Articles on Medical Diseases and Conditions

Tag: Hyperthyroidism

  • Confirmatory Tests for Hyperthyroidism

    The existence of deceptive laboratory hyperthyroidism with the various forms of pseudo toxicosis accentuates the need for reliable confirmatory tests. This is especially true when the patient has severe non thyroidal illness and symptoms such as atrial fibrillation that may be due to thyrotoxicosis. At present, the two most useful confirmatory procedures for hyperthyroidism are the T3 suppression test and the TRH test. Of these, the main advantage of T3 suppression over TRH is lower cost. Major disadvantages include potential danger in persons with cardiac disease and the prolonged time period necessary for the test. The TRH test has emerged as the gold standard for diagnosis of hyperthyroidism. The procedure appears to be safe, with relatively minor side effects. It can be completed in less than 1 day and can be used in most (but not all) patients with non thyroidal illness. The major disadvantage is that a small minority of persons without clinical or biochemical evidence of thyrotoxicosis are reported to demonstrate TRH test results compatible with hyperthyroidism. A relative disadvantage is the high cost of the test, although the cost is not prohibitive and is comparable to the cost of nuclear medicine scans or radiologic procedures such as laminograms or skeletal surveys.
    From the preceding discussion, several conclusions seem warranted:

    1. The basic screening test for hyperthyroidism is serum T4 or FT4. Some are using the newer ultra sensitive TSH assay instead.
    2. The THBR when ordered with the T4 may be useful for two reasons: (1) the assurance it provides for hyperthyroidism when the THBR value is elevated in association with an elevated T4 value and (2) as an indicator of TBG alterations when the results are compared with those of T4 assay.
    3. Free thyroxine index or FT4 assay provide T4 values corrected for effects of TBG alterations; but if the TBG value is elevated and thereby produces falsely elevated T3-RIA values, a normal FT4I or FT4 assay result may lead to misdiagnosis of T3 toxicosis.
    4. Decreased or mildly elevated T4 results (or even decreased TI or FT4 results, depending on the individual commercial kit) must be interpreted with caution when a patient has severe non thyroid illness.
    5. The T3-RIA results are not reliable when a patient has moderate or severe non thyroid illness. A normal or reduced T3-RIA result must be interpreted with caution if the patient is over age 60 or has any significant degree of non thyroid illness.
    6. An RAIU test is not recommended as a screening test but is helpful as a follow-up procedure to detect factitious hyperthyroidism and thyroiditis.
    7. Thyroid scan is useful to differentiate between Graves’ disease and Plummer’s disease and to help reveal thyroiditis.
    8. The TRH test may be necessary to confirm or exclude the diagnosis of hyperthyroidism when the patient has non thyroidal illness (not severe enough to decrease T4 below reference range), when thyroid function tests disagree, when test results are equivocal, and when test results do not fit the clinical picture. A normal test result is reasonably conclusive in ruling out hyperthyroidism, whereas an abnormal test result (abnormally low TSH response) is suggestive evidence of hyperthyroidism but is not completely reliable in confirming the diagnosis.

  • Deceptive (Misleading) Test Patterns of Laboratory Hyperthyroidism

    Each of the three categories of true laboratory thyrotoxicosis has a counterpart in which the apparent pattern does not reflect true thyroid hormone status. I would like to call the resulting test patterns “deceptive laboratory hyperthyroidism.” These patterns are misleading because of non thyroidal alteration of one or both thyroid hormone levels. Deceptive laboratory hyperthyroidism represents a significant (although relatively small) percentage of hyperthyroid patients. Therefore it is important to recognize these patients and to anticipate a potential problem when situations associated with deceptive test results arise. The categories of deceptive test results are the following:

    1. Pseudo–T4/T3 hyperthyroidism (both T4 and T3-RIA test results are elevated, not due to Graves’ disease or Plummer’s disease)
    2. Pseudo–T3 hyperthyroidism (T3-RIA value elevated; T4 test result not elevated)
    3. Pseudo–T4 hyperthyroidism (T4 test result elevated; T3-RIA value not elevated)

    Laboratory error may produce apparent abnormality in a euthyroid person or may reduce one or both of the hormone levels in true thyrotoxicosis. Therefore, unexpected test patterns or results may require repetition of one or more of the tests before a definitive diagnosis is made. Abnormality of the same type on two tests (i.e., both test results elevated) is more helpful for diagnosis than abnormality of only one.

