Inhibition of hepatic binding of thyroxine by cholecystographic agents.

Subsequent to studies indicating that cholecystographic agents and sulfobromophthalein (BSP) inhibit uptake of thyroxine (T(4)) by rat liver slices, the effect of such compounds on hepatic storage of T(4) in man has been examined. After intravenous administration of [(125)I]T(4) to five normal subjects, hepatic radioactivity, estimated by external gamma counting, rose to a peak in approximately 4 h and then declined in parallel with serum radioactivity. When a 6-g dose of the cholecystographic agent, tyropanoate (Bilopaque), was administered orally 3 d later, estimated hepatic extravascular radioactivity fell 50-60% within 4 h and then rose toward the pretyropanoate value. Concomitant with the fall in hepatic radioactivity, serum radioactivity rose 57-70%, as did stable T(4) levels in serum, suggesting that hormone discharged from the liver entered the serum. Both uptake of T(4) and discharge by tyropanoate were much less in two patients with liver disease. Ipodate (Oragrafin), 12 g orally in two subjects, caused much smaller changes in hepatic and serum radioactivity. However, ipodate also caused a doubling of the percent free T(4) in the serum as judged by equilibrium dialysis, and the ratio of hepatic radioactivity to free [(125)I]T(4) in serum declined markedly after ipodate, similar to the fall in hepatic:serum (125)I ratios after tyropanoate. BSP, 20 mg/kg i.v. in three subjects, caused a smaller change; the decline in hepatic T4 content averaged 19%. We conclude that these organic anions, tyropanoate, ipodate, and BSP, all can displace T(4) from the liver. The results imply a link between T(4) transport and organic anion transport, and indicate a mechanism for altering hepatic T(4) content in man that could be the site of physiologic regulation or of disease. A method is described whereby analysis of the change in hepatic and plasma radioactivity after tyropanoate could be employed to estimate hepatic T(4) content in diverse clinical circumstances.

Prevention and Treatment of Hypertension Study (PATHS): effects of an alcohol treatment program on blood pressure.

OBJECTIVE: To determine whether blood pressure is reduced for at least 6 months with an intervention to lower alcohol intake in moderate to heavy drinkers with above optimal to slightly elevated diastolic blood pressure, and whether reduction of alcohol intake can be maintained for 2 years. DESIGN: A randomized controlled trial. METHODS: Six hundred forty-one outpatient veterans with an average intake of 3 or more alcoholic drinks per day in the 6 months before entry into the study and with diastolic blood pressure 80 to 99 mm Hg were randomly assigned to a cognitive-behavioral alcohol reduction intervention program or a control observation group for 15 to 24 months. The goal of the intervention was the lower of 2 or fewer drinks daily or a 50% reduction in intake. A subgroup with hypertension was defined as having a diastolic blood pressure of 90 to 99 mm Hg, or 80 to 99 mm Hg if recently taking medication for hypertension. RESULTS: Reduction in average weekly self-reported alcohol intake was significantly greater (P<.001) at every assessment from 3 to 24 months in the intervention group vs the control group: levels declined from 432 g/wk at baseline by 202 g/wk in the intervention group and from 445 g/wk by 78 g/wk in the control group in the first 6 months, with similar reductions after 24 months. The intervention group had a 1.2/0.7-mm Hg greater reduction in blood pressure than the control group (for each, P = .17 and P = .18) for the 6-month primary end point; for the hypertensive stratum the difference was 0.9/0.7 mm Hg (for each, P = .58 and P = .44). CONCLUSIONS: The 1.3 drinks per day average difference between changes in self-reported alcohol intake observed in this trial produced only small nonsignificant effects on blood pressure. The results from the Prevention and Treatment of Hypertension Study (PATHS) do not provide strong support for reducing alcohol consumption in nondependent moderate drinkers as a sole method for the prevention or treatment of hypertension.

Cholecystographic agents and sulfobromophthalein inhibit the binding of L-thyroxine to plasma membranes of rat hepatocytes.

