypercalcemia occurs in patients with cancer (typically squamous, transitional cell, renal, ovarian), 5-20% of whom have no bone metastases compared to patients with widespread bone metastases (myeloma, lymphoma, breast cancer). Both groups have large tumor burden and poor prognosis.
• Occurs in 20-35% of cases of breast cancer, 10-15% of cases of lung cancer, ~70% of cases of multiple myeloma, rare in lymphoma and leukemia.
• Rarely may occur in association with benign tumors (e.g., pheochromocytoma, dermoid cyst of ovary) ("humoral hypercalcemia of benignancy").
• Very high serum calcium (e.g., >14.5 mg/dL) is much more suggestive of HHM than of primary hyperparathyroidism; less marked increase with renal tumors.
• Serum PTH is decreased or low normal inappropriate for high serum calcium.
• Serum PTHrP is increased (>1.5 pmol/L) in >90% of cases; may be increased when measured by some assay methods (e.g., RIA) but not by others (e.g., IRMA).
• ○ Serum 1,25-dihydroxy-vitamin D is usually decreased or low normal but increased in T-cell or B-cell lymphoma or Hodgkin's disease. Is increased in hyperparathyroidism.
• Urinary cAMP is increased in 90% of cases HHM and of primary hyperparathyroidism; not increased in hypercalcemia due to bone metastases.
• Hypercalciuria is much greater than in hyperparathyroidism at any serum calcium level.
• Decreased serum chloride
• Decreased serum albumin
• Alkalosis is present.
• Decreased serum phosphorus in >50% of patients
• Serum ALP is frequently increased.
• Serum proteins are not consistently abnormal.
• ○ Occult cancer should be ruled out as the cause of hypercalcemia in presence of
• Hypercalcemia without increased serum PTH together with increased urinary cAMP.
• Serum ALP >2× ULN.

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• Increased serum phosphorus.
• Serum chloride/phosphorus ratio <30.
• Serum calcium >14.5 mg/dL without florid hyperparathyroidism.
• Urine calcium >500 mg/24 hrs; urine calcium and phosphorus and renal tubular reabsorption of phosphate are not useful in differential diagnosis.
• Anemia, increased ESR.
• Positive cortisone suppression test in absence of osteitis fibrosa; failure to respond is seen in HPT, most cases of HHM, ~50% of cases of multiple myeloma.

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• Multiple and repeated tests may be necessary in differential diagnosis of some cases of hypercalcemia
• Primary HPT occurs in up to 10% of patients with HHM as well as in those receiving thiazides or those with other causes of hypercalcemia

Hyperparathyroidism (Hpt), Primary

• See Figs. 13-6, and Tables 13-8, and .

Due To

• Parathyroid adenoma in 80% of cases.
• Hyperplasia in 15% of cases.
• Parathyroid carcinoma in <5% of cases.
• No laboratory test can differentiate these.
• ~15% of these lesions may be ectopic; these must be sought if biochemical changes are not reversed by surgery.

• Increased serum calcium is hallmark of HPT and first step in diagnosis. Ionized calcium is more sensitive than total calcium. Repeated determinations may be required to demonstrate increased levels in HPT. Rapid decrease after excision of adenoma may cause tetany during next few weeks, especially when serum ALP is increased. Drug-induced hypercalcemia should be reevaluated after discontinuation for 1-2 mos; cessation of thiazides may unmask primary HPT. ≤5% of hypercalcemia patients have simultaneous HPT and HHM. Any increased serum calcium must be confirmed by repeat test in fasting state and discontinuance for several days of drugs that may increase serum calcium (e.g., thiazide diuretics). Serum total protein and albumin must always be measured simultaneously, as marked decrease may cause a decrease in calcium.
• Normal calcium level may occur with coexistence of conditions that decrease serum calcium level (e.g., malabsorption, acute pancreatitis, nephrosis, infarction of parathyroid adenoma); also beware of laboratory error as a cause of "normal" serum calcium. High phosphate intake can abolish increased serum and urine calcium and decreased serum phosphorus; low-phosphate diet unmasks these changes.
• Serum PTH level is elevated; a few patients have only high-normal PTH levels. Considerable overlap of serum PTH levels is seen in normal patients and those with HPT. Serum calcium must always be measured concurrently, because PTH in the upper normal range may be inappropriately high in relation to a distinctly increased calcium level, which is consistent with HPT. Blood should always be drawn after 10 a.m. because of circadian rhythm. PTH >2× ULN is almost always due to primary HPT. Failure to detect PTH in the presence of simultaneous hypercalcemia argues against

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the diagnosis of primary HPT and surgical exploration of the parathyroid glands. In general, nonparathyroid disease causing hypercalcemia (e.g., sarcoidosis, vitamin D intoxication, hyperthyroidism, milk-alkali syndrome, most malignancies) have a normal or low (suppressed) PTH value (see Parathyroid Hormone, Serum). Selective catheterization of veins draining the thyroid-parathyroid region for determination of PTH levels may confirm the diagnosis of HPT due to tumor by showing a significant elevation at one site compared to at least one other site. A low PTH rules out HPT.

