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1

Structure and synthesis of insulin

2

Normal blood glucose values

Fasting: 72 – 100 mg/dl (4.0 – 5.7 mmol/L)

Random: < 180 mg/dl (10 mmol/L)

3

Other causes of DM

 

Hormonal/ Genetic syndromes 

– Pancreatic disease

– Hormonal antagonists to insulin (eg, cortisol,

growth hormone, catecholamines)

– Drug - &chemical-induced

– Genetic syndromes: Down’s, turner’s

4

 Gestational DM is typically resolved

after delivery

5

Features of type1 and type 2 DM

6

Etiology of Type I DM

caused by immune- mediated destruction of the pancreas

7

Genetic Etiology of Type I DM

concordance between monozygotic twins is 40%

– association with

HLA-DR3  

DR4/DQA1

DQB1

8

Environmental factors Type I DM

 

Viruses 

Association with viruses: coxsackie B4, Rubella, Mumps

and some drugs and toxins

 

To destroy insulin Rub your Mumps b4 you get kicked in your coxsackie

9

Etiology of Type I DM (2)

• Autoimmunity

islet cell antibodies (ICA), other antibodies against pancreatic components and infiltration of the pancreatic islets by T-cells

– There is a long pre-diabetic phase during which the destruction of Beta cells continues

10

autoimmune system which destroys the pancreas is triggered by

viral or chemical attack on beta cells, leading to exposing new proteins or due to molecular mimicry between viral and beta cell structures. The HLA system is relevant because it is involved in antigen presentation.

11

Etiology and Pathogenesis: Type 2 DM GeneticFactors

– stronger than Type 1 - (80 % concordance in identical

twins).

– no HLA associations

– typically a polygenic disorder: depends on the simultaneous presence of several genes but environmental factors (eg obesity) are involved

12

Etiology and Pathogenesis: Type 2 DM(2) • Environmental factors

– Obesity is associated with around 80% of patients with Type 2 DM.

– More than half of patients with diabetes have BMI between 25 – 29 kg/m2

– Relative risk (RR) for DM for BMI >35kg/m2 100- fold than BMI <22 kg/m2

– DM is rare at BMI 21-22

13

How does obesity lead to DM

Increased production of insulin antagonists, such as fatty acids and tumour necrosis factor (TNF) by adipose

tissue, specially in central obesity

14

Pancreatic pathology in DM

• Type 1 DM

– selective destruction of insulin-secreting beta cells.

– insulitis, a chronic inflammatory infiltrate of the islets affecting primarily insulin containing islets.

15

Pancreatic pathology in DM

Type 2 DM

– Moderate reduction islet tissue

– Variable degrees of deposition of amyloid

16

Long-term complications diabetes

– Including : nephropathy, neuropathy, eye disease, heart disease, stroke and problems of feet.

17

Biohemical signs in DM

• Hyperglycaemia: • Glycosuria

• Ketoacidosis

• Ketonuria

• Hyperlactatemia

• Hyperlipidemia

• Hypovolemia

• Hyperosmolarity

18

Diagnosis of DM

• A1c > 6.5% OR

• Fasting plasma glucose (FPG) level > 126 mg/dL (7 mmol/L) OR

• Two-hour plasma glucose > 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT)

OR

• Classical signs and symptoms (polyuria, polydipsia and unexplained weight loss), plus random glucose level > 200 mg/dL (11.1 mmol/L)

19

Diagnosis of DM

• OGTT (oral glucose tolerance test):

– Patient fasts overnight

– Take basal glucose level

– Give 75 gram glucose and measure blood glucose level at 120 minutes

20

Oral Glucose Tolerance Test (OGTT) graph

21

Prediabetic states • Impaired fasting glycaemia (IFG)

– A fasting plasma glucose above normal and below the diabetic range i.e. FPG > 100mg/dl but < 126 mg/dl (between 5.6 mmol/L and 6.9 mmol/L)

22

Prediabetic states Impaired glucose tolerance (IGT)

– A 2-h value in the OGTT of > 140 mg/dl but < 200

mg/dl (between 7.8 and 11.1 mmol/L, during an OGTT)

23

Prediabetic states A1c level

5.7–6.4%

24

Prediabetic states epi

• 10 -25% of Western populations are IGT or IFG

• 4 - 9% annual conversion of prediabetic state to clinical diabetes

• It is possible to prevent this conversion by

encouraging weight loss through diet, exercise

and medications

25

Glycosylated hemoglobin method

Hemoglobin reacts with glucose non-enzymatically to produce HbA1. HbA1c is the major fraction of glycosylated hemoglobin ( about 5% of total hemoglobin concentration ). HbA1c levels give an integrated measure of glucose concentrations over the previous 2 -3 months