    Pseudo–T4/T3 hyperthyroidism (T4 and T3-RIA both elevated)

    Causes of pseudo–T4/T3 Graves’ disease or Plummer’s disease are listed in the box. Pseudohyperthyroidism is most commonly produced by increase of thyroid binding proteins, principally TBG. The most common etiology is increased estrogens, either in pregnancy or through use of birth control pills. Both T4 and T3-RIA values are elevated in many of these patients. However, in some, the T3-RIA value may remain in upper reference range while only the T4 value is elevated.

    Effects of TBG alterations on T4 levels can be counteracted in most instances by using the FT4I or by measuring FT4 rather than total T4 values.

    Pseudo–T4/T3 Hyperthyroidism

    Increased TBG values
    Thyroiditis
    Subacute
    Painless (silent) thyroiditis
    Some patients with Hashimoto’s thyroiditis
    Peripheral resistance to thyroid hormones
    Factitious (self-medication with thyroid hormone)

    The FT4I or FT4 value will usually be normal in TBG abnormalities. If the FT4I or FT4 and the T3-RIA values are measured in a patient with increased TBG, the T3-RIA will appear to be elevated since TBG alterations affect T3-RIA as well as T4, and the combination of elevated T3-RIA plus normal. FT4I values or FT4 value would suggest T3 toxicosis. Therefore, “correction” of TBG effect on T4 may prevent pseudo-T4/T3 toxicosis but produce pseudo-T3 toxicosis. This hazard can be prevented by either applying the same basic FT4I formula to T3-RIA (thus generating an FT3I) or simply inspecting the two separate components of the FT4I, the T4 and THBR (T3U). If T4 and TBHR are at the opposite ends of their respective reference ranges, this suggests artifact due to TBG alteration. Unfortunately, many laboratories that generate FT4I report only the single FT4I result without separate T4 and THBR values. The FT4I value alone has no feature that could lead anyone to suspect TBG abnormality.

    Occasionally patients have been discovered with the syndrome of peripheral tissue resistance to thyroid hormone. These patients are usually euthyroid but have elevated T4 and T3-RIA values. TSH is normal or elevated.

    Factitious (self-administered) ingestion of T4 compounds by a patient may be deliberate, may be due to prior therapy that is not mentioned by the patient, or may represent T4 included in diet-control pills unknown to the patient. In both factitious T4 ingestion and subacute thyroiditis the RAIU value is typically low. Spurious causes for a low RAIU value must be excluded, such as iodine ingestion (e.g., SSKI or amiodarone) or x-ray contrast medium administration within the past 3-4 weeks (see the box).

    Thyrotoxicosis in thyroiditis is usually temporary and is produced by release of thyroid hormone from damaged thyroid tissue rather than by hypersecretion. Subacute thyroiditis typically has pain in the thyroid area and is accompanied by a low RAIU value. The erythrocyte sedimentation rate (ESR) is usually elevated (>50 mm/hour, Westergren method). Occasional cases of thyroiditis (“painless thyroiditis”) may present with the clinical picture of subacute thyroiditis, including hyperthyroidism, but without a painful thyroid gland and with a normal ESR. Chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) typically is associated with normal thyroid hormone blood levels, normal or decreased 24-hour RAIU value, normal ESR, and increased thyroid autoantibody levels. However, in occasional patients, chronic lymphocytic thyroiditis presents with hyperthyroidism that is clinically similar to nonpainful thyroiditis. The 24-hour RAIU value is typically decreased (although a few patients are reported to have normal values, and one study included a few patients with elevated values). Thyroid hormone levels are elevated, and the ESR is normal. Therefore, an elevated ESR favors subacute thyroiditis rather than factitious hyperthyroidism, painless thyroiditis, or thyrotoxic chronic lymphocytic thyroiditis.