Cholecystographic agents and sulfobromophthalein (BSP) cause a major discharge of labeled T4 from the liver in man in vivo. In the present study we sought to determine if this discharge is partially due to inhibition of T4 binding to plasma membrane sites. Plasma membranes were isolated from hepatocytes of female Sprague-Dawley rats, and 5'-nucleotidase levels were measured to demonstrate plasma membrane viability. Specific binding of T4 (Ka, 1.01 X 10(8) M) was confirmed by displacement of labeled T4 by unlabeled hormone (10(-10)-10(-5) M). Displacement of labeled hormone was also produced by addition of tyropanoate, iopanoate, ipodate, or BSP. At 5-mM concentrations of inhibitor, the Ka for T4 declined to 4.00 X 10(7) M with BSP, 5.07 X 10(7) M with ipodate, 5.62 X 10(7) M with tyropanoate, and 7.43 X 10(7) M with iopanoate. Thus, a portion of the discharge of hepatic T4 after administration of these agents may be due to competitive inhibition of binding to plasma membrane sites.

Effects of cholecystographic agents and sulfobromophthalein on binding of thyroid hormones to serum proteins.

A number of interactions between thyroid hormones and cholecystographic agents have previously been demonstrated. In the present study we show that cholecystographic agents also interfere with the binding of thyroid hormones to serum proteins. A commercial kit (Tri-Tab) was used in which the uptake of labeled hormone from serum by a silicate adsorbent tablet is measured. In the presence of cholecystographic agents or sulfobromophthalein (BSP), the amount of labeled hormone bound to adsorbent increased in a dose-dependent fashion, reflecting displacement from protein-binding sites. The order of potency was BSP greater than ipodate greater than iopanoate greater than tyropanoate. Displacement of hormone was confirmed by a second methodology in which graded amounts of unlabeled T4 were added to the system. This allowed a Scatchard analysis to be performed for binding sites on T4-binding globulin. The cholecystographic agents and BSP caused displacement of the Scatchard slopes, again demonstrating interference with binding to serum protein sites. A method is described in which the change in Scatchard slope produced by an inhibitor is employed to compute the association constant between T4-binding sites on T4-binding globulin and the inhibitors. The values were: BSP, 14.6 X 10(3) M-1; ipodate, 4.7 X 10(3) M-1, iopanoate, 2.2 X 10(3) M-1; and tyropanoate, 0.1 X 10(3) M-1. Because of these relatively low values and the rapidity with which these agents are normally cleared from serum, it seems likely that effects on free hormone levels would be transient and of small magnitude during routine cholecystography. Also, ipodate, in the 1 g/day dose that has been employed experimentally to treat hyperthyroidism, should have a negligible effect on protein binding. On the other hand, when high levels of these compounds are used in experimental settings to study other aspects of thyroid hormone metabolism, changes in protein binding can occur and confound interpretation of results.

Decreased adrenal responsiveness in hypothermic patients.

We have performed ACTH simulation tests in a total of 14 subjects who were hypothermic at the time of initial presentation. Plasma cortisol values were measured before and 1 h after an iv dose of 25 U synthetic ACTH. The cortisol response was depressed in these subjects, with a mean rise of 32% and an absolute mean rise of 5.0 microgra/dl. There appeared to be a temperature threshold effect, with only minimal responses observed below 32 C. A subgroup of 5 patients with sluggish responses to ACTH while hypothermic (mean cortisol rise, 12.5%) were retested after warming and responded normally (mean rise, 166%). Thus, ACTH stimulation tests may be misleading in the hypothermic patient and should be performed only after body temperature has returned to normal.

Systemic hypertension in diabetes mellitus.

Hypertension occurs more frequently in diabetics and markedly exacerbates the vascular morbidity and mortality resulting from this metabolic disorder. However, the etiology of hypertension in diabetics remains poorly understood. Like aging persons, diabetics have increased systemic resistance and a probable reduction in baroreceptor sensitivity. They also have an expanded total body sodium pool and a tendency to lower levels of plasma renin activity. Some of these factors suggest that a subtle calcium deficiency could also be of etiologic importance.

Endocrine changes with critical illness.

Many alterations in hormonal economy occur predictably with critical illnesses, including changes in thyroid hormones, glucocorticoids, mineralocorticoids, and gonadotrophins. These effects are generally nonspecific and relate primarily to the severity of the illness, rather than to the exact nature of the illness. Thus a wide variety of critical illnesses, ranging from severe pneumonia to hepatic or renal failure, all tend to produce a similar pattern of "stress-induced" hormonal alterations.

Selecting antihypertensive drug therapy: the JNC-V controversy.

