Flashcards in Endocrine Deck (43):
Diabetes Mellitus Type 1
chronic hyperglycemia, disturbances of carb, fat and protein metabolism due to defects in insulin secretion, insulin action and both.
Etiology- most caused by immune mediated destruction of pancreas
-genetic susceptibility- association with HLA-DR3 and DR4/DQA1 & DQB1
-environmental factors- coxsackie B4, Rubella, Mumps, drugs, tocins
Pathogenesis_ Islet cell antibodies or other antibodies against pancreatic components and infiltration of pancreatic islets by t- cells-, there will be a long pre-diabetic phase while the Beta islet cells are being destroyed
- autoimmune system which destroys the pancreas can be triggered by viral or chemical attack on beta cells, leading to exposing new proteins or due to molecular mimicry, the HLA is involved in antigen pressentation.
-insulitis- a chronic inflammatory infiltrate of islets affecting primarily insulin containin islets.
Clinical- can be asymptomatic,
classical symptoms: increased polyuria, thirst, obese, blood glucose 257, severe acute presentation or coma
Type 1 features- onset before 40, rapid onset, lean body mass, prone to ketosis, insulin is low or absent, HLA link is present, autoantibodies common
-symptoms- polyuria, osmotic diuresis, Nocturia, Thirst dehydration, Weight loss(catabolic state), Tiredness (muscular wearkness due to proteolysis and lack of glucose ), Blurred vision( dehydration of lens, aqueous and viterious humour), Vomiting (ketones stimulate the area postrema, Hyperventilation (Kussmaul breathing, response to acidosis)
Lab findings- hyperglycemia, glycosria, ketoacidosis, ketonuria, hyperlactatemia, hyperlipidemia, hypovolemai, hyperosmolarity, increased levels of beta hydroxybutyrate if undergoing DKA.
Diagnosis- A1c greater than 6.5 %
-or FPG greater than 126
-or Two hour plasma glucose greater than 200 during oral glucose tolerance test
-or clinical signs and symptoms with random glucose level greater than 200
- single test doesn't confirm diagnosis, need to confirm positive test.
Long term Complications: nephropathy, neuropathy, eye disease, heart disease, stroke, problems of feet
Diabetes Mellitus type 2
Etiology: both genetic AND environment factors
-Beta cell failure and insulin resistance
- genetic factors- stronger than type 1, no HLA association, usually a polygenic disorder which depends on simultaneous presence of several genes with environmental factors like obesity involved.
- environmental factors- obesity is associated with aroudn 80% of patients with type 2 DM, more than half obetween 25-29 BMI, RR of of BMI above 35 is 100 x more than BMI less than 22 (rare in BMI 21-22.
---increased production of insulin antagonists such as fatty acids and tumour necrosis factor by adipose tissue, especially in central obesity.
Pathogenesis- moderate reduction of islet tissue with variable degress of deposition of amyloid.
Type 2 features: Usually over 40 years old with slow onset, obese/normal body mass, ketosis is rare, insulin is normal to reduced, HLA link is absent, autoantibodies- absent
Long term Complications: nephropathy, neuropathy, eye disease, heart disease, stroke, problems of feet
usually resolves after pregnancy
Oral glucose tolerance test
patient fasts overnight, take a basal glucose level, give 75 gram glucose and measure blood glucose level at 120 minutes
IFG- impaired fasting glycemia: A fasting plasma glucose above normal and below the diabetic range- (FPG greater than 100 but less than 126)
IGT- impaired glucose tolerance- 2 hour value in OGTT of greater than 140 mg but less than 200
-possible to prevent by weight loss through diet, exercise, and medications.
