Special topics in endocrinology and metabolism最新文献

The development of radiolabeled cholesterols in 1969 as precursors of adrenocortical steroid production allowed the first noninvasive imaging of the adrenal cortices. FDA-NDA approval in 1984 should allow routine use of these agents in most hospitals. NP-59 is most commonly used in the diagnosis and management of Cushing syndrome; the second most common use is in the diagnosis of primary aldosteronism. It is also helpful in the differential diagnosis of adrenal and ovarian hyperandrogenism and hirsutism, and is the only noninvasive method of detecting unilateral adrenocortical hypofunction. The newest and most popular use is in the differential diagnosis of asymptomatic masses in the region of the adrenal gland discovered incidentally with CT scan ("incidentalomas"). In this situation, the NP-59 scan can define whether the tumor is in the adrenal gland and if it is functional or nonfunctional. We believe that, in the future, radiolabeled enzyme inhibitors might offer better diagnostic imaging of the adrenal cortex, although these agents will probably not be available for routine use for some time. Our development of a radioiodinated guanethidine analog, 131I-MIBG, has allowed differentiation of normal adrenal medullary function from bilateral adrenal medullary hyperplasia before the development of hypertension or tachycardia, diagnostic increases in plasma or urinary catecholamines, or abnormal CT scans. The search for a pheochromocytoma should begin with 131I-MIBG scintigraphy. While over 90% of primary pheochromocytomas occur in the abdomen, neither a survey of the abdomen nor the finding of a single tumor should conclude the search. Whereas the CT scan can only detect a mass, the MIBG scan not only detects the mass but proves whether the mass is a pheochromocytoma. We have detected small or recurrent pheos when all other localizing studies were normal. Present drug and X-ray therapy is relatively ineffective in treating metastatic cancer of the adrenal medulla. Preliminary results in five patients indicate that, for the first time, a complex organic molecule can carry 131I into adrenal neoplasms reproducibly and in therapeutically effective doses of irradiation. We may also be able to select which patients will respond to therapeutic doses of 131I-MIBG and which patients will not respond.

After a lag between the recognition of the biologic activity of material derived from seminal vesicles and the actual isolation and identification of prostaglandins, information on the structure, biosynthesis, physiology, and biomedical relevance of this family of substances has expanded explosively in recent years. Their ubiquitous presence in mammalian tissues has contributed to the intense interest in and investigation of their role in normal physiology and a variety of pathologic states. The availability of pure compounds of known chemistry, as well as of numerous agents that interfere with their production or metabolism, continues to allow unravelling of their regulatory influences, mechanism of action, and participation in disease processes. Understanding of the role of prostaglandins in reproductive physiology has led to widespread and effective applications in clinical obstetrics and gynecology, including menstrual disorders, therapeutic abortion, and labor. Their implication in the pathogenesis of toxemia of pregnancy, coupled with expanding information on the general role of prostaglandins in the regulation of hemostasis, has advanced understanding of hemorrhagic and thromboembolic disorders and opened innovative avenues for potential therapeutic intervention.

Three distinct classes of receptors for lipoproteins exist. The best studied is the LDL receptor, the primary function of which is the delivery of cholesterol in response to cellular needs. Although originally thought to be specific for LDL, it clearly recognizes lipoproteins that contain either apo B or E. It plays an important role in the catabolism of LDL and could also be involved in reverse cholesterol transport. The hepatic remnant receptor, a distinct binding site on liver membranes that recognizes apo E but not apo B, appears to function in the clearance of chylomicrons (and probably VLDL) remnants from the circulation, but also is likely to be important in the recognition of apo E-containing HDL, and hence is likely to participate in the reverse cholesterol transport. Finally, there is now evidence for a third group of lipoprotein receptors that are present on the cell surface of macrophages. They appear to bind lipoproteins that have been altered chemically or biologically and probably serve a scavenger function. While many of the model systems for studying these macrophage receptors have focused on chemical modifications that are unlikely to occur in vivo, several lipoproteins that have been shown to interact with these receptors may be naturally occurring or result from biological processes. The discovery of the three receptor classes has resulted in a dramatic increase in the understanding of lipoprotein physiology and pathophysiology, and future studies should further expand our understanding of the regulation of lipoprotein metabolism and its relationship to hyperlipoproteinemia and atherosclerosis.

