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Pituitary Adrenal
Thyroid
PMS Adrenal and Thyroid cases
HYPOTHALAMUS
0.5cm
CSF
CSF
SPHENOID
SINUS
SELLA TURCICA
ANT POST
PITUITARY
OPTIC
CHIASMA
Hypothalamus
Pituitary
Target Gland
CNS inputs
Hypothalamic
hormones
Intrapituitary
cytokines
Peripheral
hormones
Pituitar...
Control of Pituitary
Hormone Secretion
Hypothalamic/pituitary/end organ axis
Points to note
- CNS inputs
- pulsatile secre...
Hormone Structure
HYPOTHALAMIC
Hormone Amino acids Notes
GnRH 10 High potency
Analogues available
TRH 3 Use in TRH test
GH...
Anterior Pituitary Hormones
LH - Glycoproteins (30% CHO)
FSH - ≅ 30000 mw
TSH α + β subunits (15000 mw)
(HCG) common hormo...
Prolactin
• Single chain polypeptide
• mw ≅ 22,500
• High mw forms present
• Homology with HGH, HPL
ACTH
• Single chain polypeptide 39AA (mw = 4541)
• 24 N terminal AA for biological activity
• Large family of precursors a...
Growth Hormone
• Single chain polypeptide (mw 22,000)
• Multiple molecular weight variants present
in plasma
• Homology wi...
Synthesis of Pituitary Hormones
Cell type % in pituitary
LH Gonadotrophs 5 - 10
FSH
Prolactin Lactotrophs 10 - 25
TSH Thyr...
Hypothalamus (+ve) Pituitary Hypothalamus (-ve)
GnRH LH
FSH
GABA
Prolactin Dopamine
TRH TSH
Growth hormone Somatostatin
GH...
Intrapituitary cytokines
• The net secretion of pituitary hormones is determined from
signals from
– Hypothalamus
– Intrap...
Presentation of Pituitary Tumours
Space-occupying effects
• Headache
• Visual field defects
• Disorders of eye movement
Sy...
Types of pituitary adenomas
Prolactinomas
50-55%
Somatotroph
20-23%
Gonadotroph
< 5%
Non-functional
20-25%
Corticotroph
5-...
Investigation of
Pituitary Tumours
• CT/MRI scan
• Visual fields
• Endocrine
Treatment
• Medical therapy
– Bromocriptine
–...
Hypopituitarism
total selective
Causes
Infection
Infarction
Cysts, Tumours, Pituitary surgery or irradiation
Head injury
L...
Assessment of hypothalamic
pituitary end organ axis
1. Baseline hormone levels
- pituitary
- end organ
2. Dynamic function...
Measurement of anterior
pituitary hormones
1. Baseline measurements
ACTH (Cortisol 9am, 12mn), TSH (T4), Prolactin, LH/FSH...
Measurement factors
1. Patient - pulsitility
- diurnal/(monthly) variation
- stress, drugs etc.
2. Samples - serum/plasma
...
Thyroid
Thyroid
• Largest Endocrine organ in the body
• Involved in production, storage, and release
of thyroid hormone
• Function...
Thyroid (cont)
• Regulates basal metabolic rate
• Improves cardiac contractility
• Increases the gain of catecholamines
• ...
Secretion of Thyroid Hormone
• Stimulated by TSH
• Endocytosis of colloid on apical membrane
• Coupling of MIT & DIT resid...
Thyroid Hormones
Thyroid Hormone
– Majority of circulating hormone is T4
• 98.5% T4
• 1.5% T3
– Total Hormone load is influenced by serum b...
Hormone Binding Factors
• Increased TBG
– High estrogen states (pregnancy, OCP, HRT, Tamoxifen)
– Liver disease (early)
• ...
Thyroid Hormone Control
Thyroid Lab Evaluation
• TRH
• TSH
• FT3, FT4
• TPO Ab, Thyroglobulin Ab
• Stimulation Tests
Hypothyroid
• Symptoms – fatigability, coldness, weight gain,
constipation, low voice
• Signs – Cool skin, dry skin, swell...
Hypothyroid
• Cause is determined by
geography
• Diagnosis
– Low FT4, High TSH (Primary,
check for antibodies)
– Low FT4, ...
Hashimoto’s
(Chronic, Lymphocytic)
• Most common cause of hypothyroidism
• Result of antibodies to TPO, TBG
• Commonly pre...
Goiter
• Endemic goiter
– Caused by dietary deficiency of Iodide
– Increased TSH stimulates gland growth
– Also results in...
Hyperthyroid
• Symptoms – Palpitations, nervousness, fatigue,
diarrhea, sweating, heat intolerance
• Signs – Thyroid enlar...
Hyperthyroid
• Common Causes
– *Graves
– Adenoma
– Multinodular Goiter
– *Subacute Thyroiditis
– *Hashimoto’s Thyroiditis
...
Graves
• Most common cause of hyperthyroidism
• Result of anti-TSH receptor antibodies
• Diagnosis
– Symptoms of hyperthyr...
Subacute Thyroiditis
(DeQuervain’s, Granulomatous)
• Acute viral infection of thyroid gland
• Presents with viral prodrome...
