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Clinical Investigation Unit Testing. Endocrinology Rounds July 28, 2010 Selina Liu PGY5 Endocrinology. Outline. Background - Dynamic Endocrine Testing Clinical Investigation Unit - Available Tests Examples Growth Hormone Deficiency Adrenal Insufficiency Other. Background.

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clinical investigation unit testing

Clinical Investigation Unit Testing

Endocrinology Rounds

July 28, 2010

Selina Liu

PGY5 Endocrinology

outline
Outline
  • Background - Dynamic Endocrine Testing
  • Clinical Investigation Unit - Available Tests
  • Examples
    • Growth Hormone Deficiency
    • Adrenal Insufficiency
    • Other
background
Background
  • What can we measure?
    • basal hormone levels
    • stimulated or suppressed hormone levels
  • Why do we do dynamic endocrine testing?
    • test of secretory reserve
background1
Background
  • INSUFFICIENCY/DEFICIENCY
  • OVERPRODUCTION

Stimulate!

Suppress!

available tests
Available Tests
  • Which glands/axes can we stimulate or suppress?
  • Pituitary
  • Other
pituitary hormones
Pituitary Hormones

http://cal.man.ac.uk/student_projects/2002/MNBY9APB/Project_Images/pithormones1.gif

pituitary hormone disorders
Pituitary Hormone Disorders

Hormone Underproduction Overproduction

GH

GH Deficiency

Acromegaly

LH/FSH

Hypogonadotropic

Hypogonadism

TSH

Central Hypothyroidism

Central Hyperthyroidism

ACTH

Central Adrenal Insufficiency

Cushing’s

Hyperprolactinemia

Prolactin

Diabetes Insipidus

ADH

pituitary hormone disorders1
Pituitary Hormone Disorders

Hormone Underproduction Overproduction

GH

IGF-1

GH

GH Deficiency

Acromegaly

/normal LH, FSH,

estradiol, testosterone

LH/FSH

Hypogonadotropic

Hypogonadism

TSH

/normal TSH, fT3, fT4

Central Hypothyroidism

Central Hyperthyroidism

/normal ACTH,  cortisol

ACTH

Central Adrenal Insufficiency

Cushing’s

Hyperprolactinemia

Prolactin

Diabetes Insipidus

ADH

available ciu tests
Available CIU Tests

Insulin Tolerance Test

GH Deficiency

Hypogonadotropic

Hypogonadism

GnRH Stimulation Test

Triple Bolus Test

TRH Stimulation Test

Central Hypothyroidism

ACTH Stimulation Test

CRH Stimulation Test

Insulin Tolerance Test

Adrenal Insufficiency

Diabetes Insipidus

Water Deprivation Test

Glucose Tolerance Test

Acromegaly

examples
Examples
  • Growth Hormone Deficiency
growth hormone secretion
Growth Hormone Secretion

GHRH = GH releasing hormone

SRIF = somatotropin release inhibiting factor

(aka somatostatin)

IGFBP = IGF binding protein

Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

growth hormone secretion1
Growth Hormone Secretion
  • pulsatile secretion
  • healthy adult ~10 pulses/day
  • longest ~1h after sleep onset
  • if suspect GH deficiency, random GH level not useful

Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

slide13

GH Deficiency - Causes

http://www.endo-society.org/guidelines/final/upload/042506_CG_HormoneBook.pdf

gh deficiency clinical presentation
GH Deficiency – Clinical Presentation
  • CV Risk factors
    • abnormal lipid profile, atherosclerosis, insulin resistance
  • Body composition
    • increased body fat mass with altered distribution, increased waist:hip, decreased lean body mass
  • Exercise capacity
    • reduced muscle mass, impaired max oxygen uptake
  • QOL
    • decreased energy, poor concentration, low self-esteem
gh deficiency diagnosis
GH Deficiency - Diagnosis
  • screening test - IGF-1 level ?
  • IGF-1 – affected by age, obesity, nutrition, comorbidities etc.
  • Marzullo P et al. 2001 Usefulness of Different Biochemical Markers of the Insulin-Like Growth Factor (IGF) Family in Diagnosing Growth Hormone Excess and Deficiency in Adults

J Clin Endocrinol Metab 26:3001-3008

slide16

58 healthy, 83 acromegalic, 34 GH deficient subjects

  • GH deficient: 34 hypopituitarism
    • prev pituitary tumour/craniopharyngioma/meningioma resection, except for 2 with idiopathic GH deficiency
    • diagnosed based on arginine-GHRH stimulation test
    • 19 female, 15 male
    • ages 18-60

2001 J Clin Endocrinol Metab 26:3001-3008

slide17

GH deficient subjects had significantly lower mean IGF-1

levels vs healthy control subjects

Marzullo P et al. 2001 J Clin Endocrinol Metab 26:3001-3008

slide19

Sensitivity: IGF-1 41%

therefore – not a good screening test!