26

Elution profile of glycosylated hemoglobin

27

Acute complications of DM

• Hypoglycemia

– Is a complication of diabetes treatment • Diabetic ketoacidosis

• Hyperosmolar nonketotic coma

• Lactic acidosis

28

Diabetic Ketoacidosis (DKA) • Precipitating factors

– Infection or acute illness

– Trauma

– Emotional disturbance

– Missed insulin dose

29

pathophys of DKA 

30

Pathophysiology of DKA

• Acute insulin deficiency, and the rise in stress hormones levels lead to progressive hyperglycaemia; severe hyperglycemia cause a huge osmotic diuresis and gross dehydration.

• Acute insulin deficiency and the rise in levels of stress hormones (due to cellular starvation and hypovolemia) lead to development of ketosis. Ketosis cause vomiting.

• Electrolyte disturbance is caused by (i) insulin deficiency (ii) osmotic diuresis (iii)vomiting

• Acidosis is caused by (i) ketosis (ii) lactic acidosis, caused by dehydration and vasoconstriction by stress hormones.

31

Management of DKA

• Salineinfusiontoreplacefluids

• Restoremetaboliccontrol – Insulin

– potassium supplements

– Bicarbonate “sometimes”

32

• Occurs in elderly patients with type 2 DM

• Relativeinsulindeficiency-sufficienttoprevent

ketosis but cannot suppress hyperglycaemia

• Usuallyveryhighglucoselevelscausingdehydration

Hyperosmolar hyperglycemic state (HSS)

33

Hyperosmolar hyperglycemic state (HSS) TX

fluid replacement and insulin

34

Long-term Complications Microangiopathy

– affects capillaries, arterioles and small blood vessels

– Characterized by thickening of basement membranes, which causes leakiness

– manifestation: retinopathy, nephropathy, neuropathy

35

Long-term Complications Macroangiopathy

– atherosclerosis in large-to-medium-size arteries that manifests as: ischemic heart disease, Stroke peripheral vascular disease

36

important cause of end-stage renal failure  in diabetics 

Diabetic nephropathy

37

Diabetic nephropathy in end-stage renal failure features  

• Firstfunctionalchange:hyperfiltration

• Microalbuminuria (urinary albumin 30 - 300 mg/day), is the first biochemical sign

• First morphological sign: basement membrane thickening and mesangial expansion. Subsequently nodular deposits and diffuse glomerulosclerosis.

• Proteinuria(urinaryalbumin>300mg/day)is associated with established nephropathy

• Renal impairment is delayed by excellent glucose control and treating hypertension

38

Eye complications in diabetics

Diabetic retinopathy, cataract, glaucoma

39

commonest cause of blindness in adults between 30 and 65 years of age

Diabetic retinopathy

40

Diabetic neuropathy

causes pain, impotence, orthostatic hypotension, muscle atrophy and weakness

41

Diabetic foot; Causes

– Ischemia

– Neuropathy

– Infection

42

Mechanisms of Long-term complications Glycosylation

 Involves basement membrane of capillaries and structural proteins . After glycosylation of proteins, further metabolism of glycosylated proteins produce advanced glycosylation end products (AGE). AGE has been implicated in some diabetic complications like retinopathy

43

 implicated in some diabetic complications like retinopathy

advanced glycosylation end products

44

Mechanisms of Long-term complications Accumulation of sugar alcohols (polyols), in tissues which do not require insulin for glucose uptake

– glucose(sorbitol)fructose

– Sorbitol accumulation cause osmotic effects and depletion of myoinositol, amino acids and potassium. This mechanism is probably involved in mediating neuropathy and cataract

45

Mechanisms of Long-term complications Free radicals

production of free radicals is increased in DM. Free radicals are capable of tissue destruction and they likely contribute to complications in diabetes

46

Mechanisms of Long-term complications Hypertension, dyslipidemia, obesity and insulin resistance

These are associated with DM and they are known risk factors for atherosclerosis. It is therefore likely that they contribute to diabetic complications.