Subacute Thyroiditis
(DeQuervain’s, Granulomatous)
Euthyroid Sick
• Results from inactivation of 5’-Deiodinase, resulting
in conversion of FT4 to rT3.
• Generally occurs in ...
Thyroid Storm
• Causes
– Surgery
– Radioactive Iodine Therapy
– Severe Illness
• Diagnosis
– Clinical – tachycardia, hyper...
Adrenal Disease
• Clinical manifestations result from:-
– Overproduction or deficiency of: -
• Glucocorticoids
• Mineraloc...
Adrenal Disease
• Causes of dysfunction: -
– Hyper-secretion:-
• Primary adrenal pathology:-
– Adenoma
– Hyperplasia
– Car...
Adrenal Disease
– Hypo-function:-
• Primary adrenal dysfunction: -
– Autoimmune
– Infiltration
– Infection
– Enzyme defici...
Adrenal Disease
• General Concept for Investigations: -
• Establish Hyper - or Hypo-function: -
– Use screening tests:-
• ...
Investigation of Adrenal Disease
• Requires knowledge of: -
– Biological rhythms
– Concept of feedback controls
• Limitati...
Glucocorticoid Excess
• Cushing’s syndrome:-
– Features of glucocorticoid excess.
– Low ACTH.
– High ACTH: ectopic or exog...
Cushing's Syndrome
• Epidemiology:
– Prevalence 1/100.000
• Age:
– Cushing’s disease 25-45 years old.
– Ectopic ACTH 40-65...
Cushing’s Syndrome
Clinical Features
• Skin
– Thin Skin
– Hirsutes
– Acne
– Striae
– Bruising
• Cardio-vascular
– Hyperten...
Cushing’s Syndrome
Laboratory Findings: Non-Endocrine
• Haematology:
– Polycythaemia, leucocytosis, low eosinophil count
•...
Screening for Cushing’s Syndrome
• Low dose dexamethasone suppression test.
Ann Clin Biochem 1997;34:222-229.
– Procedure:...
Screening for Cushings Syndrome
• Low dose dexamethasone suppression test.
– Drug effects = false positive:-
• Oestrogen &...
Screening for Cushing's Syndrome
• Urinary Free Cortisol: -
– 24 hour collection to give an integrated result.
– Reference...
Screening for Cushing's Syndrome
• Diurnal variation: -
– Serum Cortisol at Midnight and 09.00h.
• Avoid stress.
– Normal:...
Differential Diagnosis of Cushing’s
Syndrome
• Primary Adrenal disease? Non-ACTH
dependant.
– ACTH measurement = low.
– Hi...
Differential Diagnosis of Cushing’s
Syndrome
• High dose dexamethasone: -
– Helps differentiate between pituitary and
ecto...
Differential Diagnosis of Cushing’s
Syndrome
• High dose dexamethasone Cont.: -
– Cushing’s disease (pituitary adenoma):-
...
Differential Diagnosis of Cushing’s
Syndrome
• Imageing: -
– Adrenal CT: Adenoma, carcinoma
– Pituitary CT/MRI: Adenoma
– ...
Adrenal Failure
• Epidemiology:
– Prevalence 5/100,000
• Sex:
– Autoimmune Addison’s more common in women
• Genetics
– May...
Adrenal Failure
Clinical Features
• Early:
– Anorexia, lethargy &
weakness.
• Skin:
– Hyperpigmentation
• Sun exposed area...
Adrenal Failure
Laboratory Findings: Non-Endocrine
• Haematology:
– Lymphocytosis & eosinophilia
• Biochemistry:
– hyperka...
Adrenal Failure.
Aetiology.
• Primary Adrenal Failure
– 75% Auto-immune
– 20% Tuberculosis
– 5% Rare destructive processes...
Adrenal Failure.
Endocrine Investigation .
• Test adrenal reserve.
• Random and “normal” 09.00h serum
cortisol may be misl...
Investigation Adrenal Failure.
Endocrine Investigation.
• Establish whether patient is receiving
steroid replacement.
– Pr...
Adrenal Failure.
Endocrine Investigation .
• Establish Deficiency: -
– Short Synacthen test:-
– Can be performed at any ti...
Adrenal Failure.
Endocrine Investigation .
• Primary or Secondary Failure: -
– Patient history
– Previous steroid therapy....
Mineralocorticoid Excess.
• Primary hyperaldosteronism :-
– Overproduction of aldosterone independent of it’s
normal chron...
Mineralocorticoid Excess.
• Secondary hyperaldosteronism: -
• High Aldosterone
• High or Inappropriate Plasma Renin
– Rena...
Mineralocorticoid Excess.
When to Investigate?
• Hypertension: -
– Long-standing & resistant to drugs
• Hypokalaemia and a...
Mineralocorticoid Excess.
When to Investigate?
• Inappropriate loss of urine potassium in the
presence of K+ deficit (Urin...
Mineralocorticoid Excess.
Biochemical diagnosis.
• Plasma aldosterone, Plasma Renin Activity (PRA) and
K+
from a supine pa...
Mineralocorticoid Excess.
Biochemical diagnosis.
