slide about Acromegaly amongs children.pdf

acromegaly

1. A rare disease : ACROMEGALY
Dr. JeyakanthaRatnasingam
Consultant Endocrinologist
University Malaya Medical Centre

2. MrSB
•45 year old newspaper vendor
•Type 2 DM & Hypertension since 2010
Managed at primary care:
•HbA1c : 6.7-7.0% since 2010-2015, BP well controlled
•Metformin 850mg bd, Sitagliptin100mg od, Telmisartan40mg od
Last two years : HbA1c: 8.0-8.9%, BP : 170/90mmHg
•2016 -add GliclazideMR 60mg OM, Amlodipine10mg OD
•Referred to me for uncontrolled DM

3. MrSB
Images shown with patient consent
Worsening Diabetes, Hypertension
With Acromegaloidfeatures

4. