selected endocrine test strategies

Selected endocrine test strategies

M. Desmond Burke, MDDepartment of Pathology, Division of Laboratory Medicine,

Weill Medical College, Cornell University, 525 East 68th Street,

New York, NY 10021, USA

In the ordinary course of clinical practice, the use of laboratory tests ismostly confined to integrating routine test panel results (eg, the completeblood count, urinalysis, chemistry panels, and so forth) with clinical infor-mation. Less commonly, sequential test strategies are required to solve moredifficult clinical problems. Those problems most amenable to defined teststrategies tend to be heavily test dependent (eg, thyroid dysfunction). Also,management in these cases is often more problem-dependent than patient-dependent, making prescriptions of a general nature more acceptable [1].Although experts in various disciplines may agree on the general outlineof test strategies, there may still be differences of opinion with respect to spe-cifics. The examples chosen for inclusion in this article include common prob-lems and those reflecting advances made in recent years. Some of the teststrategies presented (eg, for the diagnosis of diabetes mellitus and thyroiddysfunction screening) are those recommended by authoritative nationalgroups [2,3]. Others (eg, hypoglycemia, Cushing’s syndrome, and primaryaldosteronism) represent a composite of expert opinion.

Diabetes mellitus

Before the 1970s, glucose tolerance testing was commonly used for thediagnosis of diabetes mellitus. Two standard deviations above the meanvalues encountered in healthy volunteers were the criteria used to defineabnormal results. By these criteria, more than half the population was desig-nated glucose intolerant [4]. In 1979, the National Diabetes Data Groupproposed criteria based on the bimodal distribution of serum glucose values2 hours after a glucose load in populations with a high prevalence of dia-betes mellitus [3]. A fasting plasma glucose (FPG) and 2-hour postglucoseload of 140 mg/dL and 200 mg/dL, respectively, were considered best to

Clin Lab Med 22 (2002) 421–434

E-mail address: dburke2mail.med.cornell.edu (M.D. Burke).

0272-2712/02/$ – see front matter � 2002, Elsevier Science (USA). All rights reserved.

PII: S 0 2 7 2 - 2 7 1 2 ( 0 1 ) 0 0 0 1 4 - 2

separate diabetic and nondiabetic groups. One of the difficulties with thesecriteria was that the fasting and 2-hour cutoffs were discordant. All subjectswith FPG values greater than or equal to 140 mg/dL had abnormal 2-hourvalues. On the other hand, only 25% of those with abnormal 2-hour valueshad FPG values greater than or equal to 140 mg/dL [5]. The oral glucosetolerance test (OGGT) was also regarded as more time-consuming, moreexpensive, and less reproducible than the FPG. These concerns, coupledwith observations that hyperglycemia contributes to microvascular compli-cations of diabetes mellitus that may be reduced by intensive therapy [6],prompted the American Diabetes Association in 1997 to publish new guide-lines for the classification of diabetes mellitus [7].

Diagnostic test strategy

The main difference in the 1997 recommendations is a lowering of theFPG cutoff from 140 to 126 mg/dL. This newly recommended FPG cutoffcorrelates better with the 2-hour value of 200 mg/dL, which remains un-changed from the 1979 recommendations (Table 1). Moreover, the incidenceof coronary artery disease is reported to be markedly increased in individualswith FPG greater than 120 to 125 mg/dL [8]. The 1997 guidelines (Table 2)are simpler in that diagnosis by the OGGT depends only on the 2-hour value;there is no longer a need for 0.5-, 1-, and 1.5-hour values [9]. The concor-dance of the FPG and 2-hour cutoffs should nowmake the OGGT redundantin most instances and means that the test of choice for the detection for dia-betes mellitus is the FPG.

Table 2

Diagnosis of diabetes mellitus: 1997 ADA guidelines

Classic symptoms plus a casual plasma glucose ‡200 mg/dL

FPG ‡126 mg/dL

2-h postload glucose ‡200 mg/dL

From American Diabetes Association. Report of the Expert Committee on the Diagnosis

and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183–97; with permission.

FPG¼ fasting plasma glucose.

Table 1

Plasma glucose cutoff values: 1997 ADA guidelines

Plasma glucose mg/dL

Normal Impaired Diabetic

Fasting <110 110–125 ‡1262-h OGGT <140 140–199 ‡200

From American Diabetes Association. Report of the Expert Committee on the Diagnosis

and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183–97; with permission.

OGGT¼oral glucose tolerance test.

422 M.D. Burke / Clin Lab Med 22 (2002) 421–434

Hypoglycemia

The reference range for serum or plasma glucose in healthy individuals isabout 70 to 110 mg/dL. Although technically values less than 70 mg/dL arehypoglycemic, they are not necessarily abnormal. The term hypoglycemiashould be reserved for a lower than normal glucose accompanied by symp-toms and signs attributable to a low glucose. Symptoms of hypoglycemiausually begin at about 60 mg/dL [10]. They have been classified into twogroups: autonomic (sweating, trembling, and palpitation) or neuroglycope-nic (dizziness, confusion, and fatigue) [11]. Postabsorptive serum glucose ismaintained within the normal range by counter-regulatory hormones (glu-cagon, epinephrine, growth hormone, and cortisol) [11,12]. With more pro-longed fasting, deficiencies of cortisol [13] and growth hormone [14] result inlower serum glucose concentrations. The traditional view that hypoglycemiacan be divided neatly into postprandial and fasting (symptoms occurringmore than 6 hours after eating) is probably erroneous [12]. A list of the moreimportant causes of hypoglycemia follows:

Medications (insulin, total parenteral nutrition, quinine, quinidine, pen-tamidine, b-adrenergic blocking agents)

Hepatic dysfunctionGlucocorticoid deficiencyFactitious hypoglycemia (insulin or sulfonylureas)Non-b cell tumor hypoglycemiaSepsisMalnutritionRenal insufficiencyShockInsulin antibody hypoglycemiaInsulinoma

The causes are likely to be different in personswho seemhealthy as opposedto those with underlying diseases or who are severely ill and hospitalized [12].For example, the most common causes of hypoglycemia in persons withoutdiabetes mellitus are medications, sepsis, malnutrition, liver disease, renalinsufficiency, and shock [15]. In such cases, the diagnosis of hypoglycemiamaybe just a matter of confirming the relationship of hypoglycemia to the under-lying condition and treating accordingly [12]. The test strategy outlined nextappliesmore to the question of hypoglycemia in the apparently healthy ambu-latory patient.Most of the causes, with the exception of postprandial hypogly-cemia, factitious insulin, or sulfonylurea administration and insulinoma, arepresumed to have been excluded by appropriate testing.

Diagnostic test strategy (Fig. 1)

For those persons exhibiting hypoglycemic symptoms spontaneously, it isnecessary to establishWhipple’s triad by verifying that, at the time symptoms

423M.D. Burke / Clin Lab Med 22 (2002) 421–434

occur, serum glucose is low and symptoms are alleviated by administrationof glucose. Failure to establish Whipple’s triad excludes hypoglycemia [12].Because most patients undergoing investigation to exclude insulinoma arenormoglycemic, hypoglycemia must be induced before test strategy begins.The recommended way to achieve this is to conduct a supervised 72-hourfast in a hospitalized setting under standardized conditions [11,12].

These conditions include repeat venipuncture at 6-hour intervals withmeasurement of glucose and insulin. Proinsulin and C peptide may alsobe ordered on the same specimen. The fast should be terminated when theserum glucose reaches 45 mg/dL and when hypoglycemic symptoms occur[12]. The absence of symptoms or signs consistent with hypoglycemiaexcludes the diagnosis [12]. The combination of symptoms, glucose less thanor equal to 45 mg/dL, and suppressed insulin indicates that the primary dis-turbance is a low glucose and is consistent with non–insulin-induced hypo-glycemia caused, for example, by cortisol deficiency, hepatic dysfunction, ora non–b-cell tumor. Failure to suppress insulin, on the other hand, implies

Fig. 1. Strategy for the laboratory evaluation of hypoglycemia. Notched corner¼ test orders

numbered in sequence 1 to n; Rounded corner¼decision points; Square corner¼ initial

presentations and diagnostic end points.


that hyperinsulinemia is primary and caused by insulinoma, factitious hypo-glycemia, or the administration of sulfonylurea. An insulin:glucose ratiocutoff of 0.3 using conventional units has been advocated as a means of dis-tinguishing between suppressed and nonsuppressed insulin [16]. Someauthorities rely more on absolute values [11,12].