• Stop diuretics: -
– Spiranolactone, amilioride & triamterine
• Reduce c...
Mineralocorticoid Excess.
Biochemical diagnosis.
• Primary hyperaldosteronism: -
– Raised/Normal Aldosterone
– Suppressed/...
CASE 4A
A 47 year old smoker with a history of asbestos exposure presented with a 6 month history of
lethargy, headache, w...
CASE 4
1. The patients symptoms are lethargy, headache, weight loss and erectile impotence.
The lethargy could be explaine...
CASE 4B
Following removal of a cystic mass from the pituitary, combined pituitary function tests using insulin, GnRH
and T...
CASE 4 cont.
4. Prior to the performance of a combined pituitary function test the patient should be resting and
under no ...
CASE 5
After stopping a combined oral contraceptive pill a 25 year old local health authority worker
presented with an eig...
CASE 5
1. Yes, the serum glucose has fallen to 1.2 mmol/l which is well within the
hypoglycaemic range.
2. Yes, the serum ...
CASE 6
A 33 year old warehouseman presented to his GP with a 3 year history of weight gain, increasing
thirst and polyuria...
CASE 6
1. The patients symptoms and the presence of a high serum osmolality without
concentration of the urine suggests a ...
Pituitary Adrenal Thyroid Axis
Pituitary Adrenal Thyroid Axis
Pituitary Adrenal Thyroid Axis
Pituitary Adrenal Thyroid Axis
Pituitary Adrenal Thyroid Axis
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Pituitary Adrenal Thyroid Axis

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Short Endocrine Lecture

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Pituitary Adrenal Thyroid Axis

  1. 1. Pituitary Adrenal Thyroid PMS Adrenal and Thyroid cases
  2. 2. HYPOTHALAMUS 0.5cm CSF CSF SPHENOID SINUS SELLA TURCICA ANT POST PITUITARY OPTIC CHIASMA
  3. 3. Hypothalamus Pituitary Target Gland CNS inputs Hypothalamic hormones Intrapituitary cytokines Peripheral hormones Pituitary trophic hormones Secretion of pituitary hormones determined by - hypothalamic hormones - intrapituitary factors - peripheral feedback
  4. 4. Control of Pituitary Hormone Secretion Hypothalamic/pituitary/end organ axis Points to note - CNS inputs - pulsatile secretion - negative feedback - diurnal/monthly rhythms - stress - drugs
  5. 5. Hormone Structure HYPOTHALAMIC Hormone Amino acids Notes GnRH 10 High potency Analogues available TRH 3 Use in TRH test GHRH 44 Analogues available CRH 41 Use in CRH test GHRIH 14 + 28 (Somatostatin) Dopamine = Dihydroxyphenyl-ethylamine (Catecholamine)
  6. 6. Anterior Pituitary Hormones LH - Glycoproteins (30% CHO) FSH - ≅ 30000 mw TSH α + β subunits (15000 mw) (HCG) common hormone specific
  7. 7. Prolactin • Single chain polypeptide • mw ≅ 22,500 • High mw forms present • Homology with HGH, HPL
  8. 8. ACTH • Single chain polypeptide 39AA (mw = 4541) • 24 N terminal AA for biological activity • Large family of precursors and related peptides
  9. 9. Growth Hormone • Single chain polypeptide (mw 22,000) • Multiple molecular weight variants present in plasma • Homology with HPL (85%) + Prolactin (16%)
  10. 10. Synthesis of Pituitary Hormones Cell type % in pituitary LH Gonadotrophs 5 - 10 FSH Prolactin Lactotrophs 10 - 25 TSH Thyrotrophs 5 - 15 GH Somatotrophs 35 - 45 ACTH Corticotrophs 1 - 2
  11. 11. Hypothalamus (+ve) Pituitary Hypothalamus (-ve) GnRH LH FSH GABA Prolactin Dopamine TRH TSH Growth hormone Somatostatin GHRH ACTH CRH + Other factors Vasopressin
  12. 12. Intrapituitary cytokines • The net secretion of pituitary hormones is determined from signals from – Hypothalamus – Intrapituitary factors – Feedback mechanisms • Intrapituitary control by cytokines is an important control mechanism for pituitary hormone secretion • Several of these cytokines signal through a common receptor subunit (GP 130) linked to the Janus kinase signal transduction activation transcription cascade (JAK-STAT) • ACTH and GH are induced by cytokines in this group including IL6 and leukaemia inhibitory factor
  13. 13. Presentation of Pituitary Tumours Space-occupying effects • Headache • Visual field defects • Disorders of eye movement Syndromes of pituitary hormone hypersecretion • Prolactinoma • Acromegaly • Cushings Disease • TSH, LH, FSH secreting adenomas Hypopituitarism Pituitary apoplexy Incidental finding
  14. 14. Types of pituitary adenomas Prolactinomas 50-55% Somatotroph 20-23% Gonadotroph < 5% Non-functional 20-25% Corticotroph 5-8% Thyrotroph < 1%
  15. 15. Investigation of Pituitary Tumours • CT/MRI scan • Visual fields • Endocrine Treatment • Medical therapy – Bromocriptine – Somatostatin analogues – Metyrapone • Surgery • Radiotherapy
  16. 16. Hypopituitarism total selective Causes Infection Infarction Cysts, Tumours, Pituitary surgery or irradiation Head injury LH/FSH ↓ - Fertility (hypogonadism) GH ↓ - ↓ Growth in children Non specific effects in adults ACTH ↓ - Adrenal dysfunction TSH ↓ - Hypothyroidism Treatment by oral replacement of steroid or thyroid hormones GH injections
  17. 17. Assessment of hypothalamic pituitary end organ axis 1. Baseline hormone levels - pituitary - end organ 2. Dynamic function tests
