Endocrine part two. Presented by Dr. Mohammad Saadeh The requirements for the Clinical Chemistry Philadelphia University Faculty of pharmacy

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1 Endocrine part two Presented by Dr. Mohammad Saadeh The requirements for the Clinical Chemistry Philadelphia University Faculty of pharmacy

2 Cushing's disease: increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma. Diagnosis by Insulin stress test (IST test) and measured the cortisol and GH. Acromegaly : increase GH secretion and the cause is a pituitary adenoma. Diagnosis by Oral glucose tolerance test (OGTT) with GH measurement. Addison s disease,: also known as primary adrenal insufficiency and hypocortisolism, is a long term endocrine disorder in which the adrenal glands do not produce enough steroid hormones

3 Pituitary function Pituitary function is regulated by the hypothalamus

4 Anterior pituitary hormones TSH (thyroid-stimulating hormone), acts on thyroid gland to elicit secretion of thyroid hormones. ACTH (adrenocorticotrophic hormone) acts on adrenal cortex to elicit secretion of cortisol. LH (luteinizing hormone) and FSH ( follicle-stimulating hormone), act cooperatively on the ovaries in women and the testes in men to stimulate sex hormone secretion and reproductive processes. GH (growth hormone) acts directly on many tissues to modulate metabolism. Metabolic fuels (e.g. glucose, free fatty acids) in turn modify GH secretion. Prolactin acts directly on the mammary glands to control lactation. Gonadal function is impaired by elevated circulating prolactin concentrations.

5 Prolactin Prolactin acts directly on the mammary glands to control lactation. Gonadal function is impaired by elevated circulating prolactin concentrations.

6 Hyperprolactinaemia Hyperprolactinaemia is common and can cause infertility in both sexes. An early indication of Hyperprolactinemia in women is 1. amenorrhoea 2. galactorrhoea Hyperprolactinaemia in men is 1. No early signs 2. Prolactinoma may be when a large growing tumor begins to interfere with the optic nerves. Causes of hyperprolactinaemia include: stress (venepuncture is sufficient to raise plasma prolactin in some patients) drugs (e.g. oestrogens, phenothiazines, metoclopramide, α-methyl dopa) seizures (acutely) primary hypothyroidism (prolactin is stimulated by the raised TRH) other pituitary disease. If these causes are excluded, the differential diagnosis is between: a prolactinoma (a prolactin-secreting pituitary tumor, commonly a microadenoma) idiopathic hypersecretion, which may be due to impaired secretion of dopamine, the hypothalamic factor that inhibits prolactin release.

7 Posterior pituitary hormones Hypothalamic neurons synthesize: 1. Arginine Vasopressin (AVP) and 2. Oxytocin, which pass along axonal nerve fibres in the pituitary stalk to the posterior pituitary. Secretion of AVP, also known as antidiuretic hormone (ADH), is stimulated by: increased plasma osmolality via hypothalamic osmoreceptors. severe blood volume depletion via cardiac baroreceptors. stress and nausea.

8 pituitary tumors Diagnosis: Pituitary tumors may be a. Functional (secrete hormones). b. Non-functional. There specific signs of hormone excess particularly in acromegaly, Cushing s syndrome and prolactinoma. There may be signs of hypopituitarism in skin, hair and musculature.

9 pituitary tumors Diagnosis: 1.The impact of the tumor on pituitary function requires formal assessment by dynamic function tests. GH and ACTH secreting cells are most vulnerable, and an insulin stress test. 2. Combined test of anterior pituitary function such as 1. Insulin stress test, 2. TRH test, 3. GnRH test **Note: Because of its associated dangers, insulin-induced hypoglycaemia is being replaced by administration of GHRH and CRH to investigate GH and cortisol secretion.

10 Hypopituitarism Hypopituitarism causes include tumor, infarction, trauma, congenital malformation, infection and hypothalamic disorder. Elderly patients may complain of symptoms relating to ACTH or TSH deficiency such as hypoglycaemia or hypothermia.

11 Thyroid pathophysiology Thyroxine (T4) and tri-iodothyronine (T3) are together known as the thyroid hormones. They are synthesized in the thyroid gland. Thyroid hormone action Thyroid hormones are essential for the normal development and metabolism of all the tissues in the body. Congenital hypothyroidism cause, 1. Permanent brain damage if not treated within 3 months. 2. Hypothyroid children have delayed skeletal maturation, short stature and delayed puberty. **NOTE: High serum cholesterol in some hypothyroid patients. This is a consequence of a reduction in cholesterol metabolism due to down regulation of low-density lipoprotein (LDL) receptors on liver cell membranes, with a subsequent failure of sterol excretion via the gut.

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13 Thyroid pathophysiology Binding plasma: Most T4 and T3 circulates in plasma bound to protein. Only a small proportion is not bound, yet it is this free fraction that is biologically important. In plasma, Around 0.05% free T4 and over 99.95% of T4 binding with Thyroxine binding globulin (TBG) carries 70% of T4, albumin approximately 25% and transthyretin (formerly called prealbumin) around 5%. Around 0.5% free T3 and Over 99.5% of T3 is transported by the same proteins. free, T4 and T3 concentrations that are important for the biological effects of the hormones, including the feedback to the pituitary and hypothalamus. Note: Changes in binding protein concentration complicate the interpretation of thyroid hormone results, e.g. in pregnancy.

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15 Regulation of thyroid hormone secretion The secretion of thyroid hormones is controlled primarily by TSH from the anterior pituitary. If thyroid hormone elevated, then the circulating TSH will be suppressed. If the thyroid is not secreting enough thyroid hormone, the TSH levels will be very high in an attempt to stimulate the gland to secrete more.

16 Thyroid function tests 1. TSH. Measurement of TSH is a good diagnosis and monitoring of disease. TSH cannot be used to diagnose primary thyroid disease, or to monitor replacement, namely hypopituitarism. So the TRH test (dynamic function test) used. 2. Total T4 or free T4. Following the introduction of replacement thyroxine or of anti-thyroid treatment, e.g. carbimazole. 3. Total T3 or free T3. In hyperthyroidism, the rise in T3 is almost always disproportionate to the rise in T4. 4. Antibodies. The titer of autoantibodies to thyroid tissue antigens may be helpful in the diagnosis and monitoring of autoimmune thyroid disease. Anti-thyroid peroxidase (anti-tpo) may be useful in hypothyroidism and stimulating thyroid receptor antibodies in thyrotoxicosis.

17 Drugs and the thyroid Various drugs affect thyroid function tests.

18 Goiter A goiter is an enlarged thyroid gland. The biochemistry laboratory can confirm if a patient is hypothyroid, hyperthyroid or euthyroid.

19 Causes of hypothyroidism Over 90% of cases of hypothyroidism occur as a consequence of: autoimmune destruction of the thyroid gland (Hashimoto s disease) radioiodine or surgical treatment of hyperthyroidism. Rarer causes include: transient hypothyroidism due to treatment with drugs such as lithium carbonate TSH deficiency, which may be a component of panhypopituitarism Congenital defects such as blocks in the biosynthesis of T4 and T3, or end-organ resistance to their action Severe iodine deficiency.

20 Diagnosis of hypothyroidism Hypothyroidism divided to: 1. Primary hypothyroidism: Failure of the thyroid gland itself. most commonly endocrine problems. مهم specimen. Confirmed by an elevated TSH in a serum 2. Secondary hypothyroidism: Failure of hypothalamic failure of the pituitary to secrete TSH. less common. TRH test is used to investigate Secondary hypothyroidism due to pituitary or hypothalamic causes. Note: Hypothyroidism is managed by thyroxine replacement, and therapy is monitored by measuring the serum TSH concentration.

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22 Non-thyroidal illness Patients with severe non-thyroidal illness may show apparent abnormalities in thyroid hormone results, known as the sick euthyroid or low T3 syndrome or non-thyroidal illness pattern of results.

23 Causes of hyperthyroidism Hyperthyroidism can result from: Autoimmune disease is the commonest cause of hypothyroidism Graves disease (diffuse toxic goitre) is an autoimmune disease in which antibodies to the TSH receptor on the surface of thyroid cells appear to mimic the action of the pituitary hormone. Toxic multinodular goitre solitary toxic adenoma Thyroiditis exogenously administered iodine and iodine-containing drugs, e.g. amiodarone. excessive T4 and T3 ingestion.

24 Diagnosis of hyperthyroidism primary hyperthyroidism 1. primary hyperthyroidism if TSH concentration undetectable and raised thyroid hormone concentration (thyrotoxicosis confirmed). 2. If TSH is undetectable patient has primary hyperthyroidism. suspected hyperthyroidism will prove more difficult; example, In pregnancy, high oestrogens cause stimulation of thyroid binding globulin (TBG) synthesis in the liver. So total T4 concentrations increase although free T4 will be normal. Free T4 analyses are invaluable in diagnoses where binding proteins are altered, e.g. in pregnancy, in women on the oral contraceptive pill and in patients with the nephrotic syndrome. Congenital TBG deficiency cause confusion even if thyroid disease is not suspected. Free T4 assays are used as first-line tests of thyroid dysfunction. TSH secretion inhibit by free T4 (negative feedback). Laboratories use TSH to screen for thyroid disease. In hyperthyroidism, TSH is undetectable, total T4 within normal limits and elevated T3 concentration. This is referred to as T3 thyrotoxicosis.

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26 Tumor markers Substances that can be measured quantitively by immunochemical means in tissue or body fluids to identify the presence of a cancer. Such as: Alpha FetoProtein (αfp), Human Chorionic Gonadotrophin (HCG), Cancer Antigen125 (CA 125), CarcinoEmbryonic Antigen (CEA).

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