    Other entities with elevated T4 or elevated T3-RIA values associated with low RAIU values include T4/T3 toxicosis with artifactual RAIU suppression by exogenous iodine, iodine-induced hyperthyroidism (Jod-Basedow disease), radiation-induced active thyroid disease (caused by RAI therapy or external radiotherapy), and ectopic T4 production (struma ovarii). In severe (not mild or moderate) iodine deficiency, T3-RIA values may be increased, T4 values may be decreased, and TSH and RAIU values may be increased.

    Pseudo–T3 hyperthyroidism (T3-RIA elevated; T4 not elevated)

    Pseudo–T3 toxicosis may be of two types: (1) true hyperthyroid type, T4/T3 hyperthyroidism with normal-range T4 test result; and (2) false hyperthyroid type, elevated T3-RIA test result without hyperthyroidism (see the box).

    True hyperthyroid type. Such cases are uncommon. It is said that T3 values may rise before T4 values in early thyrotoxicosis, and T3-RIA values are usually elevated to a greater degree than T4 values. Examples of isolated T3 elevation that eventually was joined by T4 elevation have been reported. An early or mild T4 abnormality may be masked in the upper area of population reference range (if a person’s normal T4 value were in the lower part of population reference range, the T4 value could double and still remain within reference range).

    False hyperthyroid type. This type of pseudo–T3 toxicosis may be produced by measurement of T3-RIA plus either the FT4I or the FT4 in

    Pseudo–T3 Hyperthyroidism

    True hyperthyroidism
    Rise of T3 level before T4 level in early T4/T3 hyperthyroidism
    False Hyperthyroidism
    Increased TBG with TI (or FT4) and T3-RIA results
    1-2 hr after dose of T3 (liothyronine [Cytomel])
    For several hours after dose of desiccated thyroid Severe iodine deficiency

    patients with increased TBG values. Since FT4I and FT4 values usually remain normal when TBG values are altered, an increased TBG value would be associated with normal FT4I or FT4 values plus artifactual increase in T3-RIA value. The T3-RIA value may be increased alone for 1-2 hours after T3 (liothyronine) administration. It may also be temporarily increased for several hours after desiccated thyroid intake. Iodine deficiency of moderate degree usually is associated with normal T3-RIA and T4 levels, although mean T3-RIA values are higher than in normal persons. In severe iodine deficiency, T3-RIA values are sometimes increased, T4 values may be decreased, and TSH values may be increased. The RAIU value is increased in iodine deficiency, providing additional potential for misdiagnosis. As noted previously, one report indicates that occasional free T3 index elevations can be found in amphetamine abusers.

    Pseudo–T4 hyperthyroidism (T4 elevated; T3-RIA not elevated)

    Pseudo–T4 toxicosis may be of two types: (1) true hyperthyroidism, T4/T3 toxicosis with (temporarily) reduced T3-RIA test result; and (2) false hyperthyroidism, elevated T4 test result in euthyroid patient (see the box).

    True hyperthyroidism. Ordinarily, both T4 and T3-RIA values are elevated in T4/T3 toxicosis or

    Pseudo–T4 Hyperthyroidism

    True hyperthyroidism (patient is hyperthyroid)
    Factitious ingestion of levothyroxine
    T4/T3 hyperthyroidism plus decrease in T3-RIA result due to:
    Severe non thyroid illness
    Advanced age
    Certain medications (e.g., dexamethasone, propranolol)
    False hyperthyroidism (patient is euthyroid)
    Increased TBG value plus decrease in T3-RIA result
    Severe non thyroid illness occasionally producing falsely elevated T4 levels
    Increased TBG value with disproportionate T4 increase relative to T3-RIA
    Acute psychiatric illness (some patients)
    Amphetamine abuse
    Certain x-ray contrast media
    Certain medications (e.g., propranolol, amiodarone)
    Specimen obtained 1-4 hr after levothyroxine dose rather than just before the dose
    Patient taking therapeutic levothyroxine

    when the TBG value is increased. Pseudo–T4 toxicosis may be produced in patients who have T4/T3 toxicosis if the T3-RIA level becomes decreased for some reason while the T4 level remains elevated. The most common causes for T3-RIA decrease in T4/T3 toxicosis are severe non thyroid illness and effect on T3-RIA of old age. Many severe non thyroid illnesses, particularly when chronic (see Table 28-3), depress T3-RIA levels, often to very low levels. The free T3 index also decreases but to a lesser extent. The effect of severe illness persists for variable periods of time and usually involves a shift from production of T3 toward reverse T3. Another factor that depresses T3-RIA levels but not T4 levels is the effect of advanced age. For patients over age 60 years, most T3-RIA kits have demonstrated a progressive decrease with time of approximately 10%-30% (literature range, 0%-52%). The degree of effect differs with individual manufacturers’ kits. Unfortunately, very few laboratories determine age-related values for the particular kit that they use. There is general but not unanimous agreement that T4 values are not greatly changed in old age. Certain medications (propranolol, dexamethasone) have been reported to decrease T3-RIA levels, although not severely.