• Serum chloride is increased (>102 mEq/L; <99 mEq/L in other types of hypercalcemia). HPT patients tend toward hyperchloremic (non-AG) acidosis, whereas other hypercalcemic patients tend toward alkalosis.
• Chloride/phosphorus ratio >33 supports the diagnosis of HPT and ratio <30 contradicts this diagnosis.
• ○ Serum phosphorus is decreased (<3 mg/dL) in ~50% of cases. It may be normal in the presence of high phosphorus intake or renal damage with secondary phosphate retention. It may be normal in one-half of patients, even without uremia. Low serum phosphorus supports the diagnosis of primary HPT, an increased level supports the diagnosis of nonparathyroid hypercalcemia, but a normal level is not useful.
• Serum ALP is of limited value. Normal in 50% of patients with primary HPT and only slightly increased in the rest; infrequently is markedly increased in the presence of bone disease. Level slowly decreases to normal after excision of adenoma. Increase >2× ULN and increased serum LD favors HHM rather than HPT.
• Urine calcium is increased (>400 mg on a normal diet; 180 mg on a low-calcium diet) in only 70% of patients with HPT.
• Urine calcium excretion is often >500 mg/24 hrs in malignancy, sarcoidosis, hyperthyroidism.
• Is <200 mg/24 hrs in benign familial hypocalciuric hypercalcemia.
• Lithium-induced hypercalcemia resembles that of familial hypocalciuric hypercalcemia in that both show increased PTH levels and low urine calcium concentrations.
• Urine phosphorus is increased except in cases of renal insufficiency or phosphate depletion (especially due to commonly used antacids containing aluminum). Phosphate loading unmasks the increased urine phosphorus of HPT.
• Polyuria is present, with low specific gravity.
• Cortisone suppression test (e.g., administer hydrocortisone 40 mg 3 times daily for 10 days, then withdraw slowly for 5 days; measure serum calcium at 5, 8, and 10 days). Positive result on suppression test is fall of corrected serum calcium >1.0 mg/dL.
• Test results are positive in 77% of cases with nonparathyroid causes of hypercalcemia (e.g., sarcoidosis, vitamin D intoxication, metastatic carcinoma, multiple myeloma) and in 50% of cases of HPT with osteitis fibrosa.
• Test is negative in HPT without osteitis fibrosa (77% of cases) and therefore is not helpful in this group and in those with familial benign hypercalcemia.
• Serum alpha and beta globulins are slightly increased but return to normal after parathyroidectomy. Serum protein electrophoresis should be performed in HPT to rule out multiple myeloma and sarcoidosis.
• Serum 1,25-dihydroxy-vitamin D may be elevated in primary HPT and in sarcoidosis (and other granulomatous diseases) but not in HMM; serum 25-hydroxy-vitamin D level may be useful to establish vitamin D intoxication, especially in factitious cases.
• Urinary cyclic adenosine monophosphate (cAMP) may be high (>4.0 mmol/L) in >90% of cases of primary HPT and of HHM (not increased in hypercalcemia due to osteolytic metastases) but low in vitamin D intoxication and sarcoidosis. Not usually increased in multiple myeloma or other hematologic malignancies. Drop from an elevated level to normal range within 6 hrs after surgery is said to provide functional confirmation of successful parathyroidectomy. Not widely used because of need for timed samples.
• Uric acid is increased in >15% of patients. Uric acid level is not affected by cure of HPT, but a postoperative gout attack may occur. Increased uric acid level favors hypercalcemia due to thiazides, neoplasm, or renal failure rather than HPT.
• Increased hydroxyproline in serum and urine may occur with bone disease but is of limited use.
• ○ Increased ESR is infrequent in HPT (may be due to infection or moderate renal insufficiency). Marked increase occurs in multiple myeloma.

