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Khairat Battah, MD The University of Jordan Faculty of medicine, pathology department • • • • • Divided into : Anterior pituitary. Posterior pituitary. Diseases include: Hyperpituitarism. Hypopituitarism. Local mass effect. The most common cause of hyperpituitarism is a pituitary adenoma arising in the anterior lobe. Pituitary adenomas are classified on the basis of hormone(s) produced by the neoplastic cells. Functional and non-functional adenomas usually composed of a single cell type. Nonfunctioning and hormone-negative adenomas are likely to come to clinical attention at a later stage and are, therefore, more likely to be macroadenomas than are lesions associated with endocrine abnormalities. Pituitary adenomas can be macroadenomas (>1 cm) or microadenomas (<1 cm). Are the most common type of hyperfunctioning adenoma. Hyperprolactinemia causes: amenorrhea, galactorrhea, loss of libido, and infertility. Hyperprolactinemia may be caused by other conditions or factors including pregnancy, high-dose estrogen therapy, renal failure, hypothyroidism, hypothalamic lesions, and dopamine-inhibiting drugs (e.g., reserpine) Second most common type of functional pituitary adenoma. 1. If it occurs in prepubertal children, excessive growth hormone result in gigantism . Is characterized by a generalized increase in body size, with disproportionately long arms and legs 2. If elevated levels present after closure of the epiphyses, individuals develop acromegaly: a. Growth is most conspicuous in soft tissues, skin, and viscera. b. Jaw enlargement results in its protrusion and separation of the teeth. c. The hands and feet are enlarged, with broad sausage-like fingers. Growth hormone excess also is associated with a number of other disturbances including: abnormal glucose tolerance and diabetes mellitus Generalized muscle weakness Hypertension Arthritis, osteoporosis Congestive heart failure Causes hypercortisolism because of the stimulatory effect of ACTH on the adrenal cortex (Cushing syndrome) and this is called Cushing disease Produces two hormones: oxytocin and ADH. ADH ( Antidiutitic hormone) acts on the collecting tubules of the kidney to promote the resorption of free water Syndromes of ADH excess and defficiency. 1. ADH deficiency causes diabetes insipidus, characterized by excessive urination (polyuria), polydipsia and increased serum sodium and osmolality. It results from head trauma, neoplasms, and inflammatory conditions of hypothalamus and posterior pituitary or it may be idiopathic. 2.Syndrome of inappropriate ADH (SIADH) secretion, causes resorption of excessive amounts of free water, with resultant hyponatremia, cerebral adema and neurologic dysfunction. Oxytocin stimulates the contraction of smooth muscle in the pregnant uterus and of muscle surrounding the lactiferous ducts of the mammary glands Impairment of oxytocin synthesis and release has not been associated with significant clinical abnormalities Diseases of the thyroid are divided into: 1- Hyperthyroidism and thyrotoxicosis.. 2- Hypothyroidism. Thyrotoxicosis is a hypermetabolic state due to elevated circulating levels of free T3 and T4. I. Associated with hyperthyroidism (Thyroid hyperfunction): 1. Primary: a. Graves disease. b. Hyperfunctioning thyroid adenoma. 2. Secondary: TSH-secreting pituitary adenoma (rare) II. Not associated with hyperthyroidism Such as in thyroiditis. Constitutional symptoms: Skin is soft, warm, and flushed; heat intolerance and excessive sweating are common.Weight loss despite increased appetite. Gastrointestinal: Stimulation of the gut results in hypermotility, malabsorption, and diarrhea. Cardiac: Palpitations and tachycardia are common. Neuromuscular: nervousness, tremor, and irritability and muscle weakness (thyroid myopathy). Ocular manifestations: a wide, staring gaze and lid lag are present because of sympathetic overstimulation of the levator palpebrae superioris . However, true thyroid ophthalmopathy associated with proptosis is a feature seen only in Graves disease. The diagnosis of hyperthyroidism is based on clinical features and laboratory data. The measurement of serum TSH is the most useful single screening test for hyperthyroidism, because TSH levels are decreased even at the earliest stages, when the disease may still be subclinical. In rare cases of pituitary- or hypothalamus-associated (secondary) hyperthyroidism, TSH levels are either normal or raised Causes : 1. Worldwide, the most common cause is dietary deficiency of iodine. 