Disorders of Adrenocortical Function PDF

University of Garmian Module: Metabolism College of Medicine Session: XII Second Semester (SII) Lecturer: Dr. Ayad F. Palani Diso...

University of Garmian Module: Metabolism College of Medicine Session: XII Second Semester (SII) Lecturer: Dr. Ayad F. Palani Disorders of adrenocortical function Abnormal function of the adrenal cortex produces a number of clinical problems: Hypoactivity. Decreased activity of the adrenal cortex (Addison s disease) may be due to: - diseases of the adrenal cortex (auto-immune destruction) reduces glucocorticoids and mineralocorticoids. - disorders in pituitary or hypothalamus that lead to decreased secretion of ACTH or corticotrophin releasing hormone ( CRF) only affects glucocorticoids. Hyperactivity. Increased secretion of glucocorticoids (Cushing s syndrome) may be due to - increased activity of the adrenal cortex due to tumour (adenoma). - disorders in the secretion of ACTH caused by pituitary adenoma (Cushing s disease) or ectopic secretion of ACTH. Congenital adrenal hyperplasia. A number of clinical conditions arise as a consequence of a genetic defect in one or more of the enzymes required for the synthesis of cortisol. Because of the lack of cortisol, the pituitary is not subjected to feedback control and it therefore secretes large amounts of ACTH. ACTH causes enlargement of the adrenal cortex (hyperplasia). The severity and consequences of these conditions depend on which enzyme(s) is affected. Clinical effects of excess cortisol secretion. The signs and symptoms may include: - Increased muscle proteolysis and hepatic gluconeogenesis that may lead to hyperglycaemia with associated polyuria and polydipsia ( steroid diabetes ). - Increased muscle proteolysis leads to wasting of proximal muscles and producing thin arms and legs and muscle weakness. - Increased lipogenesis in adipose tissue leading to deposition of fat in abdomen, neck 1  and face and producing characteristic body shape, moon-shaped face and weight gain. - Purple striae on lower abdomen, upper arms and thighs reflecting the catabolic effects on protein structures in the skin and leading to easy bruising because of thinning of skin and subcutaneous tissue. - Immunosuppressive, anti-inflammatory and anti-allergic reactions of cortisol leading to increased susceptibility to bacterial infections and producing acne. 2  - May be back pain and collapse of ribs due to osteoporosis caused by disturbances in calcium metabolism and loss of bone matrix protein. - Mineralocorticoid effects of excess cortisol may produce hypertension due to sodium and fluid retention. Clinical tip: Many of these signs and symptoms occur in patients receiving long-term treatment with glucocorticoids for various chronic inflammatory conditions. Clinical effects of too little cortisol secretion. Too little cortisol secretion, caused by auto-immune destruction of the adrenal gland, would also involve the loss of the mineralocorticoids producing a complex situation that may present as an acute emergency (Addisonian Crisis) or as a chronic debilitating disorder (Addison s disease): - Insidious onset with initial non-specific symptoms of tiredness, extreme muscular weakness, anorexia, vague abdominal pain, weight loss and occasional dizziness. - Extreme muscular weakness and dehydration. - A more specific sign is the increased pigmentation, particularly on the exposed areas of the body, points of friction, buccal mucosa, scars and palmar creases due to ACTH- mediated melanocyte stimulation. - Decreased blood pressure due to sodium and fluid depletion. - Postural hypotension due to fluid depletion. - Hypoglycaemic episodes especially on fasting. These effects may be exacerbated by stress such as trauma or severe infection and lead to nausea, vomiting, extreme dehydration, hypotension, confusion, fever and even coma (Addisonian crisis). This constitutes a clinical emergency that must be treated with intra-venous cortisol and fluid replacement (dextrose in normal saline) to avoid death. Clinical tests of adrenocortical function. Measurement of plasma cortisol and ACTH levels and the 24hr urinary excretion of cortisol and its breakdown products (17-hydroxysteroids) are important in investigating suspected adrenocortical disease. In addition, dynamic function tests (e.g. dexamethasone suppression 3 tests and ACTH stimulation tests) may be used in the differential diagnosis of adrenocortical disease. Dexamethasone is a potent synthetic steroid that, when given orally would normally suppress (by feedback inhibition) the secretion of ACTH and thus cortisol. Dexamethasone suppression of plasma cortisol by >50% is characteristic of Cushing s disease because for the diseased pituitary, even though it is relatively insensitive to cortisol, it does retain some sensitivity to potent synthetic steroids. Suppression does not normally occur in adrenal tumours or ectopic ACTH production. The administration of Synacthen (a synthetic analogue of ACTH) intramuscularly, would normally increase plasma cortisol by >200 nmol/l. A normal response usually excludes Addison s disease. 