endocrine disorders 2

Dr. Abdul Hussein A. Al-Agenabi Assistant Professor Clinical Chemistry

Objectives of 2nd lecture To shed light on the normal function of ADH as example of hypothalamic hormones. Draw attention to the clinical disorders that results from abnormal ADH levels.

The pituitary composed of 2 lobes: anterior lobe “ adenohypophysis”posterior lobe “neurohypophysis” Posterior Pituitary:Hormones synthesized in the hypothalamus are transported down the axons to the endings in the posterior pituitaryHormones are stored in vesicles in the posterior pituitary until release into the circulationPrincipal Hormones: Vasopressin & Oxytocin


Arginine-vasopressin (ADH) ADH is a polypeptide hormone has a short half life (15-20 min) and metabolised in kidneys and liver In hyperosmolality e.g. during dehydration, this hormone is released from posterior pituitary and acts on renal tubule through special receptors enhancing water reabsorption from tubules to the blood (without salts). it will dilute the blood and therefore corrects osmolality, but concentrated urine is produced. The reverse is true: when the subject drinks a lot of water/fluid, this will decrease blood osmolality and inhibits ADH secretion, with more loss of water in urine (dilute urine is produced),

Posterior Pituitary: Regulation of Osmolality

Plasma Osmolality is monitored by osmoreceptor in the hypothalamus Increases in plasma Osmolality stimulates secretion of vasopressin (ADH) Small changes above the normal plasma osmotic pressure (285 mosm/kg) stimulate release of vasopressin


Disorders of ADH:Is of 2 types: Def. of ADH Excess ADH Disease or trauma that causes damage of hypothalamus or posterior pituitary causes deficiency of ADH resulting in a syndrome called Central diabetes insipidus (CDI). Also, congenital absence of tubular receptors of ADH (renal cause), results in a similar syndrome called nephrogenic diabetes insipidus. Q: Are there hormones involved in control of body water? Yes, Atrial natriuretric peptide (ANP), aldosterone, prostoglandins and angiotensin II but ADH is the most imp one

Causes of central DI

Secretion of vasopressin is regulated at the paraventricular & supraoptic nuclei, which sense changes in osmolarity Destruction of the paraventricular or supraoptic nuclei or of the posterior pituitary results in decreased vasopressin secretion Brain tumor pituitary / cranial surgery closed head trauma granulomatous disease Histiocytosis X CNS infections DI may be idiopathic or inherited either as an autosomal dominant or as an autosomal recessive trait (locus 20p13)


Nephrogenic DI (NDI) Nephrogenic DI either acquired or hereditary. The acquired is due to certain drugs and chronic diseases and can occur at any time during life. The hereditary form is caused by genetic mutations, and its signs and symptoms usually become apparent within the first few months of life. NDI arises from defective or absent receptor sites at the cortical collecting duct segment of the nephron or defective or absent aquaporin, the protein that transports water at the collecting duct Aquaporin enhances water entry into the cell from the lumen

Absence of the vasopressin receptor does not allow this process to take place, causing inhibition of water uptake and polyuria Alternatively, defective or absent aquaporin impairs the process in the presence of normal V2 receptors Signs and symptoms The most common symptom of diabetes insipidus are: Polydepsia Polyuria Nocturia & bed-wetting

Diagnostic Studies

Diagnosis should be suspected in any patient with sudden increased thirst & urination Laboratory examination will reveal very diluted urine, made up mostly of water with no solute Examination of the blood will reveal very concentrated blood, high in solute and low in fluid volume The serum sodium may be as high as 170 mEq/L Specific gravity of < 1.005 (low) Urine osmolality of < 100 mOsm/kg (low) Serum osmolality > 290 mOsm/kg (High)

Diagnostic Tests

The water deprivation test is useful in patients with polyuria. The differential diagnosis of polyuria are: Diabetes insipidus (either central or nephrogenic), psychogenic polydipsia, or an osmotic diuresis (e.g., hyperglycemia ) . Patients who undergo the water deprivation test should have: The urine volume and urine osmolality every hour and Plasma sodium concentration every two hours once water deprivation begins.

The test is stopped when: patient has lost > 5% of original body weight patient has reached certain limits of low blood pressure & increased heart rate urine is no longer changing significantly from one sample to the next in terms of solute concentration The next step of the test involves injecting a synthetic form of ADH, with one last urine sample examined 60 minutes later Comparing plasma and urine osmolarity allows to diagnose either central DI, Nephrogenic DI, partial DI, or psychogenic polydepsia

These two conditions (DI or polydipsia) are characterized by polyuria with a dilute urine osmolarity, So how to distinguish between them? If the serum sodium is high (D.I.) but if it is low (polydipsia) The problem is when serum sodium is within the normal range!!! This can be solved by the next step (i.e. response to Exogenous ADH) of WDT as follow:


In central D.I., exogenous ADH leads to a rapid rise in urine osmolality: In complete D.I., the urine osm will more than double, while in partial central D.I. (which is more common) there will be an increase of at least 15% in the urine osm. Generally individuals with central D.I. are able to concentrate their urine osm > 300 mosm/kg.

How we can differentiate between DM & DI? Low urine specific gravity of DI distinguish it from DM (High urine Specific Gravity) due to presence of urine glucose in the latter case.