2. In developed nations – autoimmune Hashimoto thyroiditis. 3. Genetic defects such as thyroid dysgenesis or dyshormogentic goiter are rare. Cretinism : Hypothyroidism developing in infancy or early childhood. Endemic cretinism: common in areas of the world where dietary iodine deficiency is endemic, - Sporadic cretinism: enzyme defects that interfere with thyroid hormone synthesis - Clinical features of cretinism Impaired development of the skeletal system and central nervous system, with severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia. The severity of the mental impairment in cretinism seems to be directly influenced by the timing of onset of the deficient state in utero Myxedema : Hypothyroidism developing in older children and adults and its manifesations: Generalized apathy and mental sluggishness, may mimic depression. Cold intolerant. Obesity. Mucopolysaccharide-rich edematous fluid accumulates in skin, subcutaneous tissue, and a number of visceral sites, with resultant broadening and coarsening of facial features, enlargement of the tongue, and deepening of the voice. Bowel motility is decreased, resulting in constipation. Measurement of serum TSH is the most sensitive screening test for hypothyroidism. The serum TSH is increased in primary hypothyroidism because of a loss of feedback inhibition of thyrotropin-releasing hormone (TRH) and TSH production by the hypothalamus and pituitary, respectively. The TSH concentration is not increased in persons with hypothyroidism caused by primary hypothalamic or pituitary disease Serum T4 is decreased in patients with hypothyroidism of any origin. A. Chronic lymphocytic (Hashimoto) thyroiditis : Is the most common cause of hypothyroidism in areas where iodine is sufficient. Gradual thyroid failure secondary to autoimmune destruction of the thyroid gland. More common in women Presents as diffuse symmetric painless enlargement of the thyroid, usually associated with some degree of hypothyroidism. In the usual clinical course, hypothyroidism develops gradually. However, it may be preceded by transient thyrotoxicosis in some cases. B. Subacute granulomatous thyroiditis - Caused by a viral infection and patients have history of upper respiratory tract infection. - Acute onset with pain in the neck, fever, and variable enlargement of the thyroid. - Transient hyperthyroidism may occur, as result of disruption of thyroid follicle and release of excessive thyroid hormone. - The condition typically is self-limited. C. Riedel thyroiditis: - A rare disorder of unknown etiology and characterized by extensive fibrosis involving the thyroid gland and adjacent neck structures - Clinical evaluation demonstrates the presence of a hard and fixed mass clinically simulates a thyroid neoplasm. The most common cause of endogenous hyperthyroidism. It is characterized by a triad of manifestations: • Thyrotoxicosis, caused by a diffusely enlarged, hyperfunctional thyroid, is present in all cases. • An infiltrative ophthalmopathy with resultant exophthalmos is noted in as many as 40% of patients. • A localized, infiltrative dermopathy (sometimes designated pretibial myxedema) is seen in a minority of cases. most commonly involves the skin overlying the shins. Women affected up to seven times more commonly than men peak incidence between the ages of 20 and 40 Laboratory findings include elevated serum free T4 and T3 and depressed serum TSH - Goiter is the most common manifestation of thyroid disease and most often caused by dietary iodine deficiency - Impaired thyroid hormone synthesis leads to compensatory rise in the serum TSH, which in turn lead to gross enlargement of the thyroid gland - The compensatory increase in functional mass of the gland is able to overcome the hormone deficiency, ensuring an euthyroid metabolic state. 