  18. 18. Measurement of anterior pituitary hormones 1. Baseline measurements ACTH (Cortisol 9am, 12mn), TSH (T4), Prolactin, LH/FSH (Testosterone, Oestradiol) 2. Dynamic function tests Why? - low pituitary hormone levels not diagnostic - normal levels do not exclude pituitary disease - pulsatile excretion + diurnal variation confuse interpretation of baseline levels - if baseline levels are high dynamic tests can aid in differential diagnosis Hypofunction → stimulation tests Hyperfunction → suppression tests
  19. 19. Measurement factors 1. Patient - pulsitility - diurnal/(monthly) variation - stress, drugs etc. 2. Samples - serum/plasma - storage at 4°C for 2-3 days and -20°C for extended periods ACTH → -70°C 3. Assay - competitive immunoassay - 2 site immunometric assay - bioassay - in vitro, in vivo 4. Ref. ranges - units (IU/l for most pituitary hormones) - age, sex, time of day, time of month, etc
  20. 20. Thyroid
  21. 21. Thyroid • Largest Endocrine organ in the body • Involved in production, storage, and release of thyroid hormone • Function influenced by – Central axis (TRH) – Pituitary function (TSH) – Comorbid diseases (Cirrhosis, Graves, etc.) – Environmental factors (iodine intake)
  22. 22. Thyroid (cont) • Regulates basal metabolic rate • Improves cardiac contractility • Increases the gain of catecholamines • Increases bowel motility • Increases speed of muscle contraction • Decreases cholesterol (LDL) • Required for proper fetal neural growth
  23. 23. Secretion of Thyroid Hormone • Stimulated by TSH • Endocytosis of colloid on apical membrane • Coupling of MIT & DIT residues – Catalyzed by TPO – MIT + DIT = T3 – DIT + DIT = T4 • Hydrolysis of Thyroglobulin • Release of T3, T4 • Release inhibited by Lithium
  24. 24. Thyroid Hormones
  25. 25. Thyroid Hormone – Majority of circulating hormone is T4 • 98.5% T4 • 1.5% T3 – Total Hormone load is influenced by serum binding proteins (TBP, Albumin, ??) • Thyroid Binding Globulin 70% • Albumin 15% • Transthyretin 10% – Regulation is based on the free component of thyroid hormone
  26. 26. Hormone Binding Factors • Increased TBG – High estrogen states (pregnancy, OCP, HRT, Tamoxifen) – Liver disease (early) • Decreased TBG – Androgens or anabolic steroids – Liver disease (late) • Binding Site Competition – NSAID’s – Furosemide IV – Anticonvulsants (Phenytoin, Carbamazepine)
  27. 27. Thyroid Hormone Control
  28. 28. Thyroid Lab Evaluation • TRH • TSH • FT3, FT4 • TPO Ab, Thyroglobulin Ab • Stimulation Tests
  29. 29. Hypothyroid • Symptoms – fatigability, coldness, weight gain, constipation, low voice • Signs – Cool skin, dry skin, swelling of face/hands/legs, slow reflexes, myxedema • Newborn – Retardation, short stature, swelling of face/hands, possible deafness • Types of Hypothyroidism – Primary – Thyroid gland failure – Secondary – Pituitary failure – Tertiary – Hypothalamic failure – Peripheral resistance
  30. 30. Hypothyroid • Cause is determined by geography • Diagnosis – Low FT4, High TSH (Primary, check for antibodies) – Low FT4, Low TSH (Secondary or Tertiary, TRH stimulation test, MRI) • Treatment – Levothyroxine (T4) due to longer half life – Treatment prevents bone loss, cardiomyopathy, myxedema
  31. 31. Hashimoto’s (Chronic, Lymphocytic) • Most common cause of hypothyroidism • Result of antibodies to TPO, TBG • Commonly presents in females 30-50 yrs. • Usually non-tender and asymptomatic • Lab values – High TSH – Low T4 – Anti-TPO Ab – Anti-TBG Ab • Treat with Levothyroxine
  32. 32. Goiter • Endemic goiter – Caused by dietary deficiency of Iodide – Increased TSH stimulates gland growth – Also results in cretinism • Goiter in developed countries – Hashimoto’s thryoiditis – Subacute thyroiditis • Other causes – Excess Iodide (Amiodarone, Kelp, Lithium) – Adenoma, Malignancy – Genetic / Familial hormone synthesis defects
  33. 33. Hyperthyroid • Symptoms – Palpitations, nervousness, fatigue, diarrhea, sweating, heat intolerance • Signs – Thyroid enlargement (?), tremor • Lab workup – TSH – FT4 – TPO TSI – FT3 – FNA – MRI, US
  34. 34. Hyperthyroid • Common Causes – *Graves – Adenoma – Multinodular Goiter – *Subacute Thyroiditis – *Hashimoto’s Thyroiditis • Rare Causes – Thyrotoxicosis factitia, struma ovarii, thyroid metastasis, TSH-secreting tumor
  35. 35. Graves • Most common cause of hyperthyroidism • Result of anti-TSH receptor antibodies • Diagnosis – Symptoms of hyperthyroidism – Clinical exopthalmos and goiter – Low TSH, normal/high FT4, TSI (Optional) • If no clinical findings I123 may demonstrate increased uptake. • Treatments – Medical – Propothyouracil, Methimazole, Propranolol – Surgical – Subtotal Thyroidectomy – Radiation – RAI ablation [I131 (µCi/g) x weight / %RAIU]
  36. 36. Subacute Thyroiditis (DeQuervain’s, Granulomatous) • Acute viral infection of thyroid gland • Presents with viral prodrome, thyroid tenderness, and hyperthyroid symptoms • Lab values – Variable TSH, T4 – High ESR – No antibodies • Treatment – APAP, NSAID – Prednisone (?) – Levothyroxine (?)
