Lawrence M. Crapo

The epidemiology of thyroid disease and implications for screening

The burden of thyroid disease in the general population is enormous. As many as 50% of people in the community have microscopic nodules, 3.5% have occult papillary carcinoma, 15% have palpable goiters, 10% demonstrate an abnormal thyroid-stimulating hormone level, and 5% of women have overt hypothyroidism or hyperthyroidism. Despite this high prevalence of thyroid disease, screening for these disorders is not recommended by any major health agency. This article explores the epidemiologic issues surrounding this complex problem by analyzing prevalence, incidence, and mortality data from a worldwide variety of sources.

The Cushing Syndrome: An Update on Diagnostic Tests

STUDY OBJECTIVE Review and evaluation of diagnostic tests for the Cushing syndrome based on reports published since 1978. DATA IDENTIFICATION Studies published in the English literature from 1978 through 1989 were identified using Index Medicus and cross searching of bibliographies. STUDY SELECTION AND DATA EXTRACTION Studies of five or more patients for general analysis and smaller studies and case reports when pertinent. To develop criteria for the corticotropin-release hormone (CRH) stimulation test, only studies reporting individual patient data were analyzed. RESULTS No new test is clearly better than existing tests in establishing a definitive diagnosis. Among tests to determine cause, the CRH stimulation test, by newly developed criteria, has a 91% sensitivity (95% CI, 85% to 95%) and a 95% specificity (CI, 82% to 99%), and the overnight high-dose dexamethasone suppression test has an 89% sensitivity (CI, 80% to 94%) and a 100% specificity (CI, 84% to 100%) for the pituitary Cushing syndrome. Magnetic resonance imaging has greater sensitivity for detecting adrenocorticotropin (ACTH)-producing pituitary adenomas than computed tomography. Inferior petrosal sinus sampling can correctly identify a pituitary cause in 88% (CI, 79% to 94%) of cases. CONCLUSIONS Diagnosis is still best established by using 24-hour urine free cortisol measurements or low-dose dexamethasone suppression testing. The CRH stimulation test is an outpatient alternative to determine cause, and the over-night high-dose dexamethasone test may become the test of choice along with plasma ACTH measurements by radioimmunoassay in the initial evaluation of cause. Magnetic resonance imaging should be used to evaluate the pituitary Cushing syndrome, and inferior petrosal sinus sampling is most useful in problematic cases with uncertain cause.

Diagnosis of adrenal insufficiency

Adrenal insufficiency is an uncommon clinical disorder that results from an inadequate basal or stress level of plasma cortisol. It is important to diagnose adrenal insufficiency because the disorder may be fatal if left unrecognized or untreated. With diagnosis and appropriate adrenocortical hormone replacement, normal quality of life and longevity can be achieved. The presentation of adrenal insufficiency may be insidious and thus difficult to recognize. Once suspected, however, the definitive diagnosis can be confirmed by laboratory evaluation of adrenocortical function. Although many different tests for adrenal insufficiency have been developed, few have been adequately studied and many are inconvenient for testing in the outpatient clinical setting. By contrast, the cosyntropin stimulation test is widely used in many different clinical settings and is easy to perform. In addition, data on test performance in various clinical settings are plentiful. The cosyntropin stimulation test has therefore emerged as the initial test used to evaluate patients for both primary and secondary adrenal insufficiency. Methods We reviewed all English-language studies in humans identified in the MEDLINE database (1966 to 2002) through the Ovid search service. Search terms were adrenal gland hypofunction restricted to diagnosis. For the normal response to high-dose cosyntropin, we selected studies with 10 or more participants. For the diagnosis of primary adrenal insufficiency, we selected studies with 5 or more participants. For evaluation of the sensitivity and specificity of cosyntropin tests in secondary adrenal insufficiency, we selected only studies that stratified all participants with suspected adrenal insufficiency by integrated tests of adrenal function (insulin tolerance or metyrapone tests). Summary receiver-operating characteristic (ROC) curves were developed from sensitivity and specificity values derived from individual studies, as described by Littenberg, Moses, and colleagues (1, 2) (see the Appendix for detailed formulas). Summary ROC curves were compared by using area under the curves (AUCs), as described by Walter (3). For our data sets, we verify the condition (B 0; see the Appendix) that yields explicit formulas for AUC and its CI for the summary ROC curves. The slope parameter (B) did not differ significantly from 0 for all data sets used to generate summary ROC curves. We compared ROC curves for data paired by individual participants using likelihood methods with a program (ROCKIT 0.9B) developed by Metz and colleagues (4) (available at www-radiology.uchicago.edu/cgi-bin/software.cgi). The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Data Synthesis High-Dose Cosyntropin Stimulation Test The standard cosyntropin test is performed by administering one ampule (250 g) of cosyntropin intramuscularly or intravenously and measuring serum or plasma cortisol levels 30 to 60 minutes later. With a normal (negative) test result, the serum cortisol level after cosyntropin stimulation is generally greater than 500 nmol/L. A subnormal cortisol response (<500 nmol/L) is defined as a positive test result and indicates an increased probability of either primary or secondary adrenal insufficiency. The cosyntropin test may be performed at any time of the day. In patients with suspected adrenal insufficiency, a basal plasma cortisol level is not usually necessary because neither the absolute nor the percentage change from the basal level is useful as a diagnostic criterion for the cosyntropin test (5). However, in the absence of corticosteroid-binding globulin deficiency, an unstimulated serum cortisol level, determined between 6:00 and 8:00 a.m., may be helpful because a level less than 80 nmol/L strongly suggests adrenal insufficiency (5). Normal Response to the High-Dose Cosyntropin Test In healthy persons without evidence of adrenal insufficiency, serum cortisol response 30 or 60 minutes after 250 g of cosyntropin is administered intramuscularly or intravenously has been studied extensively (6-22). The responses to intramuscular and intravenous injections are similar, and the responses among normal persons vary. In 10 studies that included a total of 288 participants and that reported the entire range of postcosyntropin serum cortisol levels, the levels ranged from 415 to 2200 nmol/L (9, 10, 12-15, 17, 19-21). The broad range of normal responses to cosyntropin stimulation reflects various factors, including differences in hypothalamicpituitaryadrenal axis set point, serum corticosteroid-binding globulin level, stress level, body composition, time of testing, and performance characteristics of the cortisol assay used. In one detailed study of 100 healthy persons, the distribution curves of serum cortisol levels obtained 30 and 60 minutes after a 250-g intramuscular injection of cosyntropin displayed a non-Gaussian configuration for each of four separate cortisol assays, with the distribution skewed to the right toward higher cortisol levels (22). The 5th percentile lower cortisol cutoff limit for these four assays ranged from 510 to 615 nmol/L at 30 minutes and from 620 to 675 nmol/L at 60 minutes. Other studies also show increases in the cortisol response at 60 minutes compared with 30 minutes (16, 18, 20). In 11 studies involving 340 healthy participants, the data presented as the mean 2 SDs show lower limits ranging from 390 to 620 nmol/L at 30 minutes (6-10, 16-20) and from 500 to 725 nmol/L at 60 minutes (11, 16, 18, 20). Because the distribution curve is non-Gaussian, no conclusion can be drawn from these studies about the percentage of healthy persons with serum cortisol levels less than the lower cutoff limit. The studies described show that an appreciable number of normal persons will have a postcosyntropin cortisol level less than a cutoff limit of 500 nmol/L. However, none of the 288 participants in the 10 studies described earlier (in which the entire range of cortisol responses was reported) had a cortisol level less than 415 nmol/L. Diagnosis of Primary Adrenal Insufficiency Primary adrenal insufficiency (often called Addison disease) is an uncommon disorder that often presents with a slowly progressive increase in nonspecific symptoms. The prevalence of this disorder in the community is approximately 100 cases per 1 million people (23-26); the incidence is 5 cases per year per 1 million people (26). The prevalence of primary adrenal insufficiency is higher (although not precisely known) in persons with HIV disease, family histories of adrenoleukodystrophy, autoimmune endocrine disorders, metastatic cancer, and granulomatous disease. The prevalence among persons with nonspecific symptoms, such as tiredness, fatigue, weakness, listlessness, weight loss, nausea, and anorexia, is not known. More specific symptoms, such as unexplained darkening of the skin, orthostatic dizziness, and salt-craving, may not be among presenting symptoms. Cosyntropin Stimulation Tests in Primary Adrenal Insufficiency Table 1 summarizes the results of 8 studies in which 122 patients with primary adrenal insufficiency and controls were given 250 g of cosyntropin intravenously or intramuscularly and the serum cortisol levels were measured 30 or 60 minutes later. None of the patients in these studies underwent consecutive prospective evaluation for adrenal insufficiency; rather, they were selected for study either because previous evaluation showed that they had typical Addison disease (13, 14, 20, 27-29) or because their cosyntropin tests were compared with historical controls in retrospective surveys (23, 30). Controls in these studies varied from healthy volunteers (13, 14, 23) to participants with nonendocrine illness (14, 27) or suspected adrenal insufficiency (29). Thus, case-patients and controls were not recruited from the same setting. In general, the case-patients with Addison disease in these studies were selected on the basis of typical clinical and nonendocrine laboratory criteria, such as hyperkalemia, supplemented in many cases with elevated plasma adrenocorticotropic hormone (ACTH) levels and low urine steroid responses to intravenous ACTH infusions. In several retrospective analyses using historical controls, cosyntropin tests may have contributed to the diagnosis of Addison disease, but several patients with Addison disease in each of these surveys had normal cosyntropin test results. None of the studies indicated that patients with borderline cosyntropin test results were selectively excluded. However, it is clear that the cases of Addison disease selected in these studies were more advanced and easily recognized by well-established clinical and laboratory criteria. Thus, in most cases in these studies, the diagnosis of Addison disease was based on clinical evidence supported by serum electrolyte, plasma ACTH, and urine steroid levels. Cosyntropin tests were then performed in these patients, and the results were interpreted independently of the original diagnostic criteria. Table 1. The 250-g Cosyntropin Stimulation Test in Patients with Primary Adrenal Insufficiency For the summary ROC curve, which is based on four of the studies in Table 1 (14, 20, 27, 29), the point on the summary ROC where sensitivity and specificity are equal was 96.5% (95% CI, 94.5% to 98.5%) for the diagnosis of primary adrenal insufficiency. When specificity is set at 95%, this summary ROC curve yields a sensitivity of 97.5% (CI, 95% to 100%), with a corresponding positive likelihood ratio of 19.5 (CI, 19.0 to 20.0) and a negative likelihood ratio of 0.026 (CI, 0 to 0.6). The AUC for this summary ROC curve was 0.99 (CI, 0.985 to 1.000), indicating excellent test discrimination. As a result of the selection bias in these studies toward patients with severe Addison disease, the cosyntropin test performance characteristics derived from Table 1 are most