Managment of Diabetes Mellitus
Aims of treatment- alleviate symptoms, prevent acute and long term complications, managment of cardiovascular risk factors
Methods- education, diatary control, oral hypoglycemic agents, insulin treatment
Monitoring- Urine glucose(poor guide to severity, no value for hypoglycemia)
-blood glucose- (self monitoring)
-glycosylated hemoglobin- hemoglobin reacts with glucose non-enzymaticaly to produce HbA1, HbA1c is the major fraction of glycosylated hemoglobin which is normally about 5% of total hemoglobin concentration. gives integrated measure of glucose concentrations over the previous 2-3 months.
Acute complications of Diabetes Mellitus
Hypoglycemia- due to complication of diabetes treatment, Diabetic detoacidosis, hyperosmoalr non-ketotic coma, Lactic acidosis.
Diabetic Ketoacidosis (DKA)
Precipitating factors- infection or acute illness, trauma, emotional disturbance, missed insulin dose.
Pathogenesis: acute insulin deficiency and rise in stress hormones leads to hyperglycemia.
-severe hyperglycemia cause a huge osotic diuresis and gross dehydration
-leads to development of ketosis which can cause vomiting
-electrolyte disturbance is caused by insulin deficiency and osmotic diuresis and vomiting
-acidosis is caused by ketosis, lactic acidosis, these two are caused by dehydration and vasoconstriction by stress hormones.
- causes increased levels of beta hydroxybutyrate
Management- saline infusion to replace fluids, restore metabolic control with insulin, potassium and sometimes bicarbonate.
Hyperosmolar hyperglycemic state ( HSS)- previously hyperosmolar nonketotic coma
- occurs in elderly pateints with type 2 DM
-relative insulin deficiency sufficient to prevent ketosis but cannot suppress hyperglycemia.
-usually very high glucose levels causing dehydration
-treatment- fluid replacement and insulin
Long Term complications
microangiopathy- affects capillaries, arterioles and small blood vessels, characterized by thickening of basement membranes which causes leackiness- will show retinopathy, nephropathy, neuropathy
-macroangiopathy- athersclerosis in large to medium size arteries that manifests as ischemic heart disease, stroke peripheral vascular disease.
-Diabetic nephropathy- Important cause of ESRF,
---first functional change is hyperfiltration, -----------first biochemical signs- microalbuminuria(urinary albumin 30-300 mg/day)
---first morphological sign: basement membrane thickening and mesangil expansion with subsequent nodular deposits and diffuse glomerulosclerosis
---proteinuria greater than 300 mg/ day
---renal impairment is delayed by excellent glucose control and treateing hypertension.
-Eye complications- diabetic retinopathy(commonest cause of blindness in adults between 30-65 years of age), catarac, glaucoma
-Diabetic neuropathy: causes pain, impotence, orthostatic hypotension, muscle atrophy and weakness
-diabetic foot- ischemia, neuropathy, infection.
Mechanism of Long term- complications
Glycosylation- involves basement membrane of capillaries and structural proteins. After glycosylation of proteins, further metabolism of glcyosylated proteins produce advanced glycosylation end products (AGE). AGE has been inplicated in some diabetic complications like retinopathy
Accumulation of sugar alcohols (polyols) in tissues which do not require insulin for glucose uptake. Glucose is converted to sorbitol which is converted to fructose. Sorbitol accumulation cause osmotic effects and depletion of myoinositol, amino acids and potassium. This mechanism is probably involved in emdiating neuropathy and cataract.
Free radicals- increased in DM,
hypertenstion, dyslipidemia, obesity and insulin resistance- associated with DM and they are known risk factors for atherosclerosis,
Prevention of type 2 diabetes
IGT- IFG- pre clinical state , primary prevention
Clinical disease- secondary prevention
Complications- tertiary prevention. c
Transport of the hypothalamic releasing and inhibiting hormones
The hypophyseal portal beins arise from the primary capillary network of the superior hypophyseal arteries in the median eminence, the hypothalamic releasing and inhibiting hormones are released into these hypophyseal portal veins
in the anterior pituitary, the portal veins form a secondary capillary network into which the hormones of the anterior pituitary are secreted.