C peptide is suppressed in factitious hyperinsulinism and is unsuppressedin insulinoma or following sulfonylurea administration. C peptide and insu-lin are released from the pancreas in equimolar amounts. Because moreinsulin is extracted by the liver, the ratio of C peptide to insulin in peripheralblood is greater than 1. As with the insulin-glucose ratio, the C peptide:in-sulin ratio may be used to assess the presence or absence of suppression [17]or reliance may be placed on absolute values [11,12].

Hypoglycemia caused by administration of sulfonylureas is indistinguish-able from that of insulinoma. Methods are now available for sulfonylureameasurements in plasma [11].

Thyroid dysfunction

Thyroid dysfunction is common [18,19] and is diagnosed accurately usinglaboratory tests [20]. Serum thyrotropin (thyroid-stimulating hormone[TSH]) is the test of choice for the initial laboratory evaluation of thyroidfunction [2]. In addition to overt symptoms or signs of thyroid disease,risk factors for thyroid dysfunction and indications for TSH testing are asfollows: surgery or radiotherapy affecting the thyroid gland; perniciousanemia; vitiligo; diabetes mellitus; medications (lithium, iodine-containingcompounds); and a family history of pernicious anemia, thyroid disease, dia-betes mellitus, or primary adrenal insufficiency [2]. In addition, the AmericanThyroid Association recommends that adults have TSH tests performedevery 5 years beginning at age 35 [2].


An elevated serum TSH is present in both overt and subclinical hypothy-roidism and almost all types of hyperthyroidism encountered in clinicalpractice exhibit TSH values that are suppressed to undetectable levels[2]. ‘‘Undetectable’’ is a function of the analytical sensitivity of the TSHmethods. So-called second-generation TSH methods in current widespreaduse can measure TSH with acceptable precision (coefficient of variation<20%) to 0.1 mU/L, and third-generation techniques now available are sen-sitive to 0.01 mU/L [21]. TSH values greater than 20 mU/L, even in theabsence of overt clinical signs of hypothyroidism, mean primary hypothy-roidism. Values less than that and in particular less than 10 mU/L in asymp-tomatic patients are more difficult to evaluate. It is important to becomefamiliar with the reasons for increases and decreases in serum TSH in theabsence of thyroid dysfunction. Nonthyroidal illnesses can account for


both increases and decreases [22]. Steroid therapy and dopamine infusionscause lowTSHvalues [2,22].Heterophil antibodies (by interferingwith immu-nometric methods) and amiodarone therapy cause falsely elevated values [23].

The next step in the evaluation of an increased TSH is a serum thyroxine(T4) measurement. Because free thyroxine (FT4) techniques are unaffected

Fig. 2. Strategy for the laboratory evaluation of thyroid dysfunction. Notched corner¼ test

orders numbered in sequence 1 to n; Rounded corner¼decision points; Square corner¼ initial

presentations and diagnostic end points; TSH¼ thyroid-stimulating hormone.


by changes in thyroid binding protein (unless changes are extreme), they arethe methods of choice for T4 determinations. Antithyroid peroxidase auto-antibodies and lipid profile determinations are particularly useful in mild orsubclinical hypothyroidism. This is because antithyroid peroxidase positiv-ity increases the likelihood of developing overt hypothyroidism and togetherwith abnormal lipid profiles indicate a need for therapy despite normal FT4

values [24]. Low FT4 indicates primary hypothyroidism. Normal FT4 meanssubclinical (or mild) hypothyroidism, provided the nonthyroidal causes ofincreased TSH listed previously are excluded. Increased FT4 could indicatea TSH-producing pituitary tumor or resistance to thyroid hormone [22].When encountered in the course of thyroid hormone replacement therapy,increased TSH and FT4 may indicate intermittent therapy [22].