  37. 37. Subacute Thyroiditis (DeQuervain’s, Granulomatous)
  38. 38. Euthyroid Sick • Results from inactivation of 5’-Deiodinase, resulting in conversion of FT4 to rT3. • Generally occurs in critically ill patients, but may occur with DM, malnutrition, iodine loads, or medications (Amiodarone, PTU, glucocorticoids) • Treatment – Avoid above medications – Treat primary illness – T3, T4 not helpful
  39. 39. Thyroid Storm • Causes – Surgery – Radioactive Iodine Therapy – Severe Illness • Diagnosis – Clinical – tachycardia, hyperpyrexia, thyrotoxicosis symptoms – Labs (Low TSH, High T4, FT4) • Treatment – Propranolol IV vs. Verapamil IV – Propylthiouracil, Methimazole – Sodium Iodide – Acetamenophen, cooling blankets – Plasmapheresis (rare) – Surgical (rare)
  40. 40. Adrenal Disease • Clinical manifestations result from:- – Overproduction or deficiency of: - • Glucocorticoids • Mineralocorticoids • Androgens • Hyper-secretion may present differently depending on the disease mechanism. • Hypo-secretion may only be apparent at times of stress.
  41. 41. Adrenal Disease • Causes of dysfunction: - – Hyper-secretion:- • Primary adrenal pathology:- – Adenoma – Hyperplasia – Carcinoma – Enzyme defects • Secondary: - – Increased/autonomous ACTH production – Pathology of the Renin/angiotensin system – Receptor defects – Enzyme defects.
  42. 42. Adrenal Disease – Hypo-function:- • Primary adrenal dysfunction: - – Autoimmune – Infiltration – Infection – Enzyme deficiencies • Secondary: - – Pituitary disease – Iatrogenic
  43. 43. Adrenal Disease • General Concept for Investigations: - • Establish Hyper - or Hypo-function: - – Use screening tests:- • Short synacthen, dexamethasone suppression • Differentiate the cause of the dysfunction: - – Use secondary tests:- • ACTH measurement , long synacthen, high dose dexamethasone.
  44. 44. Investigation of Adrenal Disease • Requires knowledge of: - – Biological rhythms – Concept of feedback controls • Limitations of analytical techniques.
  45. 45. Glucocorticoid Excess • Cushing’s syndrome:- – Features of glucocorticoid excess. – Low ACTH. – High ACTH: ectopic or exogenous. • Cushing’s disease: - – Glucocorticoid excess – High ACTH: - • Pituitary origin as described by Cushing. • Pseudo-Cushing’s disease: - – Alcohol = functional 11β-OH steroid dehydrogenase deficiency?
  46. 46. Cushing's Syndrome • Epidemiology: – Prevalence 1/100.000 • Age: – Cushing’s disease 25-45 years old. – Ectopic ACTH 40-65 years. • Sex: – Pituitary = female preponderance – Ectopic = male preponderance
  47. 47. Cushing’s Syndrome Clinical Features • Skin – Thin Skin – Hirsutes – Acne – Striae – Bruising • Cardio-vascular – Hypertension • Psychiatric – Depression • Musculoskeletal – Moonface – Buffalo hump – Truncal obesity – Thin Limbs – Proximal weakness • Metabolic – Hyperglycaemia – Osteoporosis – Hypo-kalaemia
  48. 48. Cushing’s Syndrome Laboratory Findings: Non-Endocrine • Haematology: – Polycythaemia, leucocytosis, low eosinophil count • Biochemistry: – Glucose intolerance • insulin resistance due to glucocorticoid – Electrolyte disturbances • Hypokalaemia & hypernatraemia (mineralocortiocoid)
  49. 49. Screening for Cushing’s Syndrome • Low dose dexamethasone suppression test. Ann Clin Biochem 1997;34:222-229. – Procedure: - • 1mg dexamethasone 23.00-24.00h • Serum cortisol 09.00h following day. • Cortisol should = < 50 nmol/L – Interpretation: - • Cortisol should = < 50 nmol/L (not everyone agrees with this) • 2% False negatives
  50. 50. Screening for Cushings Syndrome • Low dose dexamethasone suppression test. – Drug effects = false positive:- • Oestrogen & tamoxifen due to effect on Cortisol Binding Globulin. • Nasal decongestants and oral contraceptives – Obesity = no effect – Weight reduction = false positives in 25% – Alcohol = false positives – Depressive illness = 30 - 50% false positives
  51. 51. Screening for Cushing's Syndrome • Urinary Free Cortisol: - – 24 hour collection to give an integrated result. – Reference values vary with assay:- • Males <300 nmol/24 hours • Females <210 – Elevated in 95% of Cushing’s and in stressed subjects (False +ve) – Assays are cumbersome, often involving extraction's. – Use as part of screening process for in-patients.