47

Anterior pituitary (adenohypophysis) is formed

 as an evagination from the roof of the pharynx

48

Posterior pituitary (neurohypophysis) is formed by

a downgrowth from the floor of the third ventricle of the brain

49

pituitary gland parts

50

Transport of the hypothalamic releasing and inhibiting hormones

• The hypophyseal portal veins arise from the primary capillary network of the superior hypophyseal arteries in the median eminencethe 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

51

Growth hormone 

cell type

Hypothalamic regulatory factor

Acidophil

Growth hormone releasing hormone (stimulatory)

Growth hormone release inhibiting factor (somatostatin- inhibitory)

52

Prolactin 

cell type 

Regulatory

Acidophil

Prolcatin release inhibiting hormone

53

TSH 

cell type

 Regulation

basophil

thyrotropin release hormone

54

ACTH 

cell type

regulation

basophil

corticotrophin (CRF)

55

LH 

cell type

Regulation

Basophil

GnRH

56

FSH 

Cell type 

Regulatory 

Basophil

GnRH 

57

Control of secretion of hypothalamic-releasing hormones and the pituitary hormones pic

58

Most pituitary disorders involve

anterior pituitary

59

Pituitary disorders

• Usually cause

partial hypopituitarism but they can cause panhypopituitarism

60

Hypopituitarism

underactive pituitary gland, which can result from diseases of the pituitary gland or from diseases of the hypothalamus. The most common cause is a pituitary adenoma

61

Hyperpituitarism

excess production of pituitary hormones by a tumour.

62

pituitary disease associated with

AIDS, sarcoidosis, hemochromatosis 

63

Causes of hypopituitarism

• Tumors:

adenoma, craniopharyngioma, cerebral and secondary tumors

64

Causes of hypopituitarism vascular

 Sheehan’s syndrome, severe hypotension

65

Causes of hypopituitarism Infection

meningitis, TB, syphilis, HIV/AIDS

66

 Causes of hypopituitarism Hypothalamic disorders

tumors, functional disorders, isolated deficiency of GHRH and LH/FSH-RH (GnRH secretion)

67

Causes of hypopituitarism Iatrogenic

irradiation, hypophysectomy

68

Causes of hypopituitarism Miscellaneous

sarcoidosis, hemochromatosis

69

Clinical features of hormone deficiency in the anterior pituitary

 

Hormone deficiency follows the following pattern: LH, GH and FSH, then ACTH, TSH

Vasopressin secretion is usually maintained because the posterior pituitary is typically preserved

70

Deficiency of Gonadotrophins (i.e. LH and FSH) causes:

 

– In females: menstrual disturbance, and delayed puberty

– In males: loss of libido, loss of facial and body hair, impotence.

71

GH deficiency

– In children causes growth retardation

– In adults - muscle weakness, lethargy and impaired quality of life scores

72

Loss of adrenal secretions

due to loss of ACTH, leads to hypoadrenalism

73

Loss of thyroid secretions

due to loss of TSH secretions, leads to hypothyroidism

74

Basal levels of pituitary and target hormones:

These are influenced by

(i) the residual capacity in the pituitary gland, (ii) the pulsatility of pituitary hormone secretion (iii)stress, (iv) time of day e.g. cortisol, (v) time of menstrual cycle e.g. FSH, estrogen, progesterone.

75

combined pituitary function tests

is a stimulation test used to confirm pituitary deficiency:

The test is consisting of the simultaneous administration of insulin, thyrotrophin-releasing hormone (TRH), and luteinizing hormone and follicle stimulating hormone-releasing hormone (LH/FSH-RH)

76

Investigations of suspected hypopituitarism

Basal levels of pituitary and target hormones

Stimulation and suppression tests

Localization of the tumor

Immunostaining

77

Hyperprolactinemia

Causes

Causes:

Stress

• Drugs:

– e.g. antipsychotics, oral contraceptive pill, antidopamine drugs

• Tumors:

– Prolactinoma

– Stalk section which removes inhibitory signal on prolactin secretion

• Renal failure

• Ectopic source

78

Hyperprolactinemia Clinical features and investigation

• Gonadal dysfunction:

– amenorrhea or anovulation, infertility

– decreased libido, erectile impotence in men

• Galactorrhea

• Investigations:

– Blood levels of prolactin –MRI or CT scanning

79

Hyperprolactinemia  tx

 

initially medications but surgery may be needed

80

Acromegaly etiology

occurs due to GH excess after fusion of the epiphysis (gigantism occurs due to GH excess occurring before epiphyseal fusion)

• almost always due to adenoma (v. rarely ectopic GHRH )

81

–increased growth of skeletal and soft tissue, hypertension, arthritis, headaches and local effects of the tumor

– menstrual disturbances, loss of libido and loss of potency in men, diabetes mellitus because GH antagonizes the action of insulin.