Decreased TSH values between the lower reference limit and 0.1 mU/Lshould raise questions of steroid or dopamine therapy or nonthyroidal ill-nesses. TSH values less than 0.1 mU/L using second-generation TSH tech-niques constitute presumptive evidence of primary hyperthyroidism. Thenext step is FT4. When FT4 is clearly increased and accompanied by anincreased radioiodine uptake by the thyroid gland, the conclusion is eitherGraves’ disease, a toxic nodule, or multinodular goiter. When the radioio-dine uptake is suppressed, T4 ingestion, ectopic hyperthyroid tissue (strumaovarii), iodine-induced, or amiodarone therapy should be considered [22].

When FT4 is normal, a triiodothyronine (T3) determination should be per-formed. FT3 is probably preferable to T3. Increased FT3 is consistent with pri-mary hyperthyroidism. Further evidence may be obtained by demonstratingsuppression of a third-generation TSH [21]. A normal FT3 suggests subclini-cal hyperthyroidism. Decreased FT4 and FT3 indicate nonthyroidal illnesses,recent treatment of hyperthyroidism, or pituitary hypothyroidism [22].

A normal serum TSH excludes thyroid dysfunction in most cases. Never-theless, falsely normal values may occur under the following circumstances:within 12 months of treatment for thyrotoxicosis, in pituitary disease, in thy-roid hormone resistance, TSH-producing pituitary tumors, and in nonthyroi-dal illness [22]. These are indications for the addition of FT4 and FT3.Increased FT4 is consistent with TSH-producing tumor or thyroid hormoneresistance and decreased FT4 or FT3 are consistent with nonthyroidal illness,recent treatment of thyrotoxicosis, or pituitary hypothyroidism [22].

Cushing’s syndrome

Cushing’s syndrome is the result of chronic glucocorticoid excess. Thecauses are as follows:

Adrenocorticotropic hormone-dependentPituitary Cushing’s diseaseEctopic adrenocorticotropic hormone syndrome


Adrenocorticotropic hormone-independentAdrenal adenomaAdrenal carcinomaNodular adrenal hyperplasia

Pseudo-Cushing’s syndromeMajor depressionAlcoholism

Adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome,which accounts for 60% to 80% of cases, is caused most commonly by apituitary microadenoma (Cushing’s disease) and less commonly by an ecto-pic source of ACTH production [25,26]. The most common ectopic source isa small cell lung carcinoma [25,27]. Other sources are slow-growing bron-chial and pancreatic carcinoid tumors [25,26]. The latter are often occult andtend to present with cushingoid features indistinguishable from Cushing’sdisease [27]. Moreover, their response to high-dose dexamethasone may alsobe similar to that of Cushing’s disease. On the other hand, ectopic ACTHcaused by small cell lung carcinoma is associated with high levels of ACTHand cortisol-causing hypertension, hypokalemia, muscle weakness, and glu-cose intolerance rather than the typical cushingoid appearance [25,26].

The ACTH-independent Cushing syndrome is caused by the autonomousproduction of cortisol, most commonly from an adrenal adenoma, less com-monly from an adrenal carcinoma, and rarely from autonomous microadre-nal or macroadrenal hyperplasia [25–27]. Depression and alcoholism mayexhibit the clinic and laboratory findings that are difficult to distinguishfrom Cushing’s syndrome [26–28].


Cushing’s syndrome is rare; the annual incidence of the most commonvariety, Cushing’s disease, is reported to range from 0.1 to 1 new cases per100,000 [25]. The combination of hypertension, centripetal obesity, and glu-cose intolerance is not rare, and can be mistaken for Cushing’s syndrome[28]. It is important that tests to detect the syndrome be chosen carefullyto maximize sensitivity and specificity. There continues to be considerabledifference of opinion among experts with respect to the details of test strat-egy [25,26,29]. The algorithmic approach shown is a general one designed tofocus on teaching the essentials.