  52. 52. Screening for Cushing's Syndrome • Diurnal variation: - – Serum Cortisol at Midnight and 09.00h. • Avoid stress. – Normal:- • 08.00h - 10.00h 130-690 nmol/L • 22.00h - 24.00h <260 nmol/L or 50% of 09.00h value Check local reference values – Cushings:- • Loss of diurnal variation.
  53. 53. Differential Diagnosis of Cushing’s Syndrome • Primary Adrenal disease? Non-ACTH dependant. – ACTH measurement = low. – High dose dexamethasone suppression test. – Measurement of androgens (DHEAS). • Secondary Disease? ACTH dependant. – ACTH measurement = high or inappropriate
  54. 54. Differential Diagnosis of Cushing’s Syndrome • High dose dexamethasone: - – Helps differentiate between pituitary and ectopic ACTH production. – 2mg 6h for 2 days: - • measure Cortisol & ACTH 09.00h day 1 • Give Dexamethasone 6 hourly from 09.00h day 1 • measure cortisol and ACTH 09.00h day 3.
  55. 55. Differential Diagnosis of Cushing’s Syndrome • High dose dexamethasone Cont.: - – Cushing’s disease (pituitary adenoma):- • serum cortisol suppresses to 50% of basal. • ACTH in basal sample elevated or high normal and suppresses. – Ectopic ACTH:- • ACTH may be very high >200 ng/L • Cortisol fails to suppress – Adrenal Carcinoma or adenoma: - • Cortisol does not suppress & ACTH low.
  56. 56. Differential Diagnosis of Cushing’s Syndrome • Imageing: - – Adrenal CT: Adenoma, carcinoma – Pituitary CT/MRI: Adenoma – Lung CT: Small cell carcinoma
  57. 57. Adrenal Failure • Epidemiology: – Prevalence 5/100,000 • Sex: – Autoimmune Addison’s more common in women • Genetics – May be a family history of autoimmune Addisons • Geography – Local prevalence of TB leading to adrenal failure
  58. 58. Adrenal Failure Clinical Features • Early: – Anorexia, lethargy & weakness. • Skin: – Hyperpigmentation • Sun exposed areas • Buccal cavity • Scars • Cardiovascular: – Postural hypotension • Gastrointestinal: – Nausea & vomiting • Acute: – Addisonian Crisis: • Post surgery/trauma • Infection – Hypotension, nausea, vomiting, weakness, hypovolaemic shock • Autoimmune Disease: – thyroid, ovary, pancreas
  59. 59. Adrenal Failure Laboratory Findings: Non-Endocrine • Haematology: – Lymphocytosis & eosinophilia • Biochemistry: – hyperkalaemia & hyponatraemia – Hypoglycaemia • Immunology: – Adrenal autoantibodies (70% case autoimmune). • Microbiology: – Blood culture & adrenal biobsy • Tuberculosis or fungal infection
  60. 60. Adrenal Failure. Aetiology. • Primary Adrenal Failure – 75% Auto-immune – 20% Tuberculosis – 5% Rare destructive processes – Waterhouse-Friederichson syndrome
  61. 61. Adrenal Failure. Endocrine Investigation . • Test adrenal reserve. • Random and “normal” 09.00h serum cortisol may be misleading. • Urine cortisol assay has no place in the diagnosis of adrenal failure
  62. 62. Investigation Adrenal Failure. Endocrine Investigation. • Establish whether patient is receiving steroid replacement. – Prednisone/prednisilone cross-react in assays for cortisol. – Hydrocortisone = Cortisol.
  63. 63. Adrenal Failure. Endocrine Investigation . • Establish Deficiency: - – Short Synacthen test:- – Can be performed at any time of day. – Non-stressed patient – 250 µg tetracosactrin i.m. (Check local policies for surface area corrections etc). – Blood for cortisol at 0, 30, and 60 mins. – Plasma for ACTH at time 0. • Interpretation:- – Serum cortisol should rise by 250 nmol/L to a concentration >550 nmol/L
  64. 64. Adrenal Failure. Endocrine Investigation . • Primary or Secondary Failure: - – Patient history – Previous steroid therapy. – ACTH: - – Primary = High – Secondary = Low • High dose synacthen: - – 1 mg i.m. – Cortisol 0, 30, 60, 300 mins. – Cortisol at 300 mins = >900 nmol/L – Deficient rise = secondary failure. – Pituitary function tests required.
