clinical investigation unit testing endocrinology rounds july 28, 2010 selina liu pgy5 endocrinology

Clinical Investigation Unit Testing

Endocrinology RoundsJuly 28, 2010

Selina LiuPGY5 Endocrinology

Outline

Background - Dynamic Endocrine Testing

Clinical Investigation Unit - Available Tests

Examples Growth Hormone Deficiency

Adrenal Insufficiency

Other

Background

What can we measure?

basal hormone levels

stimulated or suppressed hormone levels

Why do we do dynamic endocrine testing?

test of secretory reserve

Background

INSUFFICIENCY/DEFICIENCY

OVERPRODUCTION

Stimulate!

Suppress!

Available Tests

Which glands/axes can we stimulate or suppress?

Pituitary

Other

Pituitary Hormones

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

Pituitary Hormone Disorders

Hormone Underproduction Overproduction

GH

LH/FSH

TSH

ACTH

Prolactin

GH Deficiency Acromegaly

HypogonadotropicHypogonadism

Central Hypothyroidism

Central Adrenal Insufficiency Cushing’s

Hyperprolactinemia

Central Hyperthyroidism

ADH Diabetes Insipidus

Central Hyperthyroidism

Pituitary Hormone Disorders

Hormone Underproduction Overproduction

GH

LH/FSH

TSH

ACTH

Prolactin

GH Deficiency Acromegaly

HypogonadotropicHypogonadism


Central Adrenal Insufficiency Cushing’s

Hyperprolactinemia

ADH Diabetes Insipidus

/normal TSH, fT3, fT4

/normal ACTH, cortisol

GHIGF-1

/normal LH, FSH, estradiol, testosterone

Available CIU Tests

GH Deficiency

Hypogonadotropic Hypogonadism


Adrenal Insufficiency

Insulin Tolerance Test

GnRH Stimulation Test

TRH Stimulation Test

ACTH Stimulation Test CRH Stimulation TestInsulin Tolerance Test

Diabetes Insipidus Water Deprivation Test

Acromegaly Glucose Tolerance Test

Triple Bolus Test

Examples

Growth Hormone Deficiency

Growth Hormone Secretion

GHRH = GH releasing hormoneSRIF = somatotropin release inhibiting factor(aka somatostatin)IGFBP = IGF binding protein

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


pulsatile secretion

healthy adult ~10 pulses/day

longest ~1h after sleep onset

if suspect GH deficiency, random GH level not useful


GH Deficiency - Causes

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

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

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

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 18-602001 J Clin Endocrinol Metab 26:3001-3008

GH deficient subjects had significantly lower mean IGF-1levels vs healthy control subjects

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

Sensitivity: IGF-1 41%


therefore – not a good screening test!

2006. J Clin Endocrinol Metab 91:1621-1634


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



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)


Dynamic tests:

insulin tolerance test (ITT) – GOLD STANDARD

others arginine-GHRHarginine alone

clonidinearginine + l-dopa

(arginine – decreases SRIF from hypothalamus)


GHRH = GH releasing hormoneSRIF = somatotropin release inhibiting factor(aka somatostatin)IGFBP = IGF binding protein


arginine

-

Insulin Tolerance Test first described in 1941


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


Insulin Tolerance Test (ITT) symptomatic hypoglycemia and fall in BG < 2.2 mmol/L

will increase GH to a maximal level >10 g/Lincrement of 6 g/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

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

Normal ITT

(5.6 mmol/L)

(4.4 mmol/L)

(3.3)

(2.2)

(1.1 mmol/L)

g/L

(275.9 nmol/L)

(827.7 nmol/L)

Test GH Value < μg/L References


5.1 Biller et al

Arginine + GHRH 4.1 Biller et al

Arginine + l-Dopa 1.7 Biller et al

Hexarelin + GHRH

3.0Gasperi et

al

GHRH + GHRP-6 15.0Popovic et

al


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

deficiency


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

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

100% sens100% spec AUC 1.0

MPHD subjects vs. matched controls



To minimize misclassification: ITT – peak serum GH 5.1 g/L

(96% sens, 92% spec)Arg-GHRH – peak serum GH 4.1 g/L

(95% sens, 91% spec)

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 g/L was 95% specific for GH deficiency




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)



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



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)

2007. Eur J Endocrinol 157:695-700


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

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


pulsatile secretion circadian rhythm highest in a.m.

24:00 12:0008:00 20:00

Adrenal Insufficiency - Causes

Primary – adrenal

Secondary – pituitary

Tertiary – hypothalamus

Primary Adrenal Insufficiency - Causes

www.uptodate.com

Secondary Adrenal Insufficiency - Causes

www.uptodate.com

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

Tertiary Adrenal Insufficiency - Causes

www.uptodate.com

Chronic high dose glucocortioid therapy Post-cure Cushing’s syndrome Other

tumours cranial irradiation infiltrative diseases i.e. sarcoidosis

Adrenal Insufficiency – Clinical Presentation

www.uptodate.com

Adrenal Insufficiency – Clinical Presentation

www.uptodate.com

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

Adrenal Insufficiency – Diagnosis

Steps:

1. 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


Steps:

2.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

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

(660 pmol/L)

(0.7 pmol/L)

(6.6 pmol/L)

(1380 nmol/L)

(8 nmol/L) (83 nmol/L)(276 nmol/L)

Adrenal Insufficiency – DiagnosisDynamic Tests:

to confirm adrenal insufficiency:

high dose short ACTH stimulation test 250 g 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


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

because of high dose (only need 5 g to maximally stimulate adrenals), and if recent – adrenals will not have atrophied yet

low dose short ACTH stimulation test 1 g cosyntropin (Cortrosyn) IV

cortisol/ACTH at -15, 0, 30, 60 min

normal peak cortisol >500 nmol/LOelkers W. N Engl J Med 1996; 335(16):1206-1212


if abnormal low dose ACTH stimulation test, require further testing

insulin tolerance test will confirm if secondary/tertiary adrenal insufficiency


Adrenal Insufficiency – Diagnosis to distinguish secondary vs. tertiary adrenal insufficiency: CRH stimulation test (if you can get CRH!)

100 g 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)


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 to confirm diagnosis of acromegaly


45y M – 2 months post-pituitary macroadenoma resection inadequate suppression of GH persistent acromegaly

GnRH Stimulation Test to confirm diagnosis of hypogonadotropic hypogonadism


TRH Stimulation Test to confirm diagnosis of central hypothyroidism (and hypoprolactinemia)


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

1984. J Neurosurg 61(3):586-590

32 y F – 3 yrs post Rathke’s cleft resection

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

Medullary Thyroid Cancer – Calcium stimulation test,

Primary Hyperaldosteronism – Saline suppression test

Clinical Investigation Unit - CIU

Liz Froats, RN

Room B5-502

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

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



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

http://www.uptodate.com/

http://www.endo-society.org/




clinical investigation unit testing endocrinology rounds july 28, 2010 selina liu pgy5 endocrinology

Documents

suspect gh deficiency

idiopathic gh deficiency

suppressed hormone levels

basal hormone levels

deficiency causeshttp

random gh level

arginineghrh stimulation

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