    False hyperthyroidism. Artifactual T4 elevation may result when TBG levels are increased, artifactually elevating both T4 and T3-RIA results, but some condition is superimposed that decreases T3-RIA results, leaving only the T4 value elevated. As noted previously, the most common reason for artifactual T3-RIA decrease is severe non thyroid illness. Another possibility is the effect of advanced age. In patients with normal TBG levels, severe non thyroidal illness may be associated with T4 values that are increased, decreased, or that remain within normal population range. Thyroxine levels most commonly display slight or mild decreases but still remain within normal limits. In a significant minority of patients (depending on the severity of illness), the T4 level is decreased below its reference range to varying degrees, producing pseudo hypothyroidism (clinical euthyroidism with laboratory test results falsely suggesting hypothyroidism). A small minority of patients exhibit an increase in T4 results for poorly understood reasons. In these patients, Pseudo–T4 toxicosis would be produced without clinical hyperthyroidism or increased TBG levels (designated “T4 euthyroidism” by some investigators). The TSH value in severe non thyroidal illness is most often normal but may be mildly increased. The THBR level may be normal but is sometimes mildly increased, reflecting decreased TBG levels. Occasionally the THBR level is decreased, mainly in acute hepatitis.

    Certain conditions produce artifactual elevation of T4 values but not T3-RIA values. In some patients with increased TBG values without severe non thyroid illness, T3-RIA values remain within upper reference range while the T4 levels are elevated. One explanation is that increase in binding proteins affects T4 levels somewhat more than T3-RIA values. However, an increased TBG level frequently produces an elevated T3-RIA value as well as a T4 value. Elevated T4 values with normal T3-RIA values have been reported in some patients with acute psychiatric illness who were clinically euthyroid and where T4 values returned to the reference range after treatment of the psychiatric problem. However, the possibility of true thyrotoxicosis should not be ignored.

    Amphetamine abuse has been reported to increase serum T4 values without affecting T3-RIA values. Both the TI and FT3I are elevated in some of these patients. Some of these patients had mildly elevated serum TSH values and some did not. Increased FT3I was also found in some cases without increase of FT4 index.

    Certain x-ray contrast media such as ipodate and iopanoic acid gallbladder visualization agents decrease T3-RIA values and may increase T4 values somewhat. Dexamethasone and propranolol are reported to decrease T3-RIA values, as noted previously. Propranolol has been reported to increase T4 values, but there is some disagreement as to whether this occurs.

    If a patient is taking therapeutic levothyroxine (Synthroid, Levothroid), and a blood specimen happens to be drawn 1-4 hours after a dose has been administered, a result above steady-state level will often be obtained that might be above the reference range. Peak values after an oral dose are reached in 2-4 hours and average 1-3 µg above steady-state level. Even at steady-state levels and drawn just before the scheduled dose, patients who are clinically normal and whose TSH and T3-RIA values are within reference range may have a steady state T4 level as much as 2 µg above the upper limit of the T4 reference range (discussed later). This is a problem because the dose is not always given at the scheduled time, the laboratory usually does not know what medications the patient is receiving to schedule the time of venipuncture, and sometimes the physician is unaware that a new patient is taking levothyroxine.

    It has been reported that some hyperthyroid patients with elevated T4 levels but normal-range T3-RIA values have an elevated FT3I.

