Structure and synthesis of insulin

Normal blood glucose values
Fasting: 72 – 100 mg/dl (4.0 – 5.7 mmol/L)
Random: < 180 mg/dl (10 mmol/L)
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
Gestational DM is typically resolved
after delivery
Features of type1 and type 2 DM

Etiology of Type I DM
caused by immune- mediated destruction of the pancreas
Genetic Etiology of Type I DM
concordance between monozygotic twins is 40%
– association with
HLA-DR3
DR4/DQA1
DQB1
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
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
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.
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
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
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
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.
Pancreatic pathology in DM
Type 2 DM
– Moderate reduction islet tissue
– Variable degrees of deposition of amyloid
Long-term complications diabetes
– Including : nephropathy, neuropathy, eye disease, heart disease, stroke and problems of feet.
Biohemical signs in DM
• Hyperglycaemia: • Glycosuria
• Ketoacidosis
• Ketonuria
• Hyperlactatemia
• Hyperlipidemia
• Hypovolemia
• Hyperosmolarity
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)
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
Oral Glucose Tolerance Test (OGTT) graph

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)
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)
Prediabetic states A1c level
5.7–6.4%
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
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
Elution profile of glycosylated hemoglobin

Acute complications of DM
• Hypoglycemia
– Is a complication of diabetes treatment • Diabetic ketoacidosis
• Hyperosmolar nonketotic coma
• Lactic acidosis
Diabetic Ketoacidosis (DKA) • Precipitating factors
– Infection or acute illness
– Trauma
– Emotional disturbance
– Missed insulin dose
pathophys of DKA

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.
Management of DKA
• Salineinfusiontoreplacefluids
• Restoremetaboliccontrol – Insulin
– potassium supplements
– Bicarbonate “sometimes”
• Occurs in elderly patients with type 2 DM
• Relativeinsulindeficiency-sufficienttoprevent
ketosis but cannot suppress hyperglycaemia
• Usuallyveryhighglucoselevelscausingdehydration
Hyperosmolar hyperglycemic state (HSS)
Hyperosmolar hyperglycemic state (HSS) TX
fluid replacement and insulin
Long-term Complications Microangiopathy
– affects capillaries, arterioles and small blood vessels
– Characterized by thickening of basement membranes, which causes leakiness
– manifestation: retinopathy, nephropathy, neuropathy
Long-term Complications Macroangiopathy
– atherosclerosis in large-to-medium-size arteries that manifests as: ischemic heart disease, Stroke peripheral vascular disease
important cause of end-stage renal failure in diabetics
Diabetic nephropathy
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
Eye complications in diabetics
Diabetic retinopathy, cataract, glaucoma
commonest cause of blindness in adults between 30 and 65 years of age
Diabetic retinopathy
Diabetic neuropathy
causes pain, impotence, orthostatic hypotension, muscle atrophy and weakness
Diabetic foot; Causes
– Ischemia
– Neuropathy
– Infection
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
implicated in some diabetic complications like retinopathy
advanced glycosylation end products
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
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
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.
Anterior pituitary (adenohypophysis) is formed
as an evagination from the roof of the pharynx
Posterior pituitary (neurohypophysis) is formed by
a downgrowth from the floor of the third ventricle of the brain
pituitary gland parts

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
Growth hormone
cell type
Hypothalamic regulatory factor
Acidophil
Growth hormone releasing hormone (stimulatory)
Growth hormone release inhibiting factor (somatostatin- inhibitory)
Prolactin
cell type
Regulatory
Acidophil
Prolcatin release inhibiting hormone
TSH
cell type
Regulation
basophil
thyrotropin release hormone
ACTH
cell type
regulation
basophil
corticotrophin (CRF)
LH
cell type
Regulation
Basophil
GnRH
FSH
Cell type
Regulatory
Basophil
GnRH
Control of secretion of hypothalamic-releasing hormones and the pituitary hormones pic