Acromeg

82

Acromegaly: diagnosis

Measure GH and IGF-1(Insulin-like growth factor-1):

GH acts on liver to produce IGF-1. IGF-1 level is more stable than GH and therefore more important in diagnosis of acromegaly.

GTT with GH measurement:

In normal individuals, 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 a paradoxical rise in GH suggests acromegaly.

83

Acromegaly: treatment

• Surgical

• Medical

• Radiotherapy

84

The posterior pituitary secretes two hormones

1. Antidiuretic hormone (ADH)

2. Oxytocin

• ADH is clinically important. It's deficiency cause diabetes insipidus (DI).

• In appropriate secretion of ADH causes the syndrome of inappropriate ADH secretion (SIADH)

85

ADH is secreted in response to

decreased blood volume and raised plasma osmolality.

ADH causes water retention by increasing permeability in the distal convoluted tubules and collecting ducts in the kidney. ADH will tend therefore to restore blood volume and normalize plasma osmolality. The action of ADH will cause a decrease in urine volume and increased urinary osmolality.

86

Central DI

caused by absolute deficiency of ADH: – genetic

– hypothalamic or high pituitary stalk lesion

– idiopathic

87

Nephrogenic DI

caused by resistance to ADH action – genetic

– metabolic: hypokalemia, hypercalcemia

– Drugs: Lithium

88

Water Deprivation Test:

• Fluid restriction for 8 hours

• 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 weight hourly for up to 8 hours..

• Stop test after 8 hours or if patient’s weight is <5% off his initial weight.

• If results suggest DI, give Desmopressin:

– Measure plasma osmolality, urine volume and

osmolality

89

In normal patients the serum osmolality should not exceed

295 mosm/kg and the urine osmolality exceeds 600 mosm/kg at some time during the test.

90

Water Deprivation Test:Interpretation pic

91

 SIADH results from

inappropriate secretion of ADH i.e. ADH secretion which continues despite lack of physiological stimuli.

92

Hyponatremia can be asymptomatic or associated with nonspecific symptoms.

– Severe hyponatremia, specially if there is rapid fall in serum sodium, can cause neurological symptoms, coma and death.

SIADH

93

Causes of SIADH

 

– Post-operative

– Intra-cranial disease: encephalitis, meningitis, head injury

– Neoplasms: eg small cell carcinoma of the lung

– Pulmonary disease: pneumonia, tuberculosis

– Drugs/Medications

94

thyroid gland produces 

Thyroxine (T4) and tri-iodothyronine (T3)

• 85% of T3 is produced peripherally, by conversion from T4.

95

synthesize calcitonin

C cells

96

The structure of thyroid follicle

97

Functions of the thyroid hormones

• Essential for normal growth and development

catabolic functions 

• Stimulate basal metabolic rate

• Increase the sensitivity of the cardiovascular and nervous system to catecholamines

98

Control of thyroid hormone secretion

99

Hyperthyroidism (thyrotoxicosis*): Clinical features:

• Weight loss

• palpitations, tachycardia,

• proximal myopathy

• Diarrhea

atrial fibrillation • • sweating, heat intolerance, •

fatigue

• generalized muscle weakness,

Lid-lag

Exophthalmos

• Goiter

• Menstrual disorders and infertility

• Effects on heart (arrhythmias) and bone

(osteoporosis)

100

Thyrotoxicosis

toxicity caused by excess thyroid hormones, which may be due to a hyperactive thyroid gland; it may be due to exogenous

thyroid hormones

101

Hyperthyroidism; Causes

Grave’s disease: the most common cause:

toxic adenoma

 toxic multinodular goiter

 thyroiditis

 

 Functional thyroid cancer (produces thyroid hormones)

102

Grave’s disease

– is an autoimmune disease with HLA associations

– Causes goiter with diffuse enlargement

– Characterized by ophthalmopathy and pretibial myxedema

– thyroid stimulating immunoglobulins which bind TSH receptors

103

thyroiditis types 

– Subacute (De Quervain’s) thyroiditis: pain, tenderness, fever

– Postpartum thyroiditis due to natural immunosupression during pregnancy

104

Hypothyroidism: clinical features

• Lethargy, tiredness

• Cold intolerance

• dryness of skin and hair

• Hoarseness

• Weight gain

• slow relaxation of tendon reflexes

• Psychosis

• Carpal tunnel syndrome • Angina, bradycardia

• Menstrual disturbances • galactorrhea, infertility • Generalized myxedema • Hyperprolactinemia