4 Steroid hormone receptor homology. The steroid receptors form part of a family of nuclear DNA-binding proteins that include the thyroid and vitamin D receptors. They all have three main regions, a hydrophobic hormone- binding region, a DNA-binding region rich in cysteine and basic amino acids and a variable region. There is sequence homology in the hormone binding regions of the receptors. The percentage homology of the hormone binding region of the glucocorticoid receptor with the mineralocorticoid, androgen, oestrogen and thyroid receptors is ~64%, ~62%, ~31% and ~24% respectively. Thus, cortisol will bind to the mineralocorticoid and androgen receptors with low affinity. This binding may become significant when high levels of the hormone are present. Actions of other adrenal steroids. Aldosterone stimulates Na+ reabsorption in the kidney in exchange for K+ (or H+). Over secretion of aldosterone increases Na+ and water retention and loss of K+ causing hypertension and muscle weakness. Under secretion of aldosterone does the opposite causing hypotension. Androgens stimulate the growth and development of male genital tract and male secondary sexual characteristics including height, body shape, facial and body hair, lower voice pitch. They also have anabolic actions especially on muscle protein. Over secretion of adrenal androgens produces effects in the female that include: hair growth (hirsuitism), acne, menstrual problems, virilisation, increased muscle bulk, deepening voice. Oestrogens stimulate growth and development of female genital tract, breasts and female secondary characteristics including broad hips, accumulation of fat in breasts and buttocks, body hair distribution. They are weakly anabolic and decrease circulating cholesterol levels. 5 Adaptations of metabolism Metabolic response to pregnancy Following fertilisation and implantation the placenta and foetus begin their growth and development and this continues throughout pregnancy. A typical net weight gain by the end of pregnancy is ~8 kg (foetus ~3.5 kg, placenta ~0.6 kg, amniotic fluid ~0.8 kg, maternal fuel stores ~3 kg). The mother supplies everything that is needed for this growth (nutrients, vitamins, minerals, oxygen and water). These requirements increase as growth proceeds and they exert an ever-increasing impact on maternal metabolism. The rate of transfer of nutrients across the placenta to the foetus is dependent on their concentration in the maternal circulation. Thus, the environment in which the foetus develops is controlled by maternal metabolism and this changes as pregnancy proceeds to ensure that: - the foetus is supplied with the range nutrients it requires. - these nutrients are supplied at the appropriate rate for each stage of development. - this is achieved with minimal disturbances to maternal nutrient homeostasis. - the foetus is buffered from any major disturbances in maternal nutrient supply. The metabolism of all the major maternal nutrients is affected during pregnancy, the magnitude of the effect depending on the stage of pregnancy. These changes are long-term adaptive responses of maternal metabolism that are hormonally mediated. The hormones involved are maternal insulin and a number of hormones produced by the foetal-placental unit including oestrogens, progesterone and placental lactogen. Role of insulin. Insulin plays a major role in controlling the changes in maternal metabolism that occur in pregnancy. Its concentration in the maternal circulation increases as pregnancy proceeds and it acts to promote the uptake and storage of nutrients, largely as fat in maternal adipose tissue. Role of foetal-placental hormones. These hormones become increasingly important as pregnancy proceeds and they have a number of effects on maternal metabolism that largely oppose the actions of insulin i.e. they are anti-insulin. Metabolic changes during the first half of pregnancy. The changes to maternal nutrient homeostasis during the first 20 weeks of pregnancy are related to a preparatory increase in 6 maternal nutrient stores (especially adipose tissue) ready for the more rapid growth of the foetus, birth and subsequent lactation. Increasing levels of insulin ( insulin/anti-insulin ratio) promote an anabolic state in the mother that results in increased nutrient storage. Metabolic changes during the second half of pregnancy. The second half of pregnancy is characterised by a marked increase in growth of the placenta and foetus. Maternal metabolism adapts to meet an increasing demand by the foetal-placental unit for nutrients as well as meeting the requirements of maternal tissues. The demands of the foetal-placental unit for nutrients are met by keeping the concentration of nutrients in the maternal circulation relatively high. This is achieved by: reducing the maternal utilisation of glucose by switching tissues to fatty acids. delaying the maternal disposal of nutrients after meals. releasing fatty acids from the stores built up during the first half of pregnancy. These changes in maternal metabolism are controlled by changes in the insulin/anti-insulin