The test of choice for the detection of Cushing’s syndrome is a 24-hoururine free cortisol (UFC) [27]. Sensitivities and specificities are reported tobe greater than 95% [25,26,28]. It is important to exclude falsely negativeresults caused by inadequate 24-hour collections by measuring creatinineexcretion in the same sample. Daily creatinine excretion averages about 1 gand varies less than 10% from day to day. Repeat 24-hour creatinine valuesshould agree within 10% [27,28]. Twenty-four hour UFC values well withinthe reference range exclude Cushing’s syndrome [27]. Similarly, markedly


elevated values are confirmatory. Borderline or slightly elevated values needfurther investigation.

The overnight 1-mg dexamethasone suppression test is frequently the ini-tial test performed to detect Cushing’s syndrome [25]. Suppression of 8:00 AM

plasma cortisol to less than 1.6 lg/dL excludes Cushing’s syndrome with ahigh degree of certainty (sensitivity 98% to 100%) [28]. The overnight test

Fig. 3. Strategy for the laboratory evaluation of Cushing’s syndrome. Notched corner¼ test

orders numbered in sequence 1 to n; Rounded corner¼ decision points; Square corner¼ initial

presentations and diagnostic end points; UFC¼ urine free cortisol.


is a convenient screening version of the standard 2-day test (8:00 AM plasmacortisol after eight 0.5-mg doses of dexamethasone at 6-hour intervals) [25].There may be no suppression in patients with obesity; psychiatric illness;alcoholism; those undergoing stress; and in the presence of increased cortisol-binding globulin (eg, pregnancy and oral contraceptive therapy) [25]. Dexa-methasone suppression excludes Cushing’s syndrome. Failure to suppressrequires further investigation to exclude pseudo-Cushing’s syndrome.

A midnight plasma cortisol value taken during sleep in a hospitalized pa-tient is reported to be 100% sensitive for the detection of Cushing’s syndrome[30]. Other approaches used to exclude pseudo-Cushing’s syndrome include astandard 2-day dexamethasone suppression test followed by a corticotropin-releasing hormone (CRH) stimulation test [25,27]. In normal or pseudo-Cushing’s patients, when 1 lg of CRH is given intravenously 2 hours after thelast dexamethasone dose, plasma cortisol does not rise above 1.4 lg/dL [25].

At this stage in the test strategy, the presumptive diagnosis is Cushing’ssyndrome. The next step is to differentiate between the causes of the syn-drome, and the initial approach is to determine whether the syndrome isACTH-dependent or ACTH-independent by measuring plasma ACTH[25,27]. Adrenal tumors and autonomous adrenal hyperplasia suppress plas-ma ACTH close to undetectable levels [27]. ACTH values within the refer-ence rage or higher indicate ACTH-dependent Cushing’s syndrome causedby either Cushing’s disease or ectopic Cushing’s syndrome [27]. Severalapproaches have been suggested to make this distinction. The standardhigh-dose dexamethasone suppression test (2 mg every 6 hours for eightdoses) or the overnight test (8 mg at 11:00 PM) followed by 24-hour UFCmeasurement are comparable in terms of sensitivity and specificity [27]. Sup-pression of UFC values more than 90% over baseline values is reported tobe 70% sensitive and 100% specific for the diagnosis of Cushing’s disease[25]. As indicated previously, patients with small ACTH-producing bron-chial and pancreatic carcinoid-type tumors, as distinct from small cell lungcarcinomas, exhibit varying degrees of 24-hour UFC suppression and, as aresult, may be difficult to distinguish from a pituitary source of ACTH.Additional investigations frequently required to make the distinction in-clude CRH and desmopressin stimulation testing [26] and inferior petrosalsampling following CRH [30,31].