105

Hypothyroidism: Causes

Chronic autoimmune thyroid disease (Hashimoto’s disease)

Post-surgery,antithyroiddrugsorradioactiveiodine

Congenital hypothyroidism

• Iodinedeficiency

• Pituitary or hypothalamic disease (secondary hypothyroidism)

106

Chronic autoimmune thyroid disease (Hashimoto’s disease) Characterized by

lymphocytic infiltration, goiter, autoantibodies, HLA association

107

Congenital hypothyroidism

is inadequate thyroid hormone production

in newborn infants, because of:

– an anatomic defect in the gland

– Dyshormonogenesis: deficiency of the enzyme that makes thyroid hormones

– iodine deficiency

108

 

Cretinism signs

109

Investigation of thyroid disorders

• TSH measurement: may be used in Screening alone or with measurement of FT4 and FT3.

• You need to measure TSH and FT4 to determine the state of thyroid function (hyper-, hypo-, or euthyroid)

• Thyroidautoantibodies:

– antimicrosomal and antithyroglobulin antibodies are present in

high titres in Hashimoto’s disease

– Thyroid stimulating immunoglobulins (TSI) occur in Grave’s disease

• TRHtest(notcommonlyused)

• Thyroid isotope scan (not commonly used)

• Fine-needle aspiration (in diagnosis of thyroid cancer)

110

Goiter

is any visible enlargement of the thyroid gland.

• A goiter may be associated with hyper-, hypo- or euthyroid state

• Agoitermayproducemasseffects

• Typesofgoiter:

– Simple diffuse goiter

– Simple multinodular goiter – solitary thyroid nodule

111

Non-thyroidal illness (NTI)

Abnormal TFTs in severe illness

• (TFTs =Thyroid function tests ie TSH, FT4 and FT3 levels).

112

Non-thyroidal illness (NTI) Possible mechanisms

– decreased peripheral conversion of T4 to T3

– Abnormality of binding protein

– Effects of circulating inflammatory mediators on metabolism of thyroid hormones

113

Sub-clinical hypothyroidism

high TSH levels and normal FT4/FT3 levels in an asymptomatic individual

• Can convert to hypothyroidism, specially if anti- thyroid antibodies present

114

Sub-clinical hypothyroidism associated with

with endothelial dysfunction which may lead to atheroma

115

Sub-clinical hypothyroidism treated when

Treat when TSH >10 mU/L (Normal below 5 mU/L)

116

• Characterized by presence of papillae

• They tend to spread to local lymph nodes

Papillary carcinoma

117

Thyroid cancers benign or malignent

Mostly are benign

118

 well differentiated follicles,which can be difficult o

differentiate from normal thryoid tissue

• Invade the capsules and spread into blood vessels

Follicular carcinoma 

119

Tumours of the thyroid gland tx 

• Total Thyroidectomy. This operation is designed to remove all of the thyroid gland. It is the operation of choice for all thyroid cancers.

• Patients receive thyroid hormones to suppress TSH levels.

120

Monitor post thyroidectomy

TSH, Thyroglobulin (levels should be suppressed)

121

Medullary cancer of the thyroid originates from

parafollicular cells (also called C cells) of the thyroid; they produce calcitonin

122

Etiology of Medullary carcinoma of the thyroid

– Sporadic- accounts for 80% of all cases of medullary thyroid

cancer.

– Part of Multiple Endocrine Neoplasia Syndromes (MEN 2A or MEN 2B)

– Inherited medullary carcinoma not associated with endocrine disorders

123

Tx of Medullary carcinoma of the thyroid

 total thyroidectomy; Calcitonin measurement is useful in monitoring of treatment

124

The adrenal cortex zones 

• Zona glomerulosa

– produces mineralocorticoids

• Zona fasiculata

• Zona reticularis

– the two inner layers produce glucocorticoids and

androgens:.

– The adrenal androgs are: dehydroepiandrosterone, androstenedione, testosterone

– small amounts of progestagens and estrogens are also produced

125

Steroid synthesis in adrenal gland 

126

Cortisol effects 

– insulin antagonist

– anti-inflammatory

– has weak mineralocorticosteroid properties

127

Aldosterone effects 

increases sodium reabsorption in the kidney in exchange for potassium and hydrogen ions

128

Androgens effecst 

Excess can cause precocious puberty in boys and masculinizing effects in women

129

Estrogens effects 

The adrenal cortex typically produces small amounts; rarely an estrogen-producing tumor produces significant amounts

130

Transport of adrenocortical hormones

• 95% of cortisol is protein-bound; mostly to Cortisol-binding globulin (CBG).