anterior pituitary hormones, their cell types and hypothalamic regulatory factors
Growth hormone- acidophil, Growth hormone releasing hormone (GHRH), Growth hormone release inhibiting factor- (Somaostatin)
- Prolactin- Acidophil- Prolactin release inhibiting hormone
-Thyroid stimulating hormone (TSH)-basophil- Thyrotropin releasing hormone (TRH
- Adenocorticotrophic hormone (ACTH)- basophil-Corticotrophin (CRF)
-Leuteinizing hormone (LH)- Gonadotrophin-releasing hormone (GN-RH)
Follicle stimulating hormone- Gonadotrophin-releasing hormone (Gn-RH)(LH/FSH-RH)
underactive pituitary gland, can result from diseases of the pituitary gland or from diseases of hypothalamus, most common is a pituitary adenoma
Etiology- Tumors: adenoma, craniopharyngioma, cerebral and secondary tumors
-vascular- Sheehan's syndrome, severe hypotension
-infection: meningitis, TB, Syphilis, HIV/AIDS
-Hypothalamic disorders: tumors, functional disorders, isolated deficiency of GHRH and GnRH
-Iatrogenic: irradiation, hypophysectomy,
-Miscellaneous: sarcoidosis, Hemochromatosis
Clinical features:(anterior pituitary horome deficiency) hormone deficiency follows the following pattern: LH, GH, FSH, ACTH, TSH
-vasopressin secretion is usulaly maintained becasue th eposterior pituitary is typically preserved
- deficiency in LH and GSH: females- menstural disturbance, delayed puberty, males- loss of libido, loss of faciel and body hair, impotence.
-GH deficiency- growth retardation in children, muscle weakness, lethargy, and impaired quality of life in adults
-TSH- loss of thyroid secretions and hypothyroidsm
-panhypopituitarism may cause coma
-Basal levels of hormones influenced by resitual capacity in pituitary, pulsatility of pituitary secretion, stress, time of day, time of menstrual cucle
-Stimulation and supression tests:- simultaneous administration of insulin, TRH, and LH and GnRH
--insulin given to induce hypoglycemia creating a stress state that allows assessment of stress hormones- GH, ACTH
Localization of tumor done with MRI or CT scans
excess production of pituitary hormones by tumour
Etiology- stress, drugs (antipsychotics, oral contraceptive pill, antidopamine drugs
-tumors, prolactinoma, stalk section which removes inhibitory signal on prolactin secretion
clinical featurs and investigation- Gonadal dysfunction, amenorrhea or anovulation, infertility, decreased libido, erectile impotence in men, Galactorrhea,
Investigations- Blood levels of prolactin, MRI or CT
treatment- intially medications but surgery may be needed.
Etiology- GH excess after fusion of epiphysis (gigatism occurs due to GH excess ocurring before epiphyseal fusion
-almost always due to adenoma
Clinical Features- increased growth of skeletal and soft tissue, hypertension, arthritis, headaches, and local efects of tumor
-menstrual disturbances, loss of libido and loss of potency in men, DM, becaue GH antagonizes the action of insulin.
Diagnosis- Measure GH and IGF-1- GH acts on liver to produce IGF-1 IGF-1 level is more stable than GH and therefore more important in diagonsis of acromegaly
-GTT with GH measurement- normally GH levels fall following oral glucose and at least one of the samples during the test should have undetectable GH levels, failure of suppression or paradoxiical rise in GH suggests acromegaly
treatment- Surgical, medical, Radiotherapy
Cardiovascular disease is an important complication of acromegaly along with hyeprtensions.
Disorders of the pituatary
ADH deficiency causes Diabetes insipidus
-inappropriate secretion of ADH causes the syndrome of inappropriate ADH secretion.