ratio. Maternal insulin levels continue to increase but the production of the anti-insulin hormones by the foetal-placental unit increases at an even faster rate and the insulin/anti- insulin ratio therefore falls producing the required metabolic changes. Maternal ketogenesis. An interesting aspect of the marked decrease in the insulin/anti-insulin ratio during the second half of pregnancy is its effect on maternal ketogenesis. The increased availability of fatty acids to the liver resulting from the mobilisation of maternal adipose tissue, coupled with the fall in the insulin/anti- insulin ratio switches on the production of ketone bodies by the maternal liver. These are used as a fuel by the developing foetal brain. Gestational diabetes. Maternal insulin is a major factor in controlling the metabolic response to pregnancy and the rate of secretion of insulin (both basal and stimulated) normally increases as pregnancy proceeds. The ability of the -cells to meet this increased demand for insulin secretion is achieved by -cell hyperplasia and -cell hypertrophy. In addition, the rate of insulin synthesis in the -cells increases. In some women the endocrine pancreas is unable to respond to the metabolic demands of pregnancy and the pancreas fails to release the increased amounts of insulin required. As a consequence, there is a loss of control of metabolism, blood glucose increases and diabetes 7 results (Gestational Diabetes). After birth, when the increased metabolic demands of pregnancy are removed and hormone levels change, the endocrine pancreas can respond adequately and the diabetes disappears. Women who experience gestational diabetes are more likely to develop overt diabetes later in life than women who do not experience the condition. Gestational Diabetes Gestational diabetes is a type of diabetes that develops during pregnancy in women who didn't previously have diabetes. Like other types of diabetes, gestational diabetes affects how your cells use sugar (glucose). Gestational diabetes can cause high blood sugar levels, which can affect both the mother and the baby. During pregnancy, the placenta, which connects your baby to your blood supply, produces high levels of various hormones. Almost all of them impair insulin function, which in turn elevates blood sugar levels. Typically, the pancreas responds by producing more insulin to counteract this effect. But if the pancreas can't keep up with the increased demand for insulin during pregnancy, blood sugar levels rise too high, resulting in gestational diabetes. Women with gestational diabetes usually don't have any symptoms, which is why it's essential to get tested during pregnancy. If not managed properly, gestational diabetes can lead to complications for both the mother and the baby, including a higher risk of preeclampsia, preterm birth, and cesarean delivery. It can also increase the baby's risk of developing obesity and type 2 diabetes later in life. Diagnosis gestational diabetes Initial screening: Most pregnant women are screened for gestational diabetes between weeks 24 and 28 of pregnancy, although it may be done earlier if there are risk factors present. The initial screening involves a glucose challenge test (GCT), where the pregnant women drink a sugary solution. Then, blood sugar levels are tested after one hour. If the blood sugar levels are higher than normal at this stage, it doesn't necessarily mean you have gestational diabetes; it means you'll need further testing. 8 Follow-up testing: If the results of the glucose challenge test are higher than normal, patient will undergo a follow-up test called the glucose tolerance test (GTT). For this test, patient will fast overnight and then have fasting blood sugar level measured. Afterward, patient will drink another, more concentrated sugary solution, and the blood sugar levels will be tested periodically over the next few hours. Elevated blood sugar levels at any point during this test can indicate gestational diabetes. Metabolic response to exercise The body needs to meet the acute oxygen and fuel demands of cardiac and skeletal muscle during exercise and ensure that the end products of metabolism are removed. This involves a variety of short-lived adaptations to metabolism, temperature regulation, the cardiovascular system and the respiratory system. The metabolic response to exercise ensures: the increased energy demands of skeletal and cardiac muscle are met by mobilization of fuel molecules from energy stores. there are minimal disturbances to homeostasis by keeping the rate of mobilization equal to the rate of utilization. the glucose supply to the brain is maintained (prevent hypoglycaemia). the end products of metabolism are removed as quickly as possible. The magnitude and nature of the metabolic response depends on: type of exercise (muscles used). intensity and duration of exercise. physical condition and nutritional status of the individual. During high intensity activities of short duration (100m sprint run in ~10sec) skeletal muscle has to work under anaerobic conditions as the supply of oxygen to the muscle is inadequate to maintain aerobic metabolism. However, during lower intensity activities of longer duration (a marathon run in ~2-3hr) the supply of oxygen to muscle is adequate to allow aerobic metabolism. Thus, different types of exercise are associated with striking differences in the pattern of muscle metabolism. 