Bailliere's clinical endocrinology and metabolism最新文献

Knowledge of the physiology of male sexual differentiation and the clinical presentation of androgen insensitivity syndromes (AIS) has led to an increasing understanding of the mechanisms of androgen action. Androgens induce their specific response via the androgen receptor (AR), which in turn regulates the transcription of androgen-responsive target genes. The androgen-dependent development of male genital structures and the induction of the normal male phenotype depends on the presence of an intact AR. Structural alterations leading to malfunction of the AR are associated with variable inhibition of virilization despite normal or even supranormal serum levels of androgens. The mapping, cloning and sequencing of the AR gene have facilitated new insights into the study of androgen action. Functional investigation of the normal and the mutant AR in vivo as well as in vitro has led to the characterization of the distinct molecular steps involved in the normal androgen action pathways that are inhibited in the androgen insensitivity syndrome.

Sex steroids, both androgens and oestrogens, are made from dehydroepiandrosterone (DHEA). The biosynthesis of DHEA from cholesterol entails four steps. First, cholesterol enters the mitochondria with the assistance of a recently described factor called the steroidogenic acute regulatory protein (StAR). Mutations in the StAR gene cause congenital lipoid adrenal hyperplasia. Next, cholesterol is converted to pregnenolone by the cholesterol side chain cleavage enzyme, P450scc. Mutations in the gene for P450scc and for its electron transfer partners, ferredoxin reductase and ferredoxin, have not been described and are probably incompatible with term gestation. Third, pregnenolone undergoes 17α-hydroxylation by microsomal P450c17. Finally, 17-OH pregnenolone is converted to DHEA by the 17,20 lyase activity of P450c17. Isolated 17,20 lyase deficiency is rare, but the identification of its genetic basis and the study of P450cl7 enzymology have recently clarified the mechanisms by which DHEA synthesis may be regulated in adrenarche, and have suggested that the lesion underlying polycystic ovary syndrome might involve a serine kinase.

Isotopic labelling techniques can lead to a better understanding of the changes in substrate flow resulting from trauma and other pathological conditions. This article describes the basic approaches used to measure rates of substrate flow, especially those using stable isotopes, and their application to the study of glucose and protein kinetics. Methods for measuring glucose turnover and gluconeogenesis in the whole body by constant infusion of different labelled forms of glucose are explained. The advantages of measuring regional rates of glucose metabolism, using arteriovenous balance of tracer and tracee, are illustrated with results demonstrating the role of gluconeogenesis by the kidney. Similar approaches are used to measure protein turnover rates in the whole body and in specific regions, with labelled amino acids such as [1-¹³C]leucine. In addition, rates of protein synthesis in individual tissues can be assessed by measuring the incorporation of tracer into protein of a biopsy sample. The relative merits of two methods of giving the tracer, by constant infusion or by flooding injection, are explained, with examples of studies of muscle protein synthesis in surgical patients.

The immune system is designed to protect the individual from foreign substances or organisms. It is expressed as cellular and humoral immunity. The former is dependent upon T lymphocytes and the latter on B lymphocytes, which become plasma cells and secrete antibodies. The immune system can be influenced by protein—energy malnutrition (PEM) and by catabolic illnesses such as sepsis and trauma, which in turn cause PEM. Specific trace element and vitamin deficiencies can also alter the immune state. However, overnutrition and obesity can also influence immune mechanisms. Obesity can promote the development of diabetes, which can alter the immune state. Finally, immunity becomes less effective with ageing and this process is enhanced by associated malnutrition.

Severe injuries are associated with a systemic inflammatory response. This inflammatory response is qualitatively similar in trauma and sepsis, and its magnitude depends on the severity of the inflammatory stimulus. The hypermetabolism induced by injury does not affect the whole body uniformly. The splanchnic region appears to be the main source of the hypermetabolic response in various types of trauma and inflammation. The increased splanchnic metabolic activity is not fully matched by concomitant increases in blood flow. This mismatch of metabolic demand and blood flow increase the risk of inadequate tissue perfusion in the splanchnic region. In the acute phase of injury this risk is magnified by the common presence of inadequate blood volume during the resuscitation from trauma. Hypovolaemia-induced splanchnic vasoconstriction persists even after correction of the hypovolaemia, which further increases the risk of inadequate perfusion of the splanchnic bed. Splanchnic hypermetabolism explains most of the hypermetabolic response to injury.

Substrate fluxes in response to growth hormone administration depend on both the calorie as well as acid—base balance. Growth hormone's acidogenic action as a consequence of promoting fatty acid utilization yields protons required for driving hepatic glutamate efflux; effective uncoupling of nitrogenous precursors from ureagenesis and recycling as glutamate bound for the periphery appears dependent upon this mechanism. Subsequent peripheral retrieval of the salvaged glutamate requires insulin-like growth factor-1 (IGF-1) activated uptake and acid—base homoeostasis. In addition to this nitrogen sparing acidogenic effect, growth hormone is also basogenic in combination with IGF-1 and acting on the kidney as a target organ. Therefore acid—base and nitrogen homoeostasis are normally attuned to one another through the co-ordinated action of growth hormone/IGF-1 on substrate fluxes. However during starvation ketoacid production as the consequence of incomplete fatty acid oxidation and ketone excretion swamps the basogenic limb and full-blown metabolic acidosis prevails; under this condition growth hormone's effectiveness in sparing nitrogen for anabolic processes is curtailed as glutamate (emanating from the liver) and glutamine (derived from muscle proteolysis) are directed to the kidneys, supporting ammoniogenesis: nitrogen balance is now sacrificed for acid—base homoeostasis. Underlying this state is an intracellular acidosis that may contribute to insulin resistance and developing hyperglycaemia in response to growth hormone. In acute injury, an additional acid load contributed from muscle proteolysis and cytokines reinforces an intracellular acidosis that further blunts growth hormone responsiveness and suppresses coupled IGF-1 production. From this perspective growth hormone's acidogenic and basogenic actions should balance for an effective anabolic response during hypermetabolic catabolic illnesses.

This review outlines the conventional methods of assessing nutritional status and their limitations in the presence of acute trauma and sepsis. It also discusses the problems of attempting to improve or at least maintain nutritional status in the presence of an inflammatory stimulus. Most of the conventional markers of nutritional status are altered in trauma and sepsis with decreases in plasma protein concentrations and muscle strength, an apparent depression of immune function and an increase in extracellular fluid volume. It also appears to be impossible to improve nutritional status in the presence of a severe inflammatory stimulus, and the most one can hope for is to attenuate the rate of decline. The evidence for these observations is discussed.