Syndrome of Inappropriate antidiuretic Hormone (SIADH)

The syndrome of inappropriate secretion of ADH (SIADH) is characterized by the non-physiologic release of ADH, resulting in impaired water excretion with normal sodium excretion SIADH is characterized by: fluid retention serum hypo- osmolarity dilutional hyponatraemia hypochloremia concentrated urine in the presence of normal or increased intravascular volume normal renal function

Diagnosis of SIADH

is by measurement of urine & serum osmolarity on the same time A serum osmolarity lower than the urine osmolarity indicates the inappropriate excretion of concentrated urine in the presence of very dilute serum Dilutional hyponatraemia is indicated by serum sodium < 134mEq/l, serum osmolarity less than 280mOsm/kg & urine specific gravity > 1.005 other Labs include decreased BUN, creatinine

Treatment If symptoms are mild & serum sodium >125 meq: treatment may be fluid restriction of 800-1000ml/day This restriction should result in a gradual daily reduction in weight, progressive rise in serum sodium concentration and osmolality, and symptomatic improvement

GH & Prolactin

Human Growth Hormone
Is a glycoprotein H The half life of HGH is only 20 hours. The level of HGH in the body decreases with age. It is thought that the features of aging such as smaller muscle mass and wrinkles is due to the small amount of HGH. This hormone regulates growth and development of the body. It is also called somatotropin

Human Growth Hormone:- The highest blood level of this hormone occurs after Severe exercise, Deep sleep, Some drugs Insulin These Four Hypoglycemic factors have been used in Clinical Laboratory to estimate growth hormone level after stimulation, to diagnose HGH deficiency.

GH has 2 important functions Growth function through somatomedins { IGF I and IGF II} from liver cells in response to GH. promote their growth effect on target tissues (bone and cartilage) through cell membrane receptors. In addition, normal growth required also good nutrition, emotional stability, and normal thyroid function (T3 stimulates GH gene expression & general metabolic function).

Metabolic function it stimulates protein synthesis and lipolysis (results in increased FFA in blood which is a preferable source of energy during growth phase). but it inhibits glucose uptake by peripheral cells causing hyperglycemia, (i.e. it is one of insulin antagonist hormone)

Gigantism

If too much HGH is produced during childhood than a condition called gigantism occurs. Individuals with this disorder have abnormally long skeleton bones. Treatment for this disorder include; - Surgical removal of a tumor from the pituitary gland - Irradiation of the gland tissue.

Acromegaly

Acromegaly is a condition caused when an adult body produces too much HGH. The cause of the increased production of HGH is a tumor in the pituitary gland. Symptoms of this condition may include; -thickening of bone tissue. -abnormal growth of the head, hands and feet. -spinal deformities Treatment of acromegaly includes: - surgical removal of the tumor - radiation therapy - injection of a growth hormone blocking drugs


Q: Why we measured serum GH in laboratory? for two abnormalities. 1) Increased GH due to pituitary tumors, childhood, (gigantism), adulthood (acromegaly). Biochemical Dx: Basal S. GH level is higher than normal but it could be within normal level so we should do: 1) Glucose suppression test. Acromegaly diagnose if there is NO fall of s. hGH. 2) Plasma IGF-1 has long half life and it increased with severity of disease. GH & IGF can be used in monitoring of Rx of acromegaly.

2. GH dysfunctions: results in short- stature [dwarfism] Is of 2 types; GH-deficiency dwarfs w is due to true deficiency of GH (because of pituitary damage or hypothalamic disease) So both GH & IGF-1 levels are low They respond well to GH therapy. GH insensitivity dwarfs caused by deficiency of liver GH receptors [Laron dwarfs] or loss of IGF-1 response to GH i.e. loss of post-receptor response [Pygmies dwarfs ] These patients have low IGF-1 but normal or high serum GH level. They not respond to GH therapy.

Decreased GH (short stature), is due topituitary deficiency of GH

Lab Diagnostic Tests
Basal serum GH level…..if within high normal range exclude hGH def.But low levels not confirm hGH defSo we sd do GH provocation (Stimulation)Test after exercise or administration of drugs ex: clondine, arginine, glucagon or insulin

Prolactin

polypeptide hormone, also produced by the anterior pituitary, stimulates the development of mammary gland tissue and milk production (lactogenesis). The hypothalamus secretes a hormone called dopamine which inhibits the production of prolactin. In late pregnancy, an increase in estrogen will stimulate prolactin production. Also, after a child is born breast feeding stimulates nerve endings in the nipples which stimulates the hypothalamus to release prolactin secreting hormones.



Prolactin : It stimulates milk production from the breasts. Q: Why we measured serum prolactin in laboratory? To investigate patients with Galactorrhea (abnormal breast milk production), Headaches, Visual problems, Irregular bleeding (menses) and Infertility.

Q: Is any elevation in serum prolactin level is pathological? No/ sometimes it is temporarily elevated after: Eating, Stress, Sexual excitement and Certain drugs. If an elevation of prolactin is discovered, it should be repeated to confirm or exclude the diagnosis. Elevated prolactin levels cause: irregular periods, and infertility. How?


Elevated prolactin causes anovulation by interfering with the normal release of FSH and LH from the pituitary. i.e. high levels of prolactin suppress GnRH of hypothalamus and so associated with low LH and FSH levels in blood. Increased prolactin levels (through its effect on FSH) can interfere with clomiphene’s effectiveness so it can decreases the chance of pregnancy in treatment of infertile that is, if it is elevated it should be treated.

Elevated prolactin not only has risk of infertility, but it leads to: Thickening of the endometrium (endometrial hyperplasia or carcinoma) because of unopposed estrogen effects. Osteoporosis and heart diseases because of the generally lower estrogen levels. Q: Does PRL level affected by menstrual cycle? And does it affect menstruation? Yes; it causes irregular cycle and amenorrhea. How?????