Do Automated Calls with Nurse Follow-up Improve Self-Care and Glycemic Control among Vulnerable Patients with Diabetes?

PURPOSE We sought to evaluate the effect of automated telephone assessment and self-care education calls with nurse follow-up on the management of diabetes. SUBJECTS AND METHODS We enrolled 280 English- or Spanish-speaking adults with diabetes who were using hypoglycemic medications and who were treated in a county health care system. Patients were randomly assigned to usual care or to receive an intervention that consisted of usual care plus bi-weekly automated assessment and self-care education calls with telephone follow-up by a nurse educator. Outcomes measured at 12 months included survey-reported self-care, perceived glycemic control, and symptoms, as well as glycosylated hemoglobin (Hb A1c) and serum glucose levels. RESULTS We collected follow-up data for 89% of enrollees (248 patients). Compared with usual care patients, intervention patients reported more frequent glucose monitoring, foot inspection, and weight monitoring, and fewer problems with medication adherence (all P -0.03). Follow-up Hb A,, levels were 0.3% lower in the intervention group (P = 0.1), and about twice as many intervention patients had Hb A1c levels within the normal range (P = 0.04). Serum glucose levels were 41 mg/dL lower among intervention patients than usual care patients (P = 0.002). Intervention patients also reported better glycemic control (P = 0.005) and fewer diabetic symptoms (P <0.0001 ), including fewer symptoms of hyperglycemia and hypoglycemia. CONCLUSIONS Automated calls with telephone nurse follow-up may be an effective strategy for improving self-care behavior and glycemic control, and for decreasing symptoms among vulnerable patients with diabetes.