  65. 65. Mineralocorticoid Excess. • Primary hyperaldosteronism :- – Overproduction of aldosterone independent of it’s normal chronic regulator Angiotensin 2 :- • Adenoma: Surgical Treatment – Aldosterone – Plasma Renin – High Aldosterone/Plasma Renin Ratio • Bilateral Adrenal cortical Hyperplasia. • Sporadic or Familial hyperaldosteronism (Type FH2). • ACTH dependant release. (dexamethasone suppressible FH1).
  66. 66. Mineralocorticoid Excess. • Secondary hyperaldosteronism: - • High Aldosterone • High or Inappropriate Plasma Renin – Renal artery stenosis, renin secreting tumours, Barters syndrome, diuretic & laxative abuse. • Excessive 11-deoxycorticosteroid production: - – Adrenal adenomas, carcinomas. – Congenital adrenal hyperplasia.
  67. 67. Mineralocorticoid Excess. When to Investigate? • Hypertension: - – Long-standing & resistant to drugs • Hypokalaemia and alkalosis:- • Unprovoked by: - Diuretics, vomiting or diarrhoea • Profound provoked hypokalaemia (Gordon Lancet 1994;344:240-243. 50% of Patients are Normokalaemic but with abnormal Aldo/PRA ratios).
  68. 68. Mineralocorticoid Excess. When to Investigate? • Inappropriate loss of urine potassium in the presence of K+ deficit (Urine [K+] >30 mmol/L). • Hypertension with a family history of 10 hyperaldosteronism. • Polyuria, muscle weakness, tetany, polyuria.
  69. 69. Mineralocorticoid Excess. Biochemical diagnosis. • Plasma aldosterone, Plasma Renin Activity (PRA) and K+ from a supine patient. Calculate ratio. • Assess renal function. • K+ deficits should be corrected with plasma K+ >4.00mmol/L. • Modulates aldosterone output. • Reduce high dose β-blockers. • Lowers renin more than Aldosterone.
  70. 70. Mineralocorticoid Excess. Biochemical diagnosis. • Stop diuretics: - – Spiranolactone, amilioride & triamterine • Reduce calcium channel blockers:- – Avoid morning dose 2 – 3h before sampling. • Raises aldosterone & stimulate renin
  71. 71. Mineralocorticoid Excess. Biochemical diagnosis. • Primary hyperaldosteronism: - – Raised/Normal Aldosterone – Suppressed/low PRA – High Aldosterone/PRA ratio. • Secondary hyperaldosteronism: - – Raised Aldosterone – Raised or “normal” (inappropriate) PRA.
  72. 72. CASE 4A A 47 year old smoker with a history of asbestos exposure presented with a 6 month history of lethargy, headache, weight loss and erectile impotence. The following blood results were obtained on admission: Cortisol 65 nmol/l Growth hormone 1.9 mU/l FT4 8 pmol/l TSH 1.1 mU/l LH < 1.0 IU/l FSH 1.9 IU/l Testosterone 1.0 nmol/l Prolactin 360 mU/l Questions 1. Explain the patient's symptoms in light of these results. 2. What is the differential diagnosis at this stage? 3. What further blood/urine tests would you like to carry out?
  73. 73. CASE 4 1. The patients symptoms are lethargy, headache, weight loss and erectile impotence. The lethargy could be explained by the low levels of T4 and cortisol. A deficiency of cortisol can lead to loss of fluid and therefore weight loss. The headache could be due to the presence of a pituitary tumour and the erectile impotence due to the low testosterone level. 2. The levels of cortisol, T4 and testosterone are low coupled with normal/low levels of TSH and LH/FSH and a normal serum prolactin. A likely diagnosis is that the patient has hypopituitarism. This can be due to the presence of a pituitary tumour (non secreting) damage to the pituitary by infection, infarction, tuberculosis etc. Other possible diagnoses include hypothalamic disease , general illness or the presence of low levels of hormone binding proteins. 3. Further baseline hormone tests would include the measurement of sex hormone binding globulin (SHBG). A baseline ACTH measurement may be useful to distinguish primary from secondary adrenal failure. Due to the overlap between the baseline levels of pituitary hormones in normals and patients with hypopituitarism it would be appropriate to perform dynamic function tests of pituitary function. Tests commonly performed include the Insulin Tolerance Test, LHRH test and TRH test. Measurements of plasma urea and electrolytes and blood sugar would also be appropriate in this patient as these are frequently abnormal in patients with hypopituitarism due to low cortisol and growth hormone levels.
