Bailliere's clinical endocrinology and metabolism最新文献

Although first described more than two centuries ago, the increase in energy expenditure associated with feeding (nutrient induced thermogenesis (NIT)) is still incompletely understood. Although the magnitude of the response and the effect of varying the composition of the diet, route and rate of feeding is still the subject of controversy, the importance of taking into account NIT when designing an optimal feeding regimen is well recognised.

What is currently unclear is the effect that injury or sepsis have on NIT. This is of clinical significance because it is precisely this group of patients in whom adequate nutritional support is most difficult to achieve yet most important. Despite significant differences in the metabolic response to feeding, NIT appears to be similar in septic patients and healthy subjects. Excessive use of intravenous glucose in such patients however may lead to marked increases in energy expenditure and stimulation of the sympathetic nervous system and should be avoided.

The study of protein kinetics has entered a new era by the recognition that whole body protein turnover only poorly reflects the true events occurring in several organs and with regard to the multitude of proteins present in the body. It is also increasingly recognized that the simultaneous synthesis and degradation of proteins is important in regulation and adaptation during several metabolic conditions like starvation, feeding, after trauma, and during exercise. Expecially important is the recognition that the kinetics of individual proteins may change in opposite directions, thereby leading to fluxes of α-amino-nitrogen that serve to adapt to and survive a changing environment. At present, much emphasis is put upon molecular biological regulation. However, it is important that the metabolic processes that occur in the intact organism are still poorly defined. New technology allows the exploration of these processes, which should therefore prompt the initiation of further research in this area.

The hypercatabolic response to trauma, extensive surgery and sepsis is characterized by an increased metabolic rate, severe muscle wasting and a negative nitrogen balance. This process of ‘autocannibalism’ may be in part a consequence of a disordered growth hormone (GH)/insulin-like growth factor (IGF) axis. In this chapter the normal physiology of the GH/IGF axis is first briefly reviewed. This is followed by a discussion of the changes that accompany fasting and catabolic illness, the effects of IGF-1 administration in health and disease and a comparison of the effects of IGF-1, GH and insulin on catabolism. Although initial investigations of IGF-1 administration in animals and human volunteers have often been encouraging, studies in catabolic patients have so far proved disappointing. Combined treatment with GH, IGF-1 (and insulin) or with IGF-1 and its major binding protein, may prove more effective, especially when used in conjunction with nutritional supplements such as glutamine.

Endogenous substrate metabolism is markedly altered in critically ill patients. Glucose production is elevated not only in the post-absorptive state, but the normal suppressive effect of exogenous glucose and glucose production is greatly diminished. In the post-absorptive state, glucose clearance is generally elevated, potentially causing hypoglycaemia in extreme cases. Somewhat paradoxically, the ability of insulin to stimulate glucose uptake is diminished, so that hyperglycaemia is often evident during nutritional intake. Lipolysis, the breakdown of peripheral fat, is accelerated, meaning that free fatty acids are released into plasma at a rate far exceeding their oxidation. Some of the excess fatty acids are re-esterified in the liver, leading to accelerated hepatic triglyceride formation. A large increase in hepatic triglyceride stores can ensue if the rate of excretion of triglycerides in very low density lipoproteins is not accelerated commensurately with the increased triglyceride production. Indirect calorimetry measurements support the notion that the large increase in availability of fatty acids may lead to a greater reliance on fatty acids as energy substrates. Nonetheless, carbohydrates should be the predominant source of non-protein calories, because the accompanying insulin response effectively enhances protein synthesis. There is already ample fat available via endogenous lipolysis, and more fat given exogenously provides little further benefit.

In vitro studies of energy metabolism in isolated cells contribute to improved knowledge of human energy metabolism under normal and pathological conditions. In every cellular system energy is taken up, metabolized and finally transformed into heat, which is dissipated into the environment. Thus, energy turnover of isolated cells can be assessed by microcalorimetric determination of their heat production. Microcalorimeters of the thermopile heat conduction type facilitate direct physical determination of thermogenesis with a sensitivity of 0.2μW; 10⁴–10⁵cells being sufficient for one measurement. Peltier elements are sandwiched between the sample and a precisely thermostated heat sink, creating a detectable voltage proportional to the heat production. For adequate interpretation of the results, simultaneous biochemical investigations of relevant metabolic pathways are required. Up to now, numerous studies with blood cells, skeletal and heart muscle cells, hepatocytes, endothelial cells, fibroblasts and adipocytes have been performed in relation to various diseases and under the influence of certain hormones and pharmacological agents.

Graves' disease (GD) develops as a result of a complex interaction between genetic susceptibility genes and likely environmental factors. Most epidemiological data support an important genetic contribution to the development of GD. The concordance rate of GD in monozygotic twins is 30–60% and in dizygotic twins 3–9%, and thyroid autoantibodies have been reported in up to 50% of the siblings of patients with GD. For many years now, HLA studies have consistently shown an increased frequency of HLA-DR3 in Caucasian patients with GD; but with only a risk ratio of 3–5. However, recent advances in human genome mapping techniques have enabled the study of many other candidate genes. Of these additional, non-HLA genes, only CTLA-4 has been consistently found to be associated with GD. Using a linkage based approach which only detects highly significant susceptibility genes we have recently reported preliminary results which demonstrated that a marker located ∼25 cM from the TSH receptor gene on chromosome 14q31 is linked to GD and in the same vicinity as the IDDM-11 locus. Such results, if confirmed, may signal the presence of a gene family related to endocrine autoimmunity on chromosome 14q31.

Anti-thyroid drugs, surgery and radioiodine all represent effective forms of treatment for Graves' hyperthyroidism. There is, however, little consensus regarding the treatment of choice for specific cases. This lack of consensus prompted the development of guidelines for good practice in the management of hyperthyroidism for the United Kingdom. This chapter describes the process of development of this United Kingdom consensus statement, and associated audit measures, and highlights outstanding contentious issues in the management of Graves' hyperthyroidism.

What causes Graves' ophthalmopathy is still a mystery, but the disease process results from a complex interplay of genetic and environmental factors. Genes such as those encoding for human leukocyte antigens, cytokines or putative target antigens may determine a patient's susceptibility to the disease and the disease severity, but environmental factors may determine its course. During the last 5 years, significant progress has been made towards a more in-depth understanding of the initiating events of the orbital immune process which occur in the context of autoimmune thyroid disease. Once established, the chronic inflammatory process within the orbital tissues appears to take on a momentum of its own. The work of many investigators has recently helped to extend our knowledge about the effector and target cells, and their reciprocal interaction, in the evolution and perpetuation of the orbital immune process. This chapter's focus is on the more recent aspects of retro-orbital autoimmunity, discussing new developments concerning orbital T-cell repertoires, candidate orbital antigens, potential target and effector cells, and their role in the extrathyroidal manifestations of autoimmune thyroid disease.