1. Endemic goiter: occurs in iodine deficient areas 2. Sporadic goiter: less common than endemic goiter, more common in females, with a peak in puberty or young adult life and can be caused by several conditions that interfere with thyroid hormone synthesis such as: excessive calcium and certain vegetables (cabbage, cauliflower) and enzymatic defects. A-Primary hyperparathyroidism:- Causes 1. Parathyroid adenoma----75%-80% 2. Primary hyperplasia ----10-15% 3. Parathyroid carcinoma---- rare - The most common manifestation is an increase in serum calcium. - Characterized by painful bones, renal stones, abdominal groans, and psychotic moans. - Bone pain secondary to fractures of bone (osteoperosis) - Gastrointestinal tract disturbances: including constipation, nausea, peptic ulcer, pancreatitis and gallstones B. Secondary hyperparathyroidism The most common cause is chronic renal failure and the mechanisms: 1. Chronic renal insufficiency causes hyperphosphatemia. and the elevated phosphate levels depress serum calcium so stimulate parathyroid gland activity. 2. loss of renal substances reduces α1-hydroxylase enzyme which is necessary for the synthesis of the active vitamin D, which in turn reduces intestinal absorption of calcium. In a minority of patients, parathyroid activity may become autonomous and excessive, with resultant hypercalcemia—a process sometimes termed tertiary hyperparathyroidism. Parathyroidectomy may be necessary to control the hyperparathyroidism in such patients. C- Hypoparathyroidism: causes. 1. Surgical removal of parathyroids during thyriodectomy. 2. Congenital absence: in DiGeorge syndrome. 3. Autoimmune hypoparathyroidism. The clinical manifestations are secondary to hypocalcemia and include: a. Increased neuromuscular irritability including muscle spasm and tingling. b. Cardiac arrythmias . c. Increased intracranial pressures and seizures The adrenal glands are paired endocrine organs consisting of two regions, the cortex and medulla The adrenal cortex synthesizes three different types of steroids: o Glucocorticoids (principally cortisol), which are synthesized primarily in the zona fasciculata, with a small contribution from the zona reticularis o Mineralocorticoids, the most important being aldosterone, which are generated in the zona glomerulosa o Sex steroids (estrogens and androgens), which are produced largely in the zona reticularis The adrenal medulla is composed of chromaffin cells, which synthesize and secrete catecholamines, mainly epinephrine 1. Hypercortisolism---Cushing syndrome - In clinical practice, most cases are caused by the administration of exogenous glucocorticoids. - The remaining cases are endogenous A. ACTH-secreting- pituitary adenoma known as Cushing disease accounts for more than half of the cases of endogenous Cushing syndrome. B. Adrenal adenoma and carcinoma and hyperplasia are responsible for about 20% of cases of endogenous Cushing syndrome . This form of Cushing syndrome is called ACTHindependent Cushing syndrome. Hypertension Weight gain with truncal obesity and moon facies . Decreased muscle mass and proximal limb weakness Glucocorticoids induce gluconeogenesis and inhibit the uptake of glucose by cells resulting in hyperglycemia, glucosuria and polydipsia mimicking diabetes mellitus. Glucocorticoids suppress the immune response so patients are at high risk of infection. Hirsuitism and menstrual cycle abnormalities. Mental disturbances, including mood swings, depression, and frank psychosis. 2. Hyperaldosteronism: - Excessive levels of aldosterone cause sodium retention and potassium execretion, with resultant hypertension and hypokalemia. - Can be primary or secondary. 1. In secondary type, aldosterone release occurs in response to activation of the renin-angiotensin system. - It is characterized by high levels of plasma renin and is caused by: a. Decreased renal perfusions. (renal artery stenosis) b. Arterial hypovolemia .(cirrhosis, nephrotic syndrome) 2. Primary hyperaldosteronism: Indicates a primary autonomous overproduction of aldosterone. The potential causes of primary hyperaldosteronism are: Bilateral idiopathic hyperaldosteronism. Adrenocortical neoplasm, either an aldosteroneproducing adenoma (the most common cause) or, rarely, an adrenocortical carcinoma Genetic defect that leads to overactivity of the aldosterone synthase gene The clinical hallmark of hyperaldosteronism is hypertension The long-term effects of hyperaldosteronism-induced hypertension are cardiovascular compromise Hypokalemia results from renal potassium wasting and, when present, can cause a variety of neuromuscular manifestations, including weakness, paresthesias, visual disturbances, and occasionally frank tetany I-Acute Adrenocortical Insufficiency : Occurs most commonly in the following clinical settings: a. Crisis in patients with chronic adreno-cortical insufficiency precipitated by stress. b. Rapid withdrawal of exogenous steroid. c. Massive adrenal haemorrhage that may destroy the adrenal cortex sufficiently to cause adrenocortical insufficiency. - This hemorrhage may occur : 1. In patients maintained on anticoagulant therapy. 