Primary aldosteronism

Primary aldosteronism is usually quoted as accounting for less than 2%hypertension [32]. Recently, however, mainly because of increasing use ofthe plasma aldosterone (PAC): plasma renin activity (PRA) ratio as ascreening test in normokalemic and hypokalemic hypertensive patients, theincidence of primary aldosteronism is thought to be considerably higher[33,34]. Two thirds of the cases are caused by an aldosterone-producing


adenoma (APA), surgical removal of which in many cases cures the hyper-tension. The remaining cases are caused by adrenal hyperplasia, which isnot a surgically correctible variety of hypertension [35]. The laboratory teststrategy for the diagnosis of primary aldosteronism is analogous to that ofCushing’s syndrome. The first step is to decide whether the disease is presentor not, the next step is to confirm positive detection tests, and the third stepis to distinguish adrenal hyperplasia from APA [35–37].


The two tests of choice for detection are PAC and PRA [35–37].Although most patients with primary aldosteronism are hypokalemic, atleast 20% are normokalemic [35], thereby limiting the use of serum potas-sium as a screening test. Increasing reliance is now placed on the PAC andPRA measurements and on the PAC:PRA ratio [35–38]. Some authors haverecommended screening unselected hypertensive patients [39,40], but mostadvocate limiting testing to those most at risk [35–37]. This includes the fol-lowing: patients with spontaneous and severe diuretic-induced hypolkale-mia, treatment-resistant hypertension, adrenal abnormalities discoveredincidentally in the course of abdominal imaging procedures, and youngpatients at risk for glucocorticoid-remediable hypertension [35,37]. Themore abnormal the PRA and PAC and the higher the ratio the more likelythe diagnosis of primary aldosteronism; PAC:PRA ratios greater than 50are highly predictive [38]. It is important to point out that, if samples forPAC and PRA are not collected under standardized conditions of diet, pos-ture, time of day, and medications known to affect the assays, misleadingresults may be obtained [40].

The key to confirmatory testing is to demonstrate that salt loading (ahigh-sodium diet, intravenous infusion of normal saline, or administrationof a salt-retaining steroid) fails to suppress PAC [35,37]. Whenever possible,patients should be off antihypertensive medication for at least 3 weeks [36].

A postural test in which a patient’s PAC, determined following overnightrecumbence, increases more than 33% after being upright for 2 to 4 hours,indicates responsiveness to angiotensin II and is more likely to indicate adre-nal hyperplasia rather than APA [37]. On the other hand, lack of change or adecrease in PAC points to APA. A basal plasma 18-corticosterone (18-B) at8:00 AM greater than 100 ng/dL supports a diagnosis of APA [35–37]. In prac-tice, considerable reliance is placed on adrenal imaging and adrenal veincatheterization studies to make the distinction between hyperplasia and ade-noma [35–37]. Patients in whom imaging studies are normal or equivocal orwhose postural studies point to APA may have glucocorticoid-remediablehypertension [36]. This is a rare form of primary aldosteronism in whichaldosterone secretion is solely under the control of ACTH and is caused by achimeric gene the product of which has 11 b-hydroxylase and aldosterone syn-thase sequences and results in aldosterone synthesis in the zona fasciculata


Fig. 4. Strategy for the detection and differential diagnosis of primary aldosteronism. Notched

corner¼ test orders numbered in sequence 1 to n; Rounded corner¼ decision points; Square

corner¼ initial presentations and diagnostic end points; PAC¼ plasma aldosterone; PRA¼plasma renin activity.


under the influence of ACTH [41,42]. The presence of glucocorticoid-remedi-able hypertensionmay be confirmed by demonstrating suppression of PAC tovalues less than 4 ng/dL following 2 mg dexamethasone daily for 2 to 3 days,or by direct genetic testing [43].

Summary

The diagnosis of endocrine disorders lends itself to sequential test strat-egy. The strategies outlined in this article deal with problems that are eithercommonly encountered in clinical practice, reflect recently acquired knowl-edge, or both. Wherever possible a clearly defined algorithmic approach isused. The purpose is to emphasize the most appropriate general approachto test strategy.

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selected endocrine test strategies

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