Physiology of ADH-
ADH is secreted in repsonse to decreased blood voluem and raised plasma osmolality, ADH causes water retention by increasing permabiltiy in the distal convoluted tubules and collecting ducts in the kidney. ADH will tend therefor to restore blood volume and normalize plasma osmolality. The action of ADh will cause a decrease in urine volume and increased urinary osmolality
Etiology- caused by deficiency or resistance to action of antidiuretic hormone. characterized by polyuria and thirst
Central- caused by absolute deficiency of ADH, is genetic, itidopathic, or hypothalamic or high pituitary stalk lesion
Nephrogenic DI- caused by resistance to aDH action- genteic, metabolic (hypokalemia and hypercalcemia), Drugs (Lithium)
water deprivation test- Fluid restriction for 8 hours and then ask the patient to pass urine and discard it. Weigh patient at start of test, continue weighing at 1 hour intervals. Measure serum and urine osmolality, urine volume and wieght hourly for up to 8 hours. stop test after 8 hours or if patients' weight is more than 5% off his initial weight. If results suggest DI, give desmopressin, measure plasma osmoality, urine voluem and osmolality
-Normal serum osmolality should not exceed 295 mosm/kf and the urine osmolality exceeds 600 mosm/kg at some time during the test
-some patients show intermediate values and partial defects.
Central DI- after fluid deprivation less than 300 mosmol/kg, after administartion of vasopressin, greater than 600 mosmol/kg
Nephrogenic- less than 300 mosmol/kg, no change after administration of vaspressin.
will cause water retention and hyponatremia\
Etiology- Post op, intracranial disease like encephalitis, meningitis, head injury, neoplasms like small cell carcinoma of the lung. Pulmonary disease like pneumonia, TB. Drugs/medications
Presentation- Hyponatremia can be asymptomatic or non specific symptoms. Severe hyponatremia especially if there is a rapid fall, can cause neurological symptoms, coma and death.
functions of the thyroid hormones
Essential for normal growth and development, have many metabolic functions, mainly catabolic. stimulate basal metabolic rate. Increase the sensitivty of cardiovascular and nervous system to catecholamines.
important presentation is increased sympathetics. (acts like epinephrine and norepinephrine)
weight loss, palpitations, tachycardia, atrial fibrillation, sweating, heat intolerance, fatigue, generalized muscle weakness, proximal myopathy, diarrhea, lid lag, exophtalmos, Goiter, mesntrual disorders, infertility, effects on heart (arrythmias) and bone (osteoperosis)
Women more than men
Toxicity is caused by excess thyroid hormones
Etiology- grave's disease, most common cause, is an autoimmune disease with HLA associations, casues goiter with diffuse enlargment, characterized by opthalmopathy and pretibial myxedema. Thyroid stimulating Ig which binds to TSH receptors
-toxic multinodular goiter
-thyroiditis (subacute Dequervain') thyroiditis, pain, tenderness, fever. Postpatum throiditis due to natural immunosupression during pregnancy.
-Functional thyroid cancer (produces thyroid hormones.
Clinical features: Lethargy, tiredness, cold intelerance, dryness of skin and hair, hoarsness, weight gain, slow relaxation of tenodn reflexes, psychosis, carpal tunnel syndrome, angina, bradycardia, menstrual disturbances, galactorrhea, infertility, generalized myxedema, hyperprolactinemia.
Etiology: Chronic autoimmune thyroid disease (Haschimoto's disease) Characterized by lympohcytic infiltration, goiter, autoantibodies, HLA association,
-Post surgery, antithyroid drugs, radioactive iodine
-congenital hypothyroidsim- due to anatomic defect in gland or dyshormonogenesis, or idodine deficiency
-pituatary or hypothalamic disease (secondary hypothyroidism)
Complications- Children- cretinism- protruding tongue, dwarf, short limbs, coarse dry skin, lack of hair and teeth, mental deficiency. Pot Belly- often umbilical hernia.