• Aldosterone:

– only 60% bound to albumin

• Adrenal androgens and estrogens:

– are transported mainly bound to Sex Hormone

Binding Globulin (SHBG)

 

LEVELS are related to the amount of binding protein available 

131

Cortisol control secrection

– Level is controlled by ACTH and CRH by the negative feedback mechanism

– circadian rhythm: highest concentration of ACTH and cortisol in the morning and lowest at mid-night

– stress can override the circadian rhythm

132

Control secretion Aldosterone

 primary stimulator of aldosterone synthesis and secretion is the renin-angiotensin system, which is activated in response to hypotension and sodium loss. Also sympathetic nervous system and high potassium concentrations stimulate aldosterone release

133

Androgens- secretion controlled by

ACTH

134

 Underactivity of the adrenal cortex leading to

Primary Adrencortical insufficiency or Addison’s disease

135

Etiology of Primary Adrencortical insufficiency o rAddison’s disease

– autoimmune disease, affecting the adrenal gland alone or in association with other autoimmune diseases eg thyroid disease, premature ovarian failure and type 1 DM

– infections: TB, AIDS, meningitis ( causing Water-house- Fridericksen syndrome), which cause hemorrhage and destruction of the adrenal glands)

– Bilateral secondary carcinoma

136

Secondary adrenal insufficiency, usually due to

pituitary disorders. Not associated with hyperpigmentation or electrolytes disturbances

137

Adrenal crisis

often precipitated by infection in a patient with adrenocortical insufficiency; characterized by circulatory shock, volume depletion, anorexia, nausea and vomiting

138

Clinical features of Addison’s disease

tiredness, weakness, anorexia, apathy, abdominal pain, hyperpigmentation, postural hypotension

139

Secondary adrencortical insufficiency:

Usually due to

pituitary disorders. There is no pigmentation due to absence of ACTH, and initially there are no electrolyte disturbances due to presence of aldosterone.

140

Investigations and management of Addison’s disease

141

Cushing’s syndrome

• Causes:

– Exogenous steroids

– Pituitary dependent

– Adrenal adenoma

– EctopicACTH

142

– Moon facies, truncal obesity, buffalo hump

– Hypertension

– Thin limbs and muscular weakness

– Purple striae, fragile skin

– Impaired glucose tolerance

– Psychiatric disturbances

– Menstrual disturbances, hirsutism

Cushings syndrome 

143

Diagnosis of Cushing’s syndrome

Excludeexogenousglucocorticoids

• Perform one of the following tests to confirm hypercortisolism:

1. 24 hour urinary free cortisol: commonly used screening test

2. 1 mg Overnight DST (Dexamethasone suppression test):

• It involves taking a small dose of a cortisol-like drug called dexamethasone (1 mg) at 11 p.m. and having blood drawn for cortisol the following morning. Normal individuals typically have very low levels of cortisol in these samples (<50 nmol/L), indicating that ACTH secretion is suppressed, while cortisol level is not suppressed in patients with Cushing's disease

3. Late-night salivary cortisol: new test

144

After the diagnosis of Cushing's syndrome is established, the source of excess cortisol needs to be determined

(i) ACH-producing pituitary tumor (ii) ectopic ACTH production or (iii) adrenal gland tumor:.

8 mg over night DST or two day 8 mg DST PlasmaACTH

Localization: MRI or CT scan

Inferior petrosal sinus sampling: used to identify the source of the ACTH secretion, after diagnosis of Cushing's syndrome has been established (if no adenoma was found by MRI)

145

Conn’s syndrome

Primary hyperaldosteronism or primary aldosteronism

146

It causes sodium retention leading to hypertension, hypokalemia and metabolic alkalosis

Hyperaldosteronism adenoma (most common)

147

Hyperaldosteronism diagnosis

Aldosterone : renin ratio (ARR)

Confirm test:

Oral sodium loading test

Fludrocortisone suppression test

Ct scan

Adrenal venous sampling for lateralizing the source of excess aldosterone 

148

Congenital adrenal hyperplasia (CAH)

C-21 hydroxylase deficiency

149

Congenital adrenal hyperplasia (CAH) genetics 

Autosomal recessive disorders characterized by partial enzyme deficiency in the synthesis of adrenal steroids

150

C-21 hydroxylase deficiency clinical features 

1.