Most pituitary disorders involve
anterior pituitary
Pituitary disorders
• Usually cause
partial hypopituitarism but they can cause panhypopituitarism
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
Hyperpituitarism
excess production of pituitary hormones by a tumour.
pituitary disease associated with
AIDS, sarcoidosis, hemochromatosis
Causes of hypopituitarism
• Tumors:
adenoma, craniopharyngioma, cerebral and secondary tumors
Causes of hypopituitarism vascular
Sheehan’s syndrome, severe hypotension
Causes of hypopituitarism Infection
meningitis, TB, syphilis, HIV/AIDS
Causes of hypopituitarism Hypothalamic disorders
tumors, functional disorders, isolated deficiency of GHRH and LH/FSH-RH (GnRH secretion)
Causes of hypopituitarism Iatrogenic
irradiation, hypophysectomy
Causes of hypopituitarism Miscellaneous
sarcoidosis, hemochromatosis
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
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.
GH deficiency
– In children causes growth retardation
– In adults - muscle weakness, lethargy and impaired quality of life scores
Loss of adrenal secretions
due to loss of ACTH, leads to hypoadrenalism
Loss of thyroid secretions
due to loss of TSH secretions, leads to hypothyroidism
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.
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)
Investigations of suspected hypopituitarism
Basal levels of pituitary and target hormones
Stimulation and suppression tests
Localization of the tumor
Immunostaining
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
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
Hyperprolactinemia tx
initially medications but surgery may be needed
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 )
–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
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.
Acromegaly: treatment
• Surgical
• Medical
• Radiotherapy
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)
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.
Central DI
caused by absolute deficiency of ADH: – genetic
– hypothalamic or high pituitary stalk lesion
– idiopathic
Nephrogenic DI
caused by resistance to ADH action – genetic
– metabolic: hypokalemia, hypercalcemia
– Drugs: Lithium
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
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.
Water Deprivation Test:Interpretation pic

SIADH results from
inappropriate secretion of ADH i.e. ADH secretion which continues despite lack of physiological stimuli.
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
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
thyroid gland produces
Thyroxine (T4) and tri-iodothyronine (T3)
• 85% of T3 is produced peripherally, by conversion from T4.
synthesize calcitonin
C cells
The structure of thyroid follicle

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
Control of thyroid hormone secretion

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)
Thyrotoxicosis
toxicity caused by excess thyroid hormones, which may be due to a hyperactive thyroid gland; it may be due to exogenous
thyroid hormones
Hyperthyroidism; Causes
Grave’s disease: the most common cause:
toxic adenoma
toxic multinodular goiter
thyroiditis
Functional thyroid cancer (produces thyroid hormones)
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
thyroiditis types
– Subacute (De Quervain’s) thyroiditis: pain, tenderness, fever
– Postpartum thyroiditis due to natural immunosupression during pregnancy
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
Hypothyroidism: Causes
Chronic autoimmune thyroid disease (Hashimoto’s disease)
Post-surgery,antithyroiddrugsorradioactiveiodine
Congenital hypothyroidism
• Iodinedeficiency
• Pituitary or hypothalamic disease (secondary hypothyroidism)
Chronic autoimmune thyroid disease (Hashimoto’s disease) Characterized by
lymphocytic infiltration, goiter, autoantibodies, HLA association
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
Cretinism signs

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)
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
Non-thyroidal illness (NTI)
Abnormal TFTs in severe illness
• (TFTs =Thyroid function tests ie TSH, FT4 and FT3 levels).
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
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
Sub-clinical hypothyroidism associated with
with endothelial dysfunction which may lead to atheroma
Sub-clinical hypothyroidism treated when
Treat when TSH >10 mU/L (Normal below 5 mU/L)
• Characterized by presence of papillae
• They tend to spread to local lymph nodes
Papillary carcinoma
Thyroid cancers benign or malignent
Mostly are benign
well differentiated follicles,which can be difficult o
differentiate from normal thryoid tissue
• Invade the capsules and spread into blood vessels
Follicular carcinoma
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.
Monitor post thyroidectomy
TSH, Thyroglobulin (levels should be suppressed)
Medullary cancer of the thyroid originates from
parafollicular cells (also called C cells) of the thyroid; they produce calcitonin
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
Tx of Medullary carcinoma of the thyroid
total thyroidectomy; Calcitonin measurement is useful in monitoring of treatment
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
Steroid synthesis in adrenal gland

Cortisol effects
– insulin antagonist
– anti-inflammatory
– has weak mineralocorticosteroid properties
Aldosterone effects
increases sodium reabsorption in the kidney in exchange for potassium and hydrogen ions
Androgens effecst
Excess can cause precocious puberty in boys and masculinizing effects in women
Estrogens effects
The adrenal cortex typically produces small amounts; rarely an estrogen-producing tumor produces significant amounts
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
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
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
Androgens- secretion controlled by
ACTH
Underactivity of the adrenal cortex leading to
Primary Adrencortical insufficiency or Addison’s disease
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
Secondary adrenal insufficiency, usually due to
pituitary disorders. Not associated with hyperpigmentation or electrolytes disturbances
Adrenal crisis
often precipitated by infection in a patient with adrenocortical insufficiency; characterized by circulatory shock, volume depletion, anorexia, nausea and vomiting
Clinical features of Addison’s disease
tiredness, weakness, anorexia, apathy, abdominal pain, hyperpigmentation, postural hypotension
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.
Investigations and management of Addison’s disease