Investigations: TSH measurement. may be sued in screening alone or with FT4 and FT3, measure TSH and FT 4
-measure thyroid autoantibodies- (antimicrosomal and antithyroglubulins for hashimotos,) TSI in graves
-TRH test,, thyroid isotope scan,(both not commonly used) fine needle aspiration(Thyroid cancer)
Gross appearance, fleshy soft plae loblualr noduels that protrude above the cut surface, refelcing the marked lymphoid infiltrate in the gland, the depressed areas in between the pale nodules are due to fibrosis, some cases show a greater degee of fibrosis although the nodularit is fairly uniform it may be asymmetric. presenting as a palpable dominant nodule in some patients.
histo there is a fully developed germinal center.
visible enlargment of the thyroid gland,
assoicated with hyper, hypo or euthyroid state.
-may produce mass effects
-types simple diffuse, simple multinodular, solitary thyroid nodule.
abnormal TFT's in severe illness, could be decreased peripheral conversion of T4 to T3, abnormality of binding protein, oreffects of circulating inflammatory mediators on metabolism of thyroid hormones.
high TSH levels and normal FT4/FT3 levels and is an asymptomatic individuals.
- can convert to hypothyroidism, specially if antithyroid antibodies present
- may be associated with endothelial dysnfucntion which may lead to atheroma,
- treat when TSH is greater than 10mU/L
Tumours of the thyroid gland
tissue diagnosis is a must, due a total thyroidectomy, pateints then receive thyroid hormones to suppress TSH levels
- monitoring TSH, thyroglobulin (should be suppressed.
originates from the parafollicular cells (C cells of the thyroid, they produce calcitonin
- sporadic- 80% of all cases,
-part of multiple endocrine neoplasia syndromes (MEN2A or MEN 2B)
-inherited medullary carcinoma not associated with endocrine disorders
Treatment0 total thyroidectomy, calcitonin is useful in monitoring of treatment.
Adrenal cortex normal
Zona glomerulosa- produces mineralocorticoids
Zona fasciulata, reticularis
-produce the glucocorticoids and androgens
-the adrenal androgens are dehydroepiandrosterone, androstenedione, testosterone small amounts of progestagen and estrogen
insulin antagoinst, anti-inflamamtory, weak mineralcorticosteroid properties
- 95% bound to cortisol binding globulin
- levels of cortisol and testosterone in women are influenced by concentration of binding proteins.
-levels controlled by ACTH and CRH by the negative feedback mechanism
-circadian rythm: highest concentration of ACTH and cortison in the morning and lowest at midnight
-stress can override the circadian rythm
increases sodium reabsorptoin in the kidney in exchange for potassium and hydrogen
-50% bound to albumn
-highest stimulator is renin angiotensins system which is activated by hypotension and sodium loss.
-also stimulated by high potassium and sympathetic nervous system.
exces can cuase precocious puberty in boys and masculinizing effects in women
-transported mainly bound to sex hormone binding globulin (SHBG)
- levels of cortisol and testosterone in women are influenced by concentration of binding proteins.
-controlled by ACTH
the adrenal cortex typically produces small amounts; rarely an estrogen producing tumor produces significant amounts
transported mainly bound to sex hormone binding globulin (SHBG)
Primary Adrencortical insufficiency- Addison's disease
etiology- autoimmune disease affecting the adrenal gland alone or in association with other autoimmune disease like thyroid disease, premature ovarian failure an type 1 DM
-infections like TB, AIDS, Meningitis (causing water house fredericksen syndrome, which cause hemorrhage and destruction of the adrenal glands
- bilateral secondary carcinoma
Clinical features- tiredness, weakness, anorexia, apathy, abdominal pain, hyperpigmentation, postural hypotension
-adrenal crisis- precipiated by infection when they arleady have deficiency, characterized by circulatory shock, volume depletion, anorexia, nausea, and vomiting
Lab investiagtions, low Na, high K, serum bicarb low, BUN- high, morning cortisol, low or normal
-short synacthen test- administration of ATH analouges to asses the residual capacity of adrenal gland
- ACTH levels- high in addisons disease
- High renin activity/ low aldosterone levels
Management- replace glucocorticoids and mineral coritcoids.