9 Energy requirements of exercise The energy requirements of exercise largely reflect the increased activity of skeletal and cardiac muscles, the increased activity of the respiratory muscles being less significant. In the normal resting state (BMR) the body uses ~4 kJ/min of energy. This increases to ~80 kJ/min during a marathon and to ~200 kJ/min during the 100m sprint. The energy for muscle contraction comes from the hydrolysis of ATP: ATP + H2O >>>> ADP + Pi + energy At rest the rate of ATP turnover in skeletal muscle is ~0.06 mmol/sec/kg muscle. This increases to ~1.2 mmol/sec/kg muscle during a Marathon and to ~3 mmol/sec/kg muscle during the 100m sprint. The ATP concentration in muscle is ~5 mmol/kg muscle and could in theory last for ~2 sec during a sprint. However, the ATP concentration does not fall by more than 20% because it is regenerated from ADP by a variety of mechanisms. Initially it is regenerated from the creatine phosphate (C~P) present in muscle (~17mmol/kg muscle): Creatine~P + ADP >> ATP + Creatine Thus, the energy immediately available in muscle to drive contraction (ATP + C~P) will last for ~5 sec during the 100m sprint. This means that ADP must be rapidly converted back to ATP by coupling it to the oxidation of fuel molecules if contraction is to continue and the race finished. Fuel molecules Fuel molecules are present in tissue energy stores and in the circulation. The major tissue stores of energy that can be called upon during exercise are glycogen (~300g in muscle and ~100g in liver) and triacylglycerols (~15kg in adipose tissue and a smaller amount in muscle cells). The major circulating fuel molecules are glucose (~5mM) and free fatty acids (~0.5mM). The glycogen stores of muscle could provide the muscles with enough energy, under aerobic conditions (i.e. when completely oxidized to CO2), for ~60 min of low intensity exercise (marathon running). However, under anaerobic conditions (sprinting), where the end product is lactic acid, the glycogen stores would only last ~2 min. This striking difference reflects both the difference in the rate of ATP consumption during the two types of exercise (see above) and the relative amounts of ATP produced during the two processes (33 miles of ATP/mole glucose as glycogen under aerobic conditions and only 3 miles of ATP/mole of glucose as glycogen under anaerobic conditions). 10 The glycogen stores of liver could provide muscle with enough glucose for ~18min of low intensity exercise (marathon running). However, this store of glucose is required to prevent hypoglycaemia and the associated impairment of CNS function. In addition, there are a number of advantages of using muscle glycogen over circulating glucose: availability not affected by blood supply. no need for membrane transport into muscle cells. produces G-6-P without using ATP (glycogen phosphorylase uses Pi). mobilisation can be very rapid - highly branched structure allows many sites for enzyme attack and glycogen phosphorylase activity can be changed rapidly by a mixture of covalent modification (phosphorylation) and allosteric activation (ADP and Ca+2). A serious problem that limits the anaerobic metabolism of glucose in muscle (from glycogen or from circulating glucose) is the buildup of lactate and H+. The accumulation of H+ is so dramatic (2 miles of H+ for every mole of glucose metabolised) that it exceeds the buffering capacity of the muscle cells and impairs their function producing fatigue. Thus, anaerobic metabolism cannot continue as the sole source of ATP generation much beyond 200m. The impairment of muscle function by H+ involves a number of a number of mechanisms including: inhibition of glycolysis by H+. H+ interferes with actin/myosin interaction. H+ causes sarcoplasmic reticulum to bind calcium (inhibits contraction). The triacylglycerol stores of adipose tissue are large (~15kg) and could provide the muscles with fatty acids. The oxidation of these fatty acids under aerobic conditions, would provide sufficient energy for ~48 hr of low intensity exercise. However, there are a number of factors that limit the use of fatty acids by muscle. These include: rate of fatty acid release from adipose tissue (rate of lipolysis). limited capacity of the blood to transport fatty acids (requires binding to albumin). rate of fatty uptake into muscle cells and into muscle mitochondria. fatty acid oxidation requires more oxygen/mole of ATP produced than glucose. fatty acids can only be metabolised under aerobic conditions. The total amount of glucose and free fatty acids in the extracellular fluid are ~12g and ~4g respectively. These will provide ~180kJ and ~100kJ when oxidised completely to CO2 and H2O. Thus, the total amount of potential energy available in the circulation is ~280kJ, enough for ~4 min of marathon running. 11 12 13 14