2. Overwhelming sepsis (Waterhouse-friderichsen syndrome) associated with Neisseria meningitidis septicemia. 2. Primary Chronic Adrenocortical Insufficiency (Addison Disease) - More than 90% of all cases are caused by a. Autoimmune adrenalitis : Accounts for 60% to 70% of cases and is the most common cause of primary adrenal insufficiency in developed countries. b. Infections : mainly tuberculosis. c. Metastatic neoplasms involving the adrenal mainly carcinomas of the lung. 3. Secondary Adrenocortical Insufficiency : Caused by any disorder of the hypothalamus and pituitary that reduces the output of ACTH leads to a syndrome of hypoadrenalism having many similarities to Addison disease such as: a. Metastatic cancer b. Infection c. Infarction d. Irradiation When 90% of the adrenal cortex has been compromised. a. Progressive weakness and easy fatigability, b. Anorexia, vomiting, weight loss, diarrhea. c. Potassium retention and sodium loss, with hyperkalemia, hyponatremia, volume depletion, and hypotension; due to decreased aldosterone in primary adrenal insufficiency . d. In individuals with primary adrenal insufficiency increased levels of ACTH precursor hormone stimulate melanocytes, with resultant hyperpigmentation of the skin by contrast hyperpigmentation is not seen in individuals with secondary adrenocortical insufficiency (no ACTH). Diagnosis Blood glucose levels normally are maintained in a very narrow range, usually 70 to 120 mg/dL. The diagnosis of diabetes is established by elevation of blood glucose: 1. A random blood glucose of 200 mg/dL or higher, with classical signs and symptoms 2.A fasting glucose concentration of 126 mg /dL or higher on more than one occasion. 3. An abnormal oral glucose tolerance test (OGTT), in which the glucose levels is 200 mg/dL or higher 2 hours after a carbohydrate load (75 g of glucose). Persons with serum fasting glucose values < 110 mg/dL, or < 140 mg/dL for an OGTT, are considered euglycemic. Patients with prediabetes: - Fasting glucose > 110 but < 126 mg/dL, or OGTT values of >140 but < 200 mg/dL It accounts for 10% of all cases - It is an autoimmune disease destructing pancreatic B-cells leading to deficiency of insulin. - Most commonly develops in childhood, becomes manifest at puberty, and most patients depend on exogenous insulin for survival; without insulin they develop serious metabolic complications. - The classic manifestations of the disease occur after 90% of the beta cells have been destroyed. - Account for 80% to 90% of DM caused by peripheral resistance to insulin action . It is complex multifactorial disease and pathogenesis involves: I. Environmental factors, such as a sedentary life style and dietary habits. II. Genetic factors. Insulin resistance : Defined as the failure of target tissues to respond normally to insulin and leads to decreased uptake of glucose in muscle,and inability to suppress hepatic gluconeogenesis. Metabolic syndrome has been applied to a constellation of findings dominated by visceral obesity, which is accompanied by insulin resistance, glucose intolerance, and cardiovascular risk factors such as hypertension and abnormal lipid profiles The first 1 or 2 years of diabetes type 1(referred to as the "honeymoon period"), in which exogenous insulin requirements may be minimal because of residual ongoing endogenous insulin secretion but then the beta cell reserve is exhausted and insulin requirements increase. - The onset of the diseases is marked by polyuria, polydipsia, polyphagia. -The hyperglycemia exceeds the renal threshold for reabsorption, and glycosuria induces an osmotic diuresis and polyuria. -The obligatory renal water loss combined with the hyperosmolarity tends to deplete intracellular water, trigger the thirst centers of the brain leading to (polydipsia). - Deficiency