OBJECTIVE: To present both the supporting and the opposing arguments for the fifth set of recommendations issued by the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC). METHODS: The published studies are reviewed, and the various opinions are discussed. RESULTS: The 1993 recommendation from the JNC that diuretics or beta-adrenergic blockers be preferred for therapy in most patients with hypertension has proved controversial. This recommendation derived primarily from recent long-term studies showing convincing reductions in cardiovascular morbidity and mortality when these agents are used to control hypertension. Comparable data have not yet been obtained for newer agents, such as calcium channel blockers and angiotensin-converting enzyme inhibitors. Nonetheless, some critics of the JNC recommendation still favor the newer agents because of their putatively superior side-effect profile, from both a metabolic and a compliance standpoint. CONCLUSION: The issue of optimal antihypertensive drug therapy will not be definitively resolved until long-term studies directly comparing the various classes of agents are completed in future years.

Malignant thymic carcinoid in multiple endocrine neoplasia type I syndrome: case report and literature review.

OBJECTIVE: To describe a case of thymic carcinoid tumor in association with multiple endocrine neoplasia type I (MEN I) and discuss the various manifestations of this syndrome. METHODS: We present the clinical and laboratory data, including histopathologic and immunocytochemical findings, for our current patient and also review the literature on MEN I syndromes. RESULTS: In a 46-year-old Caucasian man with no family history of multiple endocrine neoplasia, numerous MEN I lesions developed over time. The patient had gastrinoma of the duodenum, Zollinger-Ellison syndrome, hyperparathyroidism, a nonfunctioning adrenal mass, and foregut carcinoid tumors, including gastric and malignant thymic carcinoids. He sequentially underwent partial gastrectomy in conjunction with Billroth II anastomosis, a four-gland parathyroidectomy, and palliative radiotherapy for malignant carcinoid tumor, as well as endoscopic excision of accessible tumors. CONCLUSION: The involvement in MEN I can be clinically complex. Early detection of MEN I lesions will facilitate timely implementation of treatment and help minimize complications.

Atrial natriuretic peptide attenuates the reflex sympathetic responses to lower body negative pressure.

The authors studied the effect of intravenous infusion of atrial natriuretic peptide (ANP) on the plasma catecholamine and forearm vasoconstrictor responses to cardiopulmonary baroreflex deactivation in six normal, male volunteers in order to determine whether ANP influences reflex forearm vasoconstriction in humans. Unloading of low-pressure cardiopulmonary baroreceptors (CPBR) was accomplished by application of low levels (-10 and -20 mm Hg) of lower body negative pressure (LBNP). The authors measured the plasma norepinephrine (NE) and epinephrine, the mean arterial pressure (MAP), and the forearm vascular resistance (FVR) responses to reflex sympathetic activation by LBNP. ANP infusion (0.1 microgram.kg-1.min-1) decreased (p less than 0.01) basal MAP, as well as plasma renin activity and plasma aldosterone levels (p less than 0.05). ANP infusion also reduced (p less than 0.01) plasma NE responses to both levels of LBNP and tended to decrease both epinephrine and FVR during ANP infusion at -20 mm Hg LBNP (p = 0.8). These data suggest that exogenous ANP inhibits the reflex sympathetic responses that occur with CPBR unloading. The blunted plasma NE responses to CPBR unloading parallel the attenuation of FVR response to LBNP during ANP infusion, despite significant LBNP-induced hypotension.

Thyroid changes with aging: significance and management.

A number of changes in thyroid physiology occur with normal aging, including a modest fall in T3 levels and a reduction in the rate of turnover of thyroid hormones. Additionally, the diagnosis of either hyperthyroidism or hypothyroidism can be more difficult in the elderly because the symptoms may be more subtle. Hyperthyroidism may be disguised by a very apathetic presentation, without many of the typical adrenergic symptoms such as tachycardia and nervousness. Some of the many ways in which hypothyroidism may present include occult congestive heart failure or a severe fecal impaction.

Effects of illness on thyroid function tests.

Severe illness of any type predictably leads to abnormal results on thyroid function tests. The first apparent changes are a decrease in total triiodothyronine (T3) and an increase in reverse T3. As disease progresses, a marked decline in thyroxine and an increase in T3 resin uptake are observed. Thyrotropin levels remain normal, confirming that the patient is euthyroid despite marked alterations in thyroid function tests. Supplemental thyroid hormone has never been shown to be of any value, and may indeed be harmful, in euthyroid patients with abnormal thyroid function. Recognition of the euthyroid sick syndrome is vital to avoid needless therapy.

Cushing's syndrome. How to pinpoint and treat the underlying cause.