Marzullo P et al. 2001 J Clin Endocrinol Metab 26:3001-3008

growth hormone deficiency
Growth Hormone Deficiency

Endocrine Society Clinical Practice Guidelines (2006)

Recommendation:

“Do it” or “Don’t do it” – indicating a judgement that most well-informed people would make

Suggestion:

“Probably do it” or “Probably don’t do it” – indicating a judgement that a majority of well-informed people would make but a substantial minority would not

growth hormone deficiency1
Growth Hormone Deficiency

Endocrine Society Clinical Practice Guidelines (2006)

Suggestion: IGF-1

  • if normal – does not exclude GH deficiency
    • if in context of pituitary disease, provocative testing is mandatory (level of evidence – high)
  • if low, and no catabolic disorders, liver disease, indicates severe GH deficiency
    • may be useful in identifying patients who will benefit from treatment (level of evidence – moderate)
growth hormone deficiency2
Growth Hormone Deficiency
  • Dynamic tests:
    • insulin tolerance test (ITT) – GOLD STANDARD
    • others arginine-GHRH arginine alone clonidine arginine + l-dopa

(arginine – decreases SRIF from hypothalamus)

growth hormone secretion2
Growth Hormone Secretion

arginine

-

GHRH = GH releasing hormone

SRIF = somatotropin release inhibiting factor

(aka somatostatin)

IGFBP = IGF binding protein

Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

insulin tolerance test
Insulin Tolerance Test
  • first described in 1941
insulin tolerance test1
Insulin Tolerance Test
  • To diagnose GH deficiency
    • also to diagnose adrenal insufficiency, panhypopituitarism
  • Contraindications:
    • seizure disorder, cerebrovascular disease, coronary artery disease
  • can precipitate adrenal crisis
    • check baseline 08:00 am cortisol – do not do if <100 nmol/L
  • need close monitoring, physician supervision
growth hormone deficiency3
Growth Hormone Deficiency
  • Insulin Tolerance Test (ITT)
    • symptomatic hypoglycemia and fall in BG < 2.2 mmol/L
    • will increase GH to a maximal level >10 mg/L increment of 6 mg/L = normal
    • plasma cortisol should peak at least 496-552 nmol/L

Gardner DG & Shoback D (eds) 2007 Greenspan’s Basic & Clinical Endocrinology, Eighth Edition

slide29

(5.6 mmol/L)

(827.7 nmol/L)

(4.4 mmol/L)

Normal ITT

mg/L

(3.3)

(2.2)

(275.9 nmol/L)

(1.1 mmol/L)

http://ocw.tufts.edu/data/14/134087/134097_medium.jpg

slide30

Recommended Test Sensitivity (95% CI) to diagnose adult GH deficiency

Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

slide31

39 subjects - multiple pituitary hormone deficiency (MPHD)

    • 13 female, 26 male, aged 26-70
    • adult onset hypothalamic-pituitary disease
  • 34 matched controls (age, sex, BMI, estrogen status)
    • 14 female, 20 male, age 24-68

2002. J Clin Endocrinol Metab 87:2067-2089

slide33

100% sens

100% spec

AUC 1.0

  • MPHD subjects vs. matched controls

Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089

slide34

To minimize misclassification:

  • ITT – peak serum GH 5.1 mg/L

(96% sens, 92% spec)

  • Arg-GHRH – peak serum GH 4.1 mg/L

(95% sens, 91% spec)

Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089

biller bmk et al
Biller BMK et al.
  • the ITT and the arginine-GHRH provided the greatest accuracy in discriminating between patients with MPHD and their matched controls
    • arginine- GHRH test – better preferred by patients
  • arginine-GHRH test – good alternative to ITT
  • arginine-L-dopa – reasonable 3rd option
  • basal IGF-1 < 77 mg/L was 95% specific for GH deficiency

Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089

growth hormone deficiency4
Growth Hormone Deficiency

Endocrine Society Clinical Practice Guidelines (2006)

Recommendations:

  • adults with structural hypothalamic/pituitary disease, surgery or irradiation to these areas, or other pituitary hormone deficiencies should be considered for evaluation for acquired GH deficiency (level of evidence – high)
growth hormone deficiency5
Growth Hormone Deficiency

Endocrine Society Clinical Practice Guidelines (2006)

Recommendations:

  • The ITT or arginine-GHRH test is the preferred test for establishing the diagnosis of GH deficiency
    • but – in those with clearly established recent hypothalamic causes of GH deficiency, i.e. irradiation, arginine-GHRH test may be misleading (level of evidence – high)
      • GHRH directly stimulates pituitary
growth hormone deficiency6
Growth Hormone Deficiency

Endocrine Society Clinical Practice Guidelines (2006)

Suggestions:

  • the presence of deficiencies in > 3 pituitary axes strongly suggests GH deficiency, and in this context, provocative testing is optional (level of evidence – moderate)
growth hormone deficiency7
Growth Hormone Deficiency

Growth Hormone Research Society Consensus Statement (2007)

  • ITT, arginine-GHRH, GHRH-GHRP, glucagon tests all well-validated in adults
    • glucagon useful if ITT contraindicated, if GHRH or GHRP not available
  • IGF-1 good screening test
    • normal IGF-1 does not exclude GH deficiency
examples1
Examples
  • Adrenal Insufficiency
    • Primary
      • low cortisol, high ACTH
    • Secondary/Tertiary (Central)
      • low cortisol, low or normal ACTH
acth and cortisol secretion
ACTH and Cortisol Secretion

Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

acth and cortisol secretion1
ACTH and Cortisol Secretion
  • pulsatile secretion
  • circadian rhythm
  • highest in a.m.

24:00

08:00

12:00

20:00

Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

adrenal insufficiency causes
Adrenal Insufficiency - Causes
  • Primary – adrenal
  • Secondary – pituitary
  • Tertiary – hypothalamus
slide47

Secondary Adrenal Insufficiency - Causes

  • Panhypopituitarism
  • Isolated ACTH Deficiency - ?autoimmune
  • Familial Cortisol-Binding Globulin Deficiency
  • Megestrol acetate
  • Opiates
  • Traumatic brain injury

www.uptodate.com

slide48

Tertiary Adrenal Insufficiency - Causes

  • Chronic high dose glucocortioid therapy
  • Post-cure Cushing’s syndrome
  • Other
    • tumours
    • cranial irradiation
    • infiltrative diseases i.e. sarcoidosis

www.uptodate.com

adrenal insufficiency clinical presentation2
Adrenal Insufficiency – Clinical Presentation

Central Adrenal Insufficiency (Secondary or Tertiary)

  • differ from primary:
    • no hyperpigmentation (ACTH not increased)
    • no hyperkalemia
    • dehydration, hypotension less severe
    • hypoglycemia may occur
    • GI symptoms less common
    • local symptoms (headache etc.), other signs of hypopituitarism

www.uptodate.com

adrenal insufficiency diagnosis
Adrenal Insufficiency – Diagnosis

Steps:

  • To rule out adrenal insufficiency - fasting 08:00 am cortisol
    • if 08:00 am cortisol >524 nmol/L, adrenal insufficiency excluded
    • if 08:00 am cortisol <83 nmol/L, adrenal insufficiency confirmed
    • if 08:00 am cortisol between these values, is borderline – need further testing

reviewed in Oelkers W. N Engl J Med 1996; 335(16):1206-1212

adrenal insufficiency diagnosis1
Adrenal Insufficiency – Diagnosis

Steps:

  • If suspect primary adrenal insufficiency, do both 08:00 am cortisol and ACTH
    • low cortisol and high ACTH - primary
      • if cortisol normal – rules out primary, but does not exclude mild secondary adrenal insufficiency
      • in primary adrenal insufficiency – ACTH usually >22pmol/L
    • low cortisol and low/normal ACTH – secondary/tertiary

reviewed in Oelkers W. N Engl J Med 1996; 335(16):1206-1212

slide54

(660 pmol/L)

(6.6 pmol/L)

(0.7 pmol/L)

(83 nmol/L)

(276 nmol/L)

(8 nmol/L)

(1380

nmol/L)

Oelkers W. N Engl J Med 1996; 335(16):1206-1212

adrenal insufficiency diagnosis2
Adrenal Insufficiency – Diagnosis

Dynamic Tests:

  • to confirm adrenal insufficiency:
    • high dose short ACTH stimulation test
      • 250 mg cosyntropin (Cortrosyn) IV
        • cortisol/ACTH at -15, 0, 30, 60 min
    • if peak cortisol >500 nmol/L (preferably >550 nmol/L), rules out primary adrenal insufficiency

Oelkers W. N Engl J Med 1996; 335(16):1206-1212

adrenal insufficiency diagnosis3
Adrenal Insufficiency – Diagnosis

** if suspect recent/mild secondary – can have normal high dose ACTH stimulation test

    • because of high dose (only need 5 mg to maximally stimulate adrenals), and if recent – adrenals will not have atrophied yet
  • low dose short ACTH stimulation test
      • 1 mg cosyntropin (Cortrosyn) IV
        • cortisol/ACTH at -15, 0, 30, 60 min
    • normal peak cortisol >500 nmol/L

Oelkers W. N Engl J Med 1996; 335(16):1206-1212

adrenal insufficiency diagnosis4
Adrenal Insufficiency – Diagnosis
  • if abnormal low dose ACTH stimulation test, require further testing
    • insulin tolerance test
      • will confirm if secondary/tertiary adrenal insufficiency

Oelkers W. N Engl J Med 1996; 335(16):1206-1212

adrenal insufficiency diagnosis5
Adrenal Insufficiency – Diagnosis
  • to distinguish secondary vs. tertiary adrenal insufficiency: CRH stimulation test (if you can get CRH!)
    • 100 mg CRH IV
      • ACTH, cortisol at -15, 0, 30, 60, 90 min
    • low ACTH = pituitary adrenal insufficiency (secondary)
    • high ACTH = hypothalamic adrenal insufficiency (tertiary)

(values not as well standardized as for ITT)

Oelkers W. N Engl J Med 1996; 335(16):1206-1212

other pituitary testing
Other Pituitary Testing
  • Acromegaly – Glucose Tolerance Test
  • Hypogonadism - GnRH Stimulation Test
  • Central Hypothyroidism – TRH Stimulation Test
  • Panhypopituitarism - Triple/Double Bolus Test
  • Diabetes Insipidus – Water Deprivation Test
glucose tolerance test
Glucose Tolerance Test
  • to confirm diagnosis of acromegaly

Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

slide62

45y M – 2 months post-pituitary macroadenoma resection

    • inadequate suppression of GH  persistent acromegaly
gnrh stimulation test
GnRH Stimulation Test
  • to confirm diagnosis of hypogonadotropic hypogonadism

Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

trh stimulation test
TRH Stimulation Test
  • to confirm diagnosis of central hypothyroidism (and hypoprolactinemia)

Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

triple bolus test
Triple Bolus Test
  • Components:
    • Insulin Tolerance Test
      • GH deficiency, adrenal insufficiency
    • GnRH stimulation test
      • hypogonadotropic hypogonadism
    • TRH stimulation test
      • central hypothyroidism, hypoprolactinemia
  • if suspect panhypopituitarism
water deprivation test
Water Deprivation Test
  • to confirm diagnosis of central diabetes insipidus

http://www.colorado.edu/intphys/Class/IPHY3430-200/image/figure1806.jpg

non pituitary dynamic tests
Non-Pituitary Dynamic Tests
  • Medullary Thyroid Cancer – Calcium stimulation test,
  • Primary Hyperaldosteronism – Saline suppression test
clinical investigation unit ciu
Clinical Investigation Unit - CIU
  • Liz Froats, RN
  • Room B5-502

http://dom.lhsc.on.ca/dom/divisions/endo/ciu.htm

slide78

References

  • Marzullo P et al. 2001. J Clin Endocrinol Metab 26:3001-3008
  • Molitch ME et al. 2006. J Clin Endocrinol Metab 91:1621-1634
  • Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089
  • Oelkers W. N Engl J Med 1996; 335(16):1206-1212
  • Bernstein M et al. 1984. J Neurosurg 61(3):586-590
  • Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.
  • Gardner DG & Shoback D (eds) Greenspan’s Basic & Clinical Endocrinology, Eighth Edition. 2007 McGraw-Hill.
  • http://cal.man.ac.uk/student_projects/2002/MNBY9APB/Project_Images/pithormones1.gif
  • http://ocw.tufts.edu/data/14/134087/134097_medium.jpg
  • www.uptodate.com
  • http://www.endo-society.org
  • http://www.colorado.edu/intphys/Class/IPHY3430-200/image/figure1806.jpg
  • http://dom.lhsc.on.ca/dom/divisions/endo/ciu.htm