    Hyperthyroidism with false laboratory euthyroidism. One final category of deceptive hyperthyroidism may be added, clinical hyperthyroidism with falsely normal T4 and T3-RIA values (see the box). Patients with decreased TBG

    Hyperthyroidism With False Laboratory Euthyroidism
    Hyperthyroidism plus decreased TBG value (see the box)
    Hyperthyroidism plus severe non thyroid illness

    levels may have falsely decreased T4 and T3-RIA levels that could convert elevated values to normal-range assay results. Severe non thyroidal illness decreases T3-RIA values and may decrease T4 values. This could mask expected T3-RIA elevation in T3 toxicosis and T3-RIA plus some patients with T4 elevation in some cases of T4/T3 or T4 toxicosis.

    Isolated Graves’ ophthalmopathy

    Besides the two classic types of clinical hyperthyroidism, there is one additional form known as isolated Graves’ ophthalmopathy, or “euthyroid Graves’ disease.” This consists of eye signs associated with hyperthyroidism but without other clinical evidence of thyrotoxicosis and with normal RAIU, T4, and T3-RIA values. Evidence of true hyperthyroidism consists of reports that about 50%-70% of these patients fail to demonstrate thyroid suppression on the T3 suppression test (literature range, 50%-100% in several small series of patients). About two thirds have a flat or blunted TSH response on the TRH test, suggestive of thyroid autonomy. A considerable number of these patients have detectable thyroid-stimulating immunoglobulins (TSI test;). However, published reports of the latest versions of this test show considerable differences in sensitivity between laboratories. Similar differences were reported in detection rates for Graves’ disease.

  • Laboratory Test Patterns in Hyperthyroidism

    The diagnosis of thyroid disease now depends as much on laboratory results as it does on clinical findings. One might therefore use the term “laboratory hyperthyroidism” when considering the spectrum of test results in thyrotoxicosis in the same manner that one employs the term “clinical hyperthyroidism” when evaluating patient signs and symptoms. Laboratory diagnosis is usually based on elevated values of serum T4 and T3, the two active thyroid hormones. Laboratory hyperthyroidism can be subdivided into three categories, depending on T4 and T3-RIA results:

    1. Standard T4/T3 toxicosis (both T4 and T3-RIA elevated).
    2. T3 toxicosis (T3-RIA elevated, T4 not elevated).
    3. T4 toxicosis (T4 elevated, T3-RIA not elevated).

    Standard T4/T3 toxicosis includes nearly 95% of cases of hyperthyroidism.

    T3 toxicosis is estimated to occur in 3%-5% of hyperthyroidism patients (literature range, 2.4%-30%). Although T3-RIA values are increased in T3 toxicosis, the T4, THBR, and RAIU values are usually all normal. There is some evidence that T3 toxicosis is more common in patients with atrial fibrillation, and it may be associated more often with Plummer’s disease than with Graves’ disease (although not all investigators agree). One report indicates that T3 toxicosis is more common in iodine-deficiency areas (although some of these cases might have been pseudo-T3 toxicosis with T4 levels decreased because of the iodine deficiency). TSH is decreased in T3 toxicosis.

    T4 toxicosis has not received much attention, and it was assumed to be less frequent than T3 toxicosis. In the more recent articles on this subject in the literature, incidence ranged from 0%-21% of hyperthyroid patients, although the true incidence is probably less than that of T3 toxicosis. Several investigators report that T4 toxicosis is more commonly found with iodine-induced hyperthyroidism (Jod-Basedow disease). T4 toxicosis is also found more commonly in elderly persons, but in some reports it is difficult to be certain that some cases were not actually T4/T3 toxicosis with depressed T3-RIA values due to concurrent severe illness.

  • 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.

  • Primary Hyperparathyroidism (PHPT)

    PHPT is caused by overproduction or inappropriate production of PTH by the parathyroid gland. The most common cause is a single adenoma. The incidence of parathyroid carcinoma is listed in reviews as 2%-3%, although the actual percentage is probably less. About 15% (possibly more) of cases are due to parathyroid hyperplasia, which involves more than one parathyroid gland. The most frequent clinical manifestation is renal stones (see the box). The reported incidence of clinical manifestations varies widely, most likely depending on whether the patient group analyzed was gathered because of the symptoms, whether the group was detected because of routine serum calcium screening, or whether the group was mixed in relation to the method of detection.