Secondary adrenal insufficiency
usually due to a pituitary disorder. not associated with hyperpigmentation due to absence of ACTH or electrolytes disturbances. due to presence of aldosterone
Hyperadrenalism: Cushing's syndrome
causes: exogenous steroids, pituitary dependent, adrenal adenoma, ectopic ACTH
clinical : moon facies, tuncal obesity, buffalo hump, hypertension, thin limbs and muscular weakness, purple striae, fragile skin, psychiatric disturbances, menstrual disturbances, hirsutism.
Diagnosis, exclude exogenous glucocorticoids,
-24 hour urinary free cortisol. commonly used screening test
-1 mg overnight DST (Dexmethsone suppression test). you take a small dose of cortisol like drug, desamethasone at 11 pm and having blood drawn for cortisol the following morning, normal will have very low cortisol levels below 50 nmol/L indicating that the ACTH secretion is suppresed, while cortisol level is not suppresed in patients with cushings
-late night salivary cortisol: new test.
-Low-dose DST, exclude hypercortisolism caused by depression obesity and alcoholism
-midnight serum cortisol.
Differential- source needs to be determined
-ACH-producing pituitary tumor, ectopic ACTH producint, or adrenal gland tumor
-8 mg overnight DST or two day 8 mg DST
- Plasma ACTH
- use MRI or CT scan to locilize lesion
-inferior petrosal sinus sampling: used to identify the source of ACTH secretion, after diagnosis of Cushing's syndrome has been established and no adenoma was found by MRI.
Primary hyperaldosteronism- Conn's syndrome
Etiology: adenoma, hyperplasia, carcinoma
causes sodium retention- complications- hypertension, hypokalemia, metabolic alkalosis
Diagnosis- Aldosterone Rening ratio-Primary
Confirmatory tests- Oral sodium loading test
-flucdrocortisone suppresion test- cause low urinary and plasma aldosterone levels in normal people.
-CT scanning for unilateral or bilateral, micro or macroadenoma or bliateral hyperplasia
-adrenal venous sampling for lateralizing the source of excess aldosterone.
caused by increased activity of renin angiotensin system, in response to decresed effective blood volune as in liver cirrhosis, heart failure and nephrotic syndrome, or due to decreased renal blood flow
Congential adrenal hyperplasia
AR disorder partial enzyme deficieny in synthesis of adrenal steroids
C-21 hydroxylase deficiency
Clincal PresentationGirls- ambiguous genitalia, often born with enlarged clitoris and labia may be paritally fused
-Boys: normal at birth, Penile enlargment, early pubic hair and rapid growth in height when the child is 4 or 5 years old. (NON SALT LOSING)
-Adrenal crisis (Salt losing) occurs when aldosterone production is affected leading to circulatory collapse and vomiting
- late onset- hirsutism, infertility
Investigations- screening by measuring the 17 alpha levels in a blood psot
-prenatal diagnosis, mutational analysis by chorionic villous sampling or amniocentesis, mothers are treated with dexamethasone which is started early.
11 Beta hydroxylase deficiency- causes androgen excess ambiguous genitalia and virilization in femalse, and precocious puberty in males. most have hypertension
17 Alpha hydroxylase deficiency- causes decreased prodcution of glucocorticoids and sex steroids and increased synthesis of mineral coritcoid precursors
-reduce levels of both gonadal and adrenal sex hormones, causes ambiguous genitalia in males, in females you have delayed puberty, absent secondary sex characterisitcs, or primary amenorrhea, excessive mineral corticoid activity, produces varying degrees of hypertension and hypokalemia.