of insulin leads to catabolism of proteins and fats leading to polyphagia. - Deviations from normal diet, unusual physical activity, infection, or stress may predispose to diabetic ketoacidosis. - The plasma glucose is about 500 to 700 mg/dL due to absolute insulin deficiency and effects of glucagon. - The marked hyperglycemia causes an osmotic diuresis and dehydration. - Insulin deficiency leads to activation of lipoprotein lipase, with resultant excessive breakdown of dipose stores, giving rise to increased FAs, which are oxidized by the liver to produce ketones (ketonemia and ketonuria). - Accumulating ketones decrease blood pH, resulting in metabolic ketoacidosis. - Also may manifest with polyuria and polydipsia, but in obese patients older than 40. - Unfortunately, with the increase in sedentary life in Western society, type 2 diabetes is now seen in children. - In some cases, medical attention is sought due to unexplained weakness. - Most frequently, however, the diagnosis is made after routine blood or urine testing in asymptomatic persons. In the decompensated state, patients develop hyperosmolar nonketotic coma. This syndrome is due to severe dehydration resulting from sustained osmotic diuresis and urinary fluid loss. The affected person is an elderly diabetic who is disabled by stroke or infection and unable to maintain adequate water intake. The absence of ketoacidosis and its symptoms (nausea, vomiting, respiratory difficulties) delays recognition of the seriousness of the situation until the onset of severe dehydration and coma. I. Macrovascular Disease mainly accelerated atherosclerosis a- Myocardial infarction( MI,) caused by Coronary artery athero-sclerosis is the most common cause of death in diabetics. b- Gangrene of the lower extremities, is 100 times more common in persons with diabetes than in the general population. II. Diabetic Microangiopathy: - Diffuse thickening of basement membranes, is evident in the capillaries of the skin, retina and renal glomeruli. - Diabetic capillaries are more leaky than normal to plasma proteins. - The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and neuropathy. III. Diabetic Nephropathy: Renal failure is second to MI as a cause of death from this disease. - The earliest manifestation of diabetic nephropathy is the appearance of microalbuminuria (loss of more than 30mg but less than 300 mg of albumin/day). - Over the succeeding 10 to 15 years, without specific interventions, about 80% of patients with type 1 diabetes and 40% with type 2 diabetes will develop overt nephropathy with macroalbuminuria IV. Ocular Complications: Visual impairment, is one of the feared consequences of long-standing DM. Retinopathy, the most common pattern. 1. Nonproliferative retinopathy includes: a. Intraretinal or preretinal hemorrhages, : b. (microinfarcts) or“. Microaneurysms (dilations of retinal capillaries) 2. Proliferative type is characterized by many blood vessels in the retina with fibrosis can lead to blindness. V. Diabetic Neuropathy. 1- The most frequent is peripheral , symmetric neuropathy of the lower extremities affecting motor and sensory nerves, particularly the latter. 2- Autonomic neuropathy, which produces disturbances in bowel and bladder function and impotence. - In a person with neuropathy, a trivial infection in a toe may be the first event in a long succession of complications (gangrene, bacteremia, pneumonia). Several studies have demonstrated that morbidity and mortality , from diabetes are attenuated by strict glycemic control. For patients with type 1 diabetes, insulin replacement therapy is the mainstay of treatment, Dietary restrictions and exercise (that improves insulin sensitivity) are the "first line of defense" for type 2 diabetes. Most patients with type 2 diabetes will eventually require therapeutic intervention achieved by administration of a number of agents that lower glucose levels. Glycemic control is assessed by measuring the percentage of glycosylated hemoglobin (HbA1C ) which is a measure of glycemic control over long periods of time (2 to 3 months) and is relatively unaffected by day-to-day Variations. A HbA1C value below 7% is taken as evidence of tight glycemic control, but patients with HbA1C levels in this range also have an increased risk of episodes of therapy-related hypoglycemia.