Aluminum exposure in man is unavoidable. The occurrence of dialysis dementia, vitamin D-resistant osteomalacia, and hypochromic microcytic anemia in dialysis patients underscores the potential for aluminum toxicity. Although exposure via dialysate and hyperalimentation leads to significant tissue aluminum accumulation, the ubiquitous occurrence of aluminum and the severe pathology associated with large aluminum burdens suggest that smaller exposures via the gastrointestinal tract and lungs could represent an important, though largely unrecognized, public health problem. It is clear that some aluminum absorption occurs with the ingestion of small amounts of aluminum in the diet and medicines, and even greater aluminum absorption is seen in individuals consuming large amounts of aluminum present in antacids. Aluminum absorption is enhanced in the presence of elevated circulating parathyroid hormone. In addition, elevated PTH leads to the preferential deposition of aluminum in brain and bone. Consequently, PTH is likely to be involved in the pathogenesis of toxicities in those organs. PTH excess also seems to lead to the deposition of aluminum in the parathyroid gland. The in vitro demonstration that aluminum inhibits parathyroid hormone release is consistent with the findings of a euparathyroid state in dialysis patients with aluminum related vitamin D-resistant osteomalacia. Nevertheless, it seems likely that hyperparathyroidism is at least initially involved in the pathogenesis of aluminum neurotoxicity and osteomalacia; the increases in tissue aluminum stores are followed by suppression of parathyroid hormone release, which is required for the evolution of osteomalacia. Impaired renal function is not a prerequisite for increased tissue aluminum burdens, nor for aluminum-related organ toxicity. Consequently, it is likely that these diseases will be observed in populations other than those with chronic renal disease.

Polyamine research, which began with a clinical observation more than 300 years ago, has progressed for several decades as pure basic research, sometimes considered as an academic triviality. The role of polyamines in clinical medicine is coming of age. The fruits of polyamine research are just now entering into the realm of practical application and in a very multidisciplinary manner. Basic research on polyamine metabolism and the elucidation of their physiologic functions has involved many academically interesting, even revolutionary, aspects, but the imagination of biochemists and cell biologists may no longer be sufficient to discover the best ways to translate the results of this basic research into clinical practice. It is almost certain that polyamine antimetabolites will soon find their place among the drug regimens used for the treatment of human malignancies and, possibly, also of hyperproliferative skin diseases. The elucidation of the role of polyamines in cell differentiation may offer fundamental applications regarding the regulation of cell cycle events. The discovery of the antiparasitic properties of polyamine antimetabolites may have a major impact on the well-being of millions of people in the developing world. The potential application of polyamine research in microbial and viral diseases is an area in which investigational insight is just beginning. Finally, the clinical chemistry of extracellular polyamines, although initially disappointing, has not yet been explored in depth and may offer applications useful for the diagnosis or follow-up of a variety of common diseases.

Although the nutritional aspects related to bone development and subsequent bone loss have been appreciated for many years, they are now being reemphasized in view of current information concerning the vitamin D endocrine system, the development of new assay procedures and more sensitive radiologic techniques to assess changes in bone mass, and the realization that clinical problems related to bone loss will increase as individuals live longer. The vitamin D endocrine system is complex, involving the skin, liver, and kidney for synthesis of the vitamin D metabolites and, primarily, the intestine and bone for biologic expression. Numerous factors and disorders affecting the skin, gastrointestinal tract, and kidney will adversely affect vitamin D metabolism. Vitamin D deficiency is common in elderly individuals, especially those who are chronically ill, house-bound, and poorly nourished. Subclinical vitamin D deficiency and osteomalacia may also be complicating problems in elderly patients with osteoporosis and hip fractures. At present the role of the vitamin D endocrine system in the pathogenesis and treatment of osteoporosis is unclear. There is little evidence that vitamin D or its metabolites are helpful in osteoporosis, except perhaps to heal osteomalacia which may be present. It is hoped that encouraging results will follow the use of more potent vitamin D metabolites, either alone or in combination with other agents. Calcium homeostasis is affected by numerous dietary factors (including protein, phosphorus, fiber, and lactose) and drugs (including alcohol, diuretics, and antacids), and calcium absorption in the intestine and the ability to adapt to low-calcium diets will decrease with advancing age. There are conflicting reports concerning the relation between low-calcium intake and osteoporosis, and about the role of calcium intake in the development and then maintenance of bone mass. There is little doubt that many older individuals ingest less calcium than is recommended, especially at a time when even more may be required to maintain bone mass. Several studies show that calcium supplementation producing a total calcium intake of 1,200-1,500 mg/day can slow the rate of bone loss. When the high doses of calcium are given along with vitamin D, periodic monitoring of blood and urine calcium is necessary to avoid hypercalcemia and hypercalciuria.