Simple virilizing (non salt-losing CAH):

– Girls: ambiguous genitalia. (often born with an enlarged clitoris and the labia may be partially fused

– Boys: Normal at at birth. Penile enlargement, early pubic hair and rapid growth in height when the child is 4 or 5 years old.

Adrenal crisis (salt-losing CAH): occurs when aldosterone production is affected leading to circulatory collapse, vomiting

late-onset CAH: hirsutism, infertility

151

11 hydroxylase deficiency

Deficiency causes features of androgen excess, including ambiguous genitalia and virilization in females and precocious puberty in male children. Most patients also have hypertension

152

17hydroxylasedeficiency

• Deficiency causes decreased production of glucocorticoids and sex

steroids and increased synthesis of mineralocorticoid precursors.

• Reduced levels of both gonadal and adrenal sex hormones result in ambiguous genitalia in males. In females, there is delayed puberty, absent secondary sexual characteristics, or primary amenorrhea. Excessive mineralocorticoid activity produces varying degrees of hypertension and hypokalemia

153

Investigation of CAH due to 21- hydroxylase deficiency

diagnosis made by finding of high level of 17  hydroxyprogesterone in blood in a morning sample. In borderline cases, Short synacthen test with measurement of 17  hydroxyprogesterone in blood before and after administration of synacthen

154

Prenatal diagnosis 21-hydroxylase deficiency

mutational analysis obtained by chorionic villous sampling or amniocentesis.

– Mothers are treated with dexamethasone, which is started early

155

Pheochromocytoma

A tumor of Chromaffin cells.

• Secrets mostly adrenaline and noradrenaline and rarely dopamine 

156

10% rule Pheochromocytoma

 

• 10% extraadrenal; 10% inherited; 10% malignant; 10% bilateral; 10 in childhood;10% component of multiple endocrine neoplasia, MEN2a and MEN2b

157

Investigations of pheochromocytoma

• Measure catecholamines and their metabolites in a 24- hour urine collection

• MRI or CT scanning: for localization of tumor

• 123I-metaiodobenzylguanidine(MIBG)scintigraphy:

– MIBG selectively concentrates in APUD system (Amine Precursor Uptake & Decarboxylation system)

– used selectively, such as for the rare patient with a biochemical diagnosis of pheochromocytoma and no tumor seen on exhaustive anatomical imaging.

• Selectivevenoussampling:

– used for patients in whom standard techniques fail to localize the tumour

158

Neuroblastoma

occurs mostly in the adrenals, occasionally in the sympathetic chain.

159

Neuroblastoma in adrenal most common product 

Most common product is dopamine and metabolite

homovanillic acid (HVA), but catecholamine's are secreted

160

Ionized calcium levels are affected by

blood pH; inonization of calcium

is increased in acidosis and decreased in alkalosis

161

Parathyroid hormone

hypercalcemic hormone; it’s release is regulated by the level of ionized calcium in the blood. It acts on bone to release calcium and on the kidney to increase calcium reabsorption and decrease reabsorption of phosphates and bicarbonates.

• It activates vitamin D in the kidney.

162

1,25-Dihydroxycholecalciferol

Activated vitamin D acts on the gut to enhance absorption of calcium and phosphates and acts on bone to facilitate bone resorption and release of calcium

163

Calcitonin

probably not involved in the regulation of calcium metabolism

164

Hormonal control of calcium metabolism

165

Hypercalcemia: causes

1. Hyperparathyroidism 2. Malignantdisease

• Other causes:

• Excessive vitamin D:-vitamin D intoxication

• Granulomas (tuberculosis, lymphoma, sarcoidosis) because they activate vitamin D

• Highboneturnover – thyrotoxicosis

– Paget’s disease

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Hyperclacaemia: clinical features

1. Asymotomatic: One half of patients are asymptomatic

2. Renal

– Polyuria and thirst

– Stones

– Nephrocalcinosis; deposition f calcium crystals in kidney – May lead to renal failure

3. Musculoskeletal

– Muscle weakness

– Rarely demineralization, subperiosteal bone resorption, bone cysts (osteitis fibrosa cystica)

4. Neurological

– Psychiatric/neurological symptoms

5. Gastrointestinal

– Anorexia, constipation and ulcers

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 Primary hyperparathyroidism

mostly solitary adenoma, rarely hyperplasia or carcinoma

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Secondary hyperparathyroidism 

 is the reaction of the parathyroid glands to a hypocalcemia caused by something other than a parathyroid pathology

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Tertiary hyperparathyroidism

occurs when PTH increases to maintain normocalcemia in the setting of vitamin D deficiency ; eventually parathyroid hyperplasia occurs and PTH secretion becomes independent of calcium level; often seen in patients with chronic renal failure.

