clinical investigation unit testing endocrinology rounds july 28, 2010 selina liu pgy5 endocrinology
TRANSCRIPT
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 Hypothyroidism
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
Central Hypothyroidism
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.
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.
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
Marzullo P et al. 2001 J Clin Endocrinol Metab 26:3001-3008
Sensitivity: IGF-1 41%
Marzullo P et al. 2001 J Clin Endocrinol Metab 26:3001-3008
therefore – not a good screening test!
2006. J Clin Endocrinol Metab 91:1621-1634
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 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 Deficiency
Dynamic tests:
insulin tolerance test (ITT) – GOLD STANDARD
others arginine-GHRHarginine alone
clonidinearginine + l-dopa
(arginine – decreases SRIF from hypothalamus)
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.
arginine
-
Insulin Tolerance Test first described in 1941
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 Deficiency
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
Insulin Tolerance Test
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
Kronenberg HM et al. Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.
Recommended Test Sensitivity (95% CI) to diagnose adult GH
deficiency
2002. J Clin Endocrinol Metab 87:2067-2089
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
Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089
Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089
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
Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089
2006. J Clin Endocrinol Metab 91:1621-1634
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 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 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)
2007. Eur J Endocrinol 157:695-700
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
Examples
Adrenal Insufficiency Primary
low cortisol, high ACTH
Secondary/Tertiary (Central)
low cortisol, low or normal ACTH
ACTH and Cortisol Secretion
Kronenberg HM et al. Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.
ACTH and Cortisol Secretion
Kronenberg HM et al. Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.
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
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
Adrenal Insufficiency – Diagnosis
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
Oelkers W. N Engl J Med 1996; 335(16):1206-1212
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
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 – 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)
Oelkers W. N Engl J Med 1996; 335(16):1206-1212
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
Kronenberg HM et al. Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.
45y M – 2 months post-pituitary macroadenoma resection inadequate suppression of GH persistent acromegaly
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 to confirm diagnosis of central hypothyroidism (and hypoprolactinemia)
Kronenberg HM et al. Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.
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
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