Cushing’s syndrome
• Causes:
– Exogenous steroids
– Pituitary dependent
– Adrenal adenoma
– EctopicACTH
– 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
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
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)
Conn’s syndrome
Primary hyperaldosteronism or primary aldosteronism
It causes sodium retention leading to hypertension, hypokalemia and metabolic alkalosis
Hyperaldosteronism adenoma (most common)
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
Congenital adrenal hyperplasia (CAH)
C-21 hydroxylase deficiency
Congenital adrenal hyperplasia (CAH) genetics
Autosomal recessive disorders characterized by partial enzyme deficiency in the synthesis of adrenal steroids
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
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
17hydroxylasedeficiency
• 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
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
Prenatal diagnosis 21-hydroxylase deficiency
mutational analysis obtained by chorionic villous sampling or amniocentesis.
– Mothers are treated with dexamethasone, which is started early
Pheochromocytoma
A tumor of Chromaffin cells.
• Secrets mostly adrenaline and noradrenaline and rarely dopamine
10% rule Pheochromocytoma
• 10% extraadrenal; 10% inherited; 10% malignant; 10% bilateral; 10 in childhood;10% component of multiple endocrine neoplasia, MEN2a and MEN2b
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
Neuroblastoma
occurs mostly in the adrenals, occasionally in the sympathetic chain.
Neuroblastoma in adrenal most common product
Most common product is dopamine and metabolite
homovanillic acid (HVA), but catecholamine's are secreted
Ionized calcium levels are affected by
blood pH; inonization of calcium
is increased in acidosis and decreased in alkalosis
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.
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
Calcitonin
probably not involved in the regulation of calcium metabolism
Hormonal control of calcium metabolism

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
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
Primary hyperparathyroidism
mostly solitary adenoma, rarely hyperplasia or carcinoma
Secondary hyperparathyroidism
is the reaction of the parathyroid glands to a hypocalcemia caused by something other than a parathyroid pathology
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.
Hyperparathyroidism can be part of
multiple endocrine neoplasia (MEN1 and MEN2 syndromes)
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
Investigation and management of hypercalcemia
– Correct dehydartion
– Frusemide
– Biphosphonates
– Calcitonin
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
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.
Hypoparathyroidism congenital issues
DiGeorge
Pseudohypoparathyroidism
decreased responsiveness of target organs because of problems with PTH receptors. Sex-linked; males affected twice as often as females
Hypophosphatemia: causes
• Reducedabsorption: – Malabsorption
• Increasedcellular uptake:
– treated diabetic ketoacidosis, hyperalimentation, alkalosis
• Increasedexcretion:
– hyperparathyroidism, hypomagnesaemia, renal tubular defect, dialysis
• Dilution:
– volume expansion
• Chronic alcohol abuse
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.
Hyperphosphatemia
• Causes
Artefactual – hemolysis or delay in separation of blood samples
• Chronic renal failure
• Hypoparathyroidism
Hyperphosphatemia effects
High plasma calcium and phosphate levels promote metastatic calcification which is defined as the deposition of calcium salts in previously normal tissues
Hypomagnesemia Causes
malabsorption, malnutrition, alcoholism, diuretics,
chronic mineralocorticoid excess
Effects of hypomagnesmia
Tetany, agitation, ataxia, tremors, convulsions
Hypermagnesemia:
• Causes
renal failure is the most important cause
Hypermagnesemia Effects
High levels > 6 mg/L can cause respiratory paralysis and cardiac arrest
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
Type 1(MEN1) is caused by
a mutation in the MEN1, tumor-suppressor gene
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.
MEN1 and MEN2 genetics
autosomal dominant disorders
MEN I (3 Ps) characteristics
characterized by occureceof tumors predominanntly in the anterior pituitary, parathyroid and pancreatic islets
MENIIa (1M,2Ps) classification
MedullaryThyroidCancer(MTC), Pheochromocytoma, Parathyroid adenoma
MENIIb(2Ms,1P) classification
MedullaryThyroidCancer,Marfanoid habitus/mucosal neuroma, Pheochromocytoma
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
In MEN2, carrier detection should be the basis for
recommending thyroidectomy to prevent or cure MTC