In addition to prolonged glucocorticoid therapy (not discussed here), at least five other conditions cause Cushing's syndrome. They are excessive corticotropin secretion by the pituitary gland (which results in Cushing's disease), ectopic production of corticotropin by malignant nonpituitary tumors, benign adrenal adenoma, adrenal carcinoma, and primary adrenocortical nodular dysplasia. Each can be distinguished by a specific pathophysiologic process that triggers the adrenal glands to overproduce glucocorticoids. At present, diagnosis of Cushing's syndrome or disease relies heavily on the dexamethasone (Decadron, Hexadrol) suppression test. After diagnosis, other studies, including computed tomography, magnetic resonance imaging, and corticotropin radioimmunoassay, can be used to localize the site of the lesion. Treatment, of course, depends on the underlying cause.

Painful, painless, and postpartum thyroiditis. Distinct entities or merely variants?

Subacute thyroiditis is a common disease that often goes undetected. Indeed, both painful and painless thyroiditis are easily overlooked or misdiagnosed and perhaps mistreated unless careful attention is paid to the patient's history and physical examination. Treating the hyperthyroidism of subacute thyroiditis as if it were Graves' disease, for example, would be inappropriate, since therapy for the two entities is completely different. A form of painless thyroiditis, for reasons that remain unclear, can occur in the postpartum period and may be related to postpartum psychosis or depression.

When to worry about hypoglycemia.

The important causes of hypoglycemia unrelated to known diabetes are relatively few. Postprandial hypoglycemia is a relatively benign disorder. Fasting hypoglycemia is more serious and may be caused by metabolic disturbances or tumors. Several hereditary disorders cause hypoglycemia in infants and must be diagnosed and treated before serious damage occurs. A systematic clinical approach increases the likelihood of making the correct diagnosis in a timely fashion.

Treating diabetes in the elderly. What are the special considerations?

Management of diabetes in elderly patients generally follows the same lines as in younger patients; that is, improvement of blood glucose status with diet, oral hypoglycemic, and insulin therapy as required. Older patients are more fragile, however, and more caution must be used with therapeutic interventions.

Thyroid disease in the elderly. Special features, changes in management.

Many changes in thyroid physiology occur with aging. These changes correlate with major alterations in the normal physiologic functioning of the thyroid and with changes in thyroid hormone levels as measured by radioimmunoassay. Clinical manifestations of thyroid disease in elderly patients may be somewhat different than in younger patients. Both hyperthyroidism and hypothyroidism can be more difficult to diagnose in elderly patients because of subtle changes in disease presentation. The incidence of certain thyroid diseases, from benign single nodules to malignant anaplastic carcinoma, increases with age. A deliberate and cautious approach is needed when treating thyroid disease in the elderly, who are inherently more fragile than younger patients.

Age-related changes in calcium metabolism. Why they occur and what can be done.

Aging has myriad effects on calcium homeostasis and metabolism. Levels of parathyroid hormone rise, making the diagnosis of primary hyperparathyroidism more difficult. Vitamin D levels decline, affecting the rate of calcium absorption from the intestine. As more and more physicians attempt to combat osteoporosis with calcium supplements, an increasing number of cases of hyperparathyroidism will likely be diagnosed. The use of supplemental calcium is probably appropriate for most elderly patients, particularly white women, but experimental evidence supporting this recommendation is surprisingly scanty. The patient's age is a major consideration when assessing laboratory results, disease risk, and optimal therapeutic strategies.

Hypothyroidism: a comprehensive review.

Hypothyroidism is a common clinical entity encountered frequently in most adult primary care settings. The reported prevalence in the general population is approximately 3% in men, but as high as 10% in women (Sawin, Geller, Hershman, Castelli, & Bacharach, 1989). The disease process affects every major organ system, contributing to a broad range of symptoms. Clinicians need to be familiar with the signs, the symptoms, and the appropriate laboratory studies, so that timely and accurate diagnoses can be made. This article reviews normal thyroid physiology and thyroid pathophysiology, as well as the diagnosis and treatment of several important clinical entities resulting in hypothyroidism. Research findings are included insofar as they relate to current clinical practice.

Hyperthyroidism: a comprehensive review.

Hyperthyroidism is an endocrine disorder encountered in adult primary care clinics. This article reviews normal thyroid physiology as well as the pathophysiology, diagnosis, clinical signs and symptoms, and diagnostic tests and treatment for the most common clinical hyperthyroid entities. Current research is also discussed as it relates to clinical practice.