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Hyperparathyroidism can be part of

multiple endocrine neoplasia (MEN1 and MEN2 syndromes)

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Malignancy induced hypercalcemia 

Bone mets: Local cytokine secretion or protaglandin producion causes bone destruction 

Humoral hypercalcemia of malignancy- Solid tumors secrete parathyroid hormone 

1,25- dihydroxy vitamin D induced hypercalcemia secondary to lymphomas exrpresss 1 a-hydroxylase 

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Investigation and management of hypercalcemia

– Correct dehydartion

– Frusemide

– Biphosphonates

– Calcitonin

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Hypocalcaemia 

• Causes

• Hypoalbuminemia (will cause a low total plasma calcium but

the ionized calcium level will be normal)

• ChelationbyEDTA

• PTH-related: hypoparathyroidism, pseudohypoparathyroidism, hypomagnesemia

• Defect in vitamin D metabolism: rickets, osteomalacia, Chronic renal failure, vitamin D resistant rickets, liver disease, anticonvulsive therapy

• Acute pancreatitis

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Hypocalcaemia Clinical features

increased neuromuscular excitability with tetany, parathesiae and muscle cramps.

• prolonged hypocalcaemia is associated with cataract, mental retardation, psychosis, increased intracranial pressure and seizures.

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Hypoparathyroidism congenital issues 

DiGeorge 

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Pseudohypoparathyroidism

 decreased responsiveness of target organs because of problems with PTH receptors. Sex-linked; males affected twice as often as females

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Hypophosphatemia: causes

• Reducedabsorption: – Malabsorption

• Increasedcellular uptake:

– treated diabetic ketoacidosis, hyperalimentation, alkalosis

• Increasedexcretion:

– hyperparathyroidism, hypomagnesaemia, renal tubular defect, dialysis

• Dilution:

– volume expansion

• Chronic alcohol abuse

 

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Hypophosphatemia: effects

• Muscleweakness • Hemolysis

– depletion of 2,3-diphosphoglycerate • Respiratoryfailure

– Severe hypophosphatemia in critically ill patients

• Rhabdomyolysis: is the rapid breakdown of skeletal muscle tissue. Myoglobin released by muscle destruction may lead to acute renal failure.

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Hyperphosphatemia

• Causes

Artefactual – hemolysis or delay in separation of blood samples

• Chronic renal failure

• Hypoparathyroidism

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Hyperphosphatemia effects

High plasma calcium and phosphate levels promote metastatic calcification which is defined as the deposition of calcium salts in previously normal tissues

181

Hypomagnesemia Causes

malabsorption, malnutrition, alcoholism, diuretics,

chronic mineralocorticoid excess

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Effects of hypomagnesmia

Tetany, agitation, ataxia, tremors, convulsions

183

Hypermagnesemia:

• Causes

renal failure is the most important cause

184

Hypermagnesemia Effects

High levels > 6 mg/L can cause respiratory paralysis and cardiac arrest

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Multiple endocrine neoplasia

Two or more endocrine tumor types, occur as a part of one of the defined MEN syndromes, in a single patient and there is evidence for either a causative mutation or hereditary transmission

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Type 1(MEN1) is caused by

a mutation in the MEN1, tumor-suppressor gene

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type 2 (MEN2) is caused by

mutations in the RET proto-oncogene. MEN2 has three clinical variants referred to as MEN2A, MEN2B and MTC only.

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MEN1 and MEN2 genetics 

autosomal dominant disorders

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MEN I (3 Ps) characteristics 

characterized by occureceof tumors predominanntly in the anterior pituitary, parathyroid and pancreatic islets

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MENIIa (1M,2Ps) classification 

MedullaryThyroidCancer(MTC), Pheochromocytoma, Parathyroid adenoma

191

MENIIb(2Ms,1P) classification

MedullaryThyroidCancer,Marfanoid habitus/mucosal neuroma, Pheochromocytoma

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Multiple endocrine neoplasia (MEN1) seen in

• Parathyroidtumors

• Entero-pancreatic endocrine tumors (Gastrinoma, Insulinoma, Vipoma, Glucagonoma)

• Pituitarytumor(mostlyprolactinoma).

• Other endocrine and non-endocrine neoplasms including

adrenocortical and thyroid tumors, lipomas, and carcinoids

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In MEN2, carrier detection should be the basis for

recommending thyroidectomy to prevent or cure MTC