    Symptoms or Clinical Syndromes Associated with Primary Hyperparathyroidism, with Estimated Incidence*

    Urologic: nephrolithiasis, 30%-40% (21%-81%); renal failure
    Skeletal: 15%-30% (6%-55%); osteoporosis, fracture, osteitis fibrosa cystica
    Gastrointestinal: peptic ulcer, 15% (9%-16%); pancreatitis, 3% (2%-4%)
    Neurologic: weakness, 25% (7%-42%); mental changes 25% (20%-33%)
    Hypertension: 30%-40% (18%-53%)
    Multiple endocrine neoplasia syndrome: 2% (1%-7%)
    Asymptomatic hypercalcemia: 45% (2%-47%)
    *Numbers in parentheses refer to literature range.

    About 5% (literature range, 2%-10%) of patients with renal stones have PHPT.

    Laboratory tests. Among nonbiochemical tests, the hemoglobin level is decreased in less than 10% of cases (2%-21%) without renal failure or bleeding peptic ulcer. A large number of biochemical tests have been advocated for diagnosis of PHPT. The classic findings on biochemical testing are elevated serum calcium, PTH, and alkaline phosphatase levels and a decreased serum phosphate level.

    Serum calcium (total serum calcium). Most investigators consider an elevated serum calcium level the most common and reliable standard biochemical test abnormality in PHPT. Even when the serum calcium level falls within the population reference range, it can usually be shown to be inappropriately elevated compared with other biochemical indices. However, PHPT may exist with serum calcium values remaining within the reference range; reported incidence is about 10% of PHPT patients (literature range, 0%-50%). Normocalcemic PHPT has been defined by some as PHPT with at least one normal serum calcium determination and by others as PHPT in which no calcium value exceeds the upper reference limit. Some of the confusion and many of the problems originate from the various factors that can alter serum calcium values in normal persons, as listed here.

    1. Reference range limits used. Reference range values may be derived from the literature or from the reagent manufacturer or may be established by the laboratory on the local population. These values may differ significantly. For example, the values supplied by the manufacturer of our calcium method are 8.7-10.8 mg/100 ml (2.17-2.69 mmol/L), whereas our values derived from local blood donors (corrected for effects of posture) are 8.7-10.2 mg/100 ml (2.17-2.54 mmol/L).
    2. The patient’s normal serum calcium value before developing PHPT compared with population reference values. If the predisease value was in the lower part of the population reference range, the value could substantially increase and still be in the upper part of the range.
    3. Diet. A high-calcium diet can increase serum calcium levels up to 0.5 mg/100 ml. A high-phosphate diet lowers serum calcium levels, reportedly even to the extent of producing a normal calcium value in PHPT.
    4. Posture. Changing from an upright to a recumbent posture decreases the serum calcium concentration by an average of 4% (literature range, 2%-7%). A decrease of 4% at the 10.5 mg/100 ml level is a decrease of 0.4 mg/100 ml. Therefore, reference ranges derived from outpatients are higher than those established in blood donors or others who are recumbent. This means that high-normal results for outpatients would appear elevated by inpatient standards.
    5. Tourniquet stasis. Prolonged stasis is reported to produce a small increase in serum calcium and total protein values.
    6. Changes in serum albumin concentration (discussed under ionized calcium).
    7. Laboratory error or, in borderline cases, usual laboratory test degree of variation.

    Malignancy-associated hypercalcemia (MAH)

    Malignancy may produce hypercalcemia in three ways. The first is primary bone tumor; the only common primary bone tumor associated with hypercalcemia is myeloma, which begins in the bone marrow rather than in bone itself. Hypercalcemia is found in about 30% of myeloma patients (literature range, 20%-50%). The alkaline phosphatase level is usually normal (reported increase, 0%-48%) unless a pathologic fracture develops. About 5% of acute lymphocytic leukemia patients develop hypercalcemia. The second cause of hypercalcemia in malignancy is tumor production of a hormone resembling PTH called parathyroid hormone-related protein. This is known as the “ectopic PTH syndrome,” sometimes called “pseudohyperparathyroidism” (about 50% of solid-tumor MAH). The most frequent source of solid-tumor MAH is lung carcinoma (25% of MAH cases) followed by breast (20%), squamous nonpulmonary (19%) and renal cell carcinoma (8%).