Screening for Thyroid Disease

PURPOSE To evaluate the usefulness of screening for thyroid dysfunction in various clinical settings. DESIGN Review and synthesis of the literature. MAIN RESULTS Screening in the community detects new overt thyrotoxicosis or hypothyroidism in approximately 0.5% of the general population. The yield is best among women over 40 years of age (1%) and is lowest among young men (0%). Case-finding (testing clinic patients who are seeing a physician for unrelated reasons) has a better yield and is less expensive than screening in the community. Patients hospitalized with acute illnesses do not benefit from routine thyroid function testing. However, patients who are admitted to specialized geriatric units because of general disability, failure to thrive, and other indications may benefit. In various studies, from 2% to 5% of patients admitted to geriatric units have treatable thyroid disease. The serum total thyroxine, free thyroxine index, free thyroxine, and sensitive thyrotropin assay are all effective as initial tests for screening. The sensitive thyrotropin assay is less cost-effective than the other choices. RECOMMENDATIONS Case-finding in some women over 40 years of age can be useful. Patients admitted to specialized geriatric units may also benefit from routine testing. Thyroid function tests are not indicated for community screening programs or for patients hospitalized with acute medical or psychiatric illnesses.

Cost-Effectiveness of Universal and Risk-Based Screening for Autoimmune Thyroid Disease in Pregnant Women

CONTEXT Hypothyroidism in pregnancy can lead to adverse maternal and fetal outcomes. Although screening of high-risk women is advocated, universal screening remains controversial. OBJECTIVE The objective of the study was to compare the cost-effectiveness of universal screening of pregnant women for autoimmune thyroid disease (AITD) with screening only high-risk women and with no screening. DESIGN, SETTING, AND PARTICIPANTS A decision-analytic model compared the incremental cost per quality-adjusted life-year (QALY) gained among the following: 1) universal screening, 2) high-risk screening, and 3) no screening. Screening consisted of a first-trimester thyroid-stimulating hormone level and antithyroid peroxidase antibodies. Women with abnormal results underwent further testing and, when indicated, levothyroxine therapy. Randomized controlled trials provided probabilities for adverse obstetrical outcomes. The model accounted for the development of postpartum thyroiditis and overt hypothyroidism. Additional scenarios in which therapy prevented cases of decreased child intelligence quotient were explored. MAIN OUTCOME MEASURES Medical consequences of AITD in pregnancy, QALY, and costs were measured. RESULTS Risk-based screening and universal screening were both cost-effective relative to no screening, with incremental cost-effectiveness ratios (ICERs) of

Screening pregnant women for autoimmune thyroid disease: a cost-effectiveness analysis.

6,753/QALY and

Monitoring Therapy in Patients Taking Levothyroxine

7,138/QALY, respectively. Universal screening was cost-effective compared with risk-based screening, with an ICER of

Needle in a Haystack

7,258/QALY. Screening remained cost-effective in various clinical scenarios, including when only overt hypothyroidism was assumed to have adverse obstetrical outcomes. Universal screening was cost-saving in the scenario of untreated maternal hypothyroidism resulting in decreased child intelligence, with levothyroxine therapy being preventive. CONCLUSIONS Universal screening of pregnant women in the first trimester for AITD is cost-effective, not only compared with no screening but also compared with screening of high-risk women.

Optimal therapy for the geriatric patient: The challenge to clinical pharmacology

OBJECTIVE Untreated maternal hypothyroidism during pregnancy can have adverse consequences on maternal health and child intelligence quotient (IQ). Our objective was to examine the cost-effectiveness of screening pregnant women for autoimmune thyroid disease. DESIGN We developed a state-transition Markov model and performed a cost-effectiveness analysis of screening pregnant US women, aged 15-45 years, with no known history of thyroid disease, in the first trimester. METHODS Three strategies were compared: 1) no screening, 2) one-time screening using anti-thyroid peroxidase (anti-TPO) antibodies, and 3) one-time screening using TSH. Screening tests were added to the laboratory tests of the first prenatal visit. Abnormal screening tests were followed by further testing and subsequent thyroxine treatment of hypothyroid women. RESULTS Screening pregnant women in the first trimester using TSH was cost-saving compared with no screening. Screening using anti-TPO antibodies was cost-effective compared with TSH screening with an incremental cost-effectiveness ratio of