  74. 74. CASE 4B Following removal of a cystic mass from the pituitary, combined pituitary function tests using insulin, GnRH and TRH i.v. were carried out and the results were as follows: Glu Co GH TSH LH FSH FT4 Testo Prolactin 0 4.4 580 < 1.0 1.7 2.3 4.8 20 3.5 230 20 5.8 30 1.2 280 < 1.0 6.5 5.9 60 2.8 725 3.4 4.5 7.3 7.3 90 3.1 895 2.1 120 3.3 550 1.3 Questions (cont) 4. What patient preparation is necessary before performing this test and why? 5. What is the importance of the serum glucose level during the test. 6. Interpret the response of each hormone to stimulation and suggest what medical treatment this patient might now require.
  75. 75. CASE 4 cont. 4. Prior to the performance of a combined pituitary function test the patient should be resting and under no stress. An indwelling needle should be inserted 30 minutes before the test commences. The test should be carried out under medical supervision and glucose must be available at all times. 5. The serum glucose must fall into the hypoglycaemic range (< 2.5 mmol/l) at some stage during the test. In addition the patient should show symptoms of hypoglycaemia. 6. The high baseline cortisol is probably due to the patient being stressed at the start of the test. Adequate hypoglycaemia has been achieved and the patient has shown a normal cortisol response to this. The TSH response to TRH is normal. The patient has a borderline response of LH and FSH to GnRH stimulation and a subnormal growth hormone response to hypoglycaemia. The testosterone level is still suppressed. The patient will probably require testosterone replacement therapy. The role of growth hormone replacement therapy in adults is still being investigated.
  76. 76. CASE 5 After stopping a combined oral contraceptive pill a 25 year old local health authority worker presented with an eight month history of amenorrhoea which failed to respond to the oestrogen antagonist clomiphene. She was referred to the endocrine clinic with serum prolactin 4615 mU/l. The diagnosis of a prolactinoma was supported by the findings of an 11mm diameter tumour in the pituitary gland on CT scan, which was initially treated with bromocriptine, followed by trans-sphenoidal adenomectomy. The results of the combined pituitary function tests were as follows: Pre-operatively: Glu Co GH TSH LH FSH T4 Prolactin E2 Prog 0 3.9 540 1.1 2.3 3.4 3.4 96 1190 120 < 2 20 12 30 1.2 410 2.6 19 9.6 60 1.7 670 14 13 16 9.3 90 2.1 770 28 120 2.6 840 25 Post-operatively: Glu Co GH TSH LH FSH T4 Prolactin E2 Prog 0 3.9 330 0.8 2.0 4.7 < 1.0 149 < 80 2960 > 92 20 11 30 1.1 355 11 4.8 < 1.0 60 0.8 535 26 5.6 5.1 < 1.0 90 1.7 560 37 120 4.2 580 43 Questions 1. Was adequate hypoglycaemia achieved? 2. Do you think the patient's surgery was successful? 3. Do you think that pituitary function was preserved post-operatively?
  77. 77. CASE 5 1. Yes, the serum glucose has fallen to 1.2 mmol/l which is well within the hypoglycaemic range. 2. Yes, the serum prolactin has fallen to less than 80 mu/l post operatively and the luteal phase oestradiol and progesterone levels imply that the patient is now ovulating. Note the response of the serum prolactin to bromocryptine therapy prior to surgery. In prolactin secreting pituitary tumours it is recommended that a trial of drug treatment should be given prior to surgery. 3. The post operative combined pituitary function test results imply that pituitary function has been preserved. The poor LH/FSH response to GnRH is probably due to the tests having been performed in the luteal phase of the cycle.
  78. 78. CASE 6 A 33 year old warehouseman presented to his GP with a 3 year history of weight gain, increasing thirst and polyuria. Initial investigations revealed: Na 145 mmol/l Osmolality serum 302 mosmol/kg K 4.3 mmol/l urine 80 mosmol/kg Urea 2.1 mmol/l Potassium 4.4 mmol/l Fasting glucose 4.5 mmol/l Following his admission, the results of the combined pituitary function tests were as follows: Glu Co GH TSH LH FSH FT4 Prolactin Testo 0 4.5 510 < 0.5 1.0 < 1.0 < 1.0 9 1180 1.6 20 2.5 5.1 30 2.3 350 0.5 < 1.0 < 1.0 60 2.6 355 0.6 5.9 < 1.0 < 1.0 90 3.7 465 0.6 120 4.3 310 0.8 Questions 1. What is the likely site of the pathology in this patient? 2. Can you explain the raised serum prolactin in this patient? 3. What further biochemical investigation would you recommend and what would you expect to find?
  79. 79. CASE 6 1. The patients symptoms and the presence of a high serum osmolality without concentration of the urine suggests a diagnosis of diabetes insipidus. The patient has a low basal testosterone and borderline F T4. There does appear to be a lack of growth hormone response. There is also a lack of response of LH/FSH in the GnRH test. The combination of apparent A.D.H. deficiency and pituitary dysfunction suggest that the most likely site of pathology in this patient is the hypothalamus. 2. Prolactin secretion is under inhibitory control by dopamine produced in the hypothalamus. Disorders of the hypothalamus may inhibit dopamine secretion and therefore cause an increase in serum prolactin. 3. The most helpful further investigation would be a water deprivation test. If the patient has cranial diabetes insipidus the urine will fail to concentrate after 8 hours fluid restriction but will concentrate when the patient is given desmopressin.

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