    The third cause of MAH is metastatic carcinoma to bone (about 20% of solid tumor MAH). The breast is the most frequent primary site, followed by lung and kidney. Although prostate carcinoma is frequent in males, prostatic bone lesions are usually osteoblastic rather than osteolytic and serum calcium is usually not elevated.

    In addition, in some studies about 5% of patients with hypercalcemia and cancer also had PHPT.

    Selected nonneoplastic causes of hypercalcemia Among the conditions traditionally associated with hypercalcemia is sarcoidosis. There seems to be a much lower incidence of hypercalcemia in these patients today than in the past. Estimated frequency of hypercalcemia in sarcoidosis is about 5%-10% (literature range, 1%-62%). Serum phosphate levels are usually normal. Many of these patients have increased urine calcium excretion; the exact percentage is difficult to determine from the literature. Bone lesions are reported in 5%- 16% of cases. Tertiary hyperparathyroidism is another cause of hypercalcemia. In chronic renal failure, secondary hyperparathyroidism develops, consisting of decreased serum calcium, elevated PTH, elevated serum phosphate, and elevated alkaline phosphatase levels and development of rental osteodystrophy. If renal failure persists for a long time, secondary hyperparathyroidism may become tertiary hyperparathyroidism, which displays elevated serum calcium, elevated PTH, decreased serum phosphate, and elevated alkaline phosphatase levels and bone lesions (i.e., most of the biochemical changes usually associated with PHPT, but with diffuse hyperplasia of the parathyroid glands rather than a single adenoma). Hyperthyroidism produces hypercalcemia in about 15% of thyrotoxic patients and alkaline phosphatase (ALP) elevation in about 40%. Lithium therapy frequently increases serum total calcium levels. Although most calcium values remain within population reference range, about 12% of patients on long-term lithium therapy become hypercalcemic and about 16% are reported to develop elevated PTH assay results. Thus, discovery of hypercalcemia becomes a problem of differential diagnosis, with the major categories being artifact, neoplasia, PHPT, and “other conditions.” The incidence of asymptomatic hypercalcemia in unselected populations subjected to biochemical test screening ranges from 0.1%-6%. Many of the diagnostic procedures for PHPT have been developed to separate PHPT from other possible causes of hypercalcemia.

  • Urinalysis in Miscellaneous Diseases

    Fever. Fever is the most common cause of proteinuria (up to 75% of febrile patients). If severe, it may be associated with an increase in hyaline casts (etiology unknown, possibly dehydration).

    Cystitis-urethritis. Cystitis and urethritis are lower urinary tract infections, often hard to differentiate from renal infection. Clumping of WBCs is suggestive of pyelonephritis but only WBC casts provide absolute specificity. Necrotizing cystitis may cause hematuria. The two-glass urine test helps to differentiate urethritis from cystitis. After cleansing the genitalia, the patient voids about 10-20 ml into container number 1 and the remainder into container number 2. A significant increase in the WBC count of container number 1 over that of container number 2 suggests urethral origin.

    Genitourinary tract obstruction. Neuromuscular disorders of the bladder, congenital urethral strictures and valves, intrinsic or extrinsic ureteral mechanical compressions, and intraluminal calculi produce no specific urinary changes but predispose to stasis and infection. Obstruction, partial or complete, is a frequent etiology for recurrent genitourinary tract infections.

    Amyloidosis. Renal involvement usually leads to proteinuria. In a minority of cases, when the process severely affects the kidney there may be high proteinuria and sediment typical of the nephrotic syndrome. The urinary sediment, however, is not specific, and RBC casts are not present. Renal amyloidosis is usually associated with chronic disease, such as long-standing osteomyelitis or infection, or multiple sclerosis.

    Urinary calculi. Urinary calculi often cause hematuria of varying degree and, depending on the composition of the stone, may be associated with excess excretion of calcium, uric acid, cystine, phosphates, or urates in the urine, even when calculi are not clinically evident. Frequent complications are infections or obstruction, and infection may occur even in the absence of definite obstruction. Ureteral stone passage produces hematuria, often gross. Intravenous pyelography is the best means of diagnosis. Some types of calculi are radiopaque, and others may be localized by finding a site of ureteral obstruction.