P.605

• Indirect studies of parathyroid function (e.g., phosphate deprivation, calcium infusion, tubular reabsorption of phosphate) are often borderline, and interpretation is difficult with any significant degree of renal insufficiency.
• ○ HPT must always be ruled out in the presence of
• Renal colic and stones or calcification (2-3% have HPT) (see Table 13-7)
• Peptic ulcer (occurs in 15% of patients with HPT)
• Calcific keratitis
• Bone changes (present in 20% of patients with HPT)
• Jaw tumors
• Clinical syndrome of hypercalcemia (nocturia, hyposthenuria, polyuria, abdominal pain, adynamic ileus, constipation, nausea, vomiting) (present in 20% of patients with HPT; only clue to diagnosis in 10% of patients with HPT)
• MEN (e.g., islet cell tumor of pancreas, pituitary tumor, pheochromocytoma)
• Relatives of patients with HPT or "asymptomatic" hypercalcemia
• Mental aberrations
• A changing clinical spectrum of HPT has resulted from earlier detection of hypercalcemia by multiphasic screening.
• 50% of cases are asymptomatic (most show only mild elevation of calcium).
• 20% of cases have renal stones.
• 6% of cases show osteitis fibrosa cystica.
• 15% of cases have peptic ulcer.
• Two clinical forms:
• Mild form detected by multiphasic screening, progresses slowly, total calcium 10.6-11.5 mg/dL, no bone disease, 30% have renal stones.
• Severe form progresses rapidly with higher serum calcium that rises faster, serum phosphate is lower than in mild form, renal stones are less common.
• "Asymptomatic" hypercalcemia is detected by routine multiphasic screening in 1-2% of tests.
• 21-38% of hospitalized patients had no documented clinical cause found for hypercalcemia.
• Malignancy caused one-third to two-thirds of hospitalized cases in different series.
• HPT caused 15-50% of cases in different series and is the most common cause in outpatients.
• Some patients with asymptomatic primary HPT may be followed medically, but surgery is indicated in presence of serum calcium >11.4 mg/dL or history of any episode of life-threatening hypercalcemia, decreased creatinine clearance (<70% that of age-matched normals), very increased 24-hr urine calcium (>400 mg), presence of kidney stones, or substantially decreased bone mass.

Hyperparathyroidism (Hpt), Secondary

• (Diffuse hyperplasia of parathyroid glands usually secondary to chronic advanced renal disease)
• See Fig. 13-6.
• Serum PTH should be monitored to identify autonomous HPT.
• Laboratory findings due to underlying causative disease are noted (e.g., renal insufficiency).
• Classic findings in renal osteodystrophy are
• Serum calcium is low or normal.
• Serum phosphorus is increased.
• Serum ALP is increased.
• These levels can also be used to monitor response to treatment with calcitriol or alpha-calcidiol.
• Increased serum PTH is suppressed by 1,25-dihydroxy-vitamin D, which can be used to monitor this treatment of chronic renal failure.

Hyperphosphatasemia, Benign Familial

• ○ Rare familial benign persistent increase of serum ALP (usually <5× ULN) in the absence of any known disease. Increase is usually of intestinal or bone (but occasionally of liver) origin.

P.606

• Mild increase of serum acid phosphatase in some family members does not correlate with increase or type of ALP.

Hyperphosphatasemia, Benign Transient

• ○ Sudden transient increase in serum ALP, often to very high levels, that returns to normal usually within 4 mos. Isoenzymes of bone and liver origin are increased without evidence of liver or bone disease.
• Incidental discovery in healthy children, usually <5 yrs old, especially after summer months and after recent weight loss.
• Plasma 25-hydroxy-vitamin D is 2× normal for age and time of year.
• Occasional slight increase of AST, ALT, and GGT.
• Normal serum ALP in family members.

Hyperphosphatasia

• (Autosomal recessive syndrome beginning early in life of fragile bones with multiple fractures and deformities, skeletal radiographic changes, increased serum ALP; also referred to as osteoectasia and osteochalasia desmalis familiaris)
• Serum ALP is usually chronically increased, sometimes markedly; electrophoresis indicates bone origin. Serum acid phosphatase is also increased. Indicates increased activity of osteoblasts and osteoclasts.
• Serum LAP score may also be increased.
• Serum calcium is normal or slightly decreased.
• Serum phosphorus is normal or increased.
• Serum magnesium, proteins, and electrolytes are usually normal.
• Uric acid is increased in blood and urine.

Hypervitaminosis D

• (Due to ingestion of >500 µg/day in adults or >50 µg/day in infants)
• See Table 13-8.
• Serum calcium may be increased; preceded by hypercalciuria.
• Serum phosphorus is normal
• Serum ALP is decreased.
• Serum PTH is low or normal.
• Urine calcium excretion is increased.
• Renal calcinosis may lead to renal insufficiency and uremia.
• Serum 25-hydroxy-vitamin D is increased.