    Sickle cell anemia. Hematuria frequently occurs due to kidney lesions produced by intra-capillary RBC plugs, leading to congestion, small thromboses, and microinfarctions. Hematuria is also frequent at times of hematologic crises. Hematuria may be present even without crises in sickle cell disease or sickle cell variants. Sickle cell patients may lose urine-concentrating ability for unknown reasons. This happens even with sickle cell variants but is less common.

    Chronic passive congestion. One cause of renal congestion is inferior vena cava obstruction. It produces mild diffuse tubular atrophy and hyperemia, leads to proteinuria (usually mild to moderate) and hyaline casts, and sometimes also elicits epithelial casts and a few RBCs. Occasionally, but not commonly, severe chronic passive congestion (CPC) may simulate the nephrotic syndrome to some extent, including desquamated epithelial cells containing fat plus many casts of the epithelial series. In CPC of strictly cardiac origin without significant previous renal damage, there is decreased urine volume but usually retained urine-concentrating ability. No anemia is present unless it is due to some other systemic etiology.

    Benign arteriosclerosis. Benign arteriosclerosis involves the renal parenchyma secondarily to decreased blood supply. In most cases in the earlier stages, there are few urinary findings, if any; later, there is often mild proteinuria (0.1-0.5 gm/24 hours) and a variable urine sediment, which may contain a few hyaline casts, epithelial cells, and perhaps occasional RBCs. If the condition eventually progresses to renal failure, there will be significant proteinuria and renal failure sediment with impaired renal function tests.

    Weil’s disease. Weil’s disease is leptospiral infection (Chapter 15) and clinically presents with hepatitis and hematuria. Characteristically, there are also high fever and severe muscle aching, and there may be associated symptoms of meningitis.

    Infectious mononucleosis. Renal involvement with hematuria occurs in 5%-6% of cases.

    Purpura and hemorrhagic diseases. These diseases should be recognized as causes of hematuria, either by itself or in association with glomerular lesions. The Henoch-Schцnlein syndrome (anaphylactoid purpura) is a rare condition featuring gastrointestinal bleeding (Henoch) or skin purpura (Sch?nlein) that often is concurrent with hematuria and nephritis.

    Hypersensitivities. Hypersensitivities may lead to proteinuria (usually slight) with hematuria and perhaps a moderate increase in casts. Kidney involvement may occur due to hypersensitivity to mercurials, sulfas, or other substances.

    Fat embolism. Fat embolism commonly occurs after trauma, especially fractures. Cerebral or respiratory symptoms develop the second or third day after injury, usually associated with a significant drop in hemoglobin values. Fat in the urine is found in about 50% of patients. Unfortunately, a physician’s order for a test for fat in the urine will usually result in microscopic examination of the sediment. Whereas this is the correct procedure to detect fat in the nephrotic syndrome, in which fat is located in renal epithelial cells and casts, it is worthless for a diagnosis of fat embolism, in which free fat droplets must be identified. Since free fat tends to float, a simple procedure is to fill an Erlenmeyer (thin-neck) flask with urine up into the thin neck, agitate gently to allow fat to reach the surface, skim the surface with a bacteriologic loop, place the loop contents on a slide, and stain with a fat stain such as Sudan IV.

    Hemochromatosis. This condition is suggested by hepatomegaly, gray skin pigmentation, and proteinuria in a diabetic patient. Proteinuria may exceed 1 gm/24 hours, but sediment may be scanty and fat is absent. In severe cases yellow-brown coarse granules of hemosiderin are seen in cells, in casts, and lying free. Prussian blue (iron) stains in this material are positive. Distal convoluted tubules are the areas primarily involved. Since hemochromatosis does not invariably involve the kidney until late, a negative urine result does not rule out the diagnosis. False positive results (other types of urine siderosis) may occur in pernicious anemia, hemolytic jaundice, and in patients who have received many transfusions.

    Thyroid dysfunction.

    Myxedema. Proteinuria is said to occur without other renal disease. Its incidence is uncertain, especially since some reports state that proteinuria is actually not common and usually persists after treatment.

    Hyperthyroidism. The kidney may lose its concentrating ability so that specific gravity may remain low even in dehydration; this is reversible with treatment and a return to a euthyroid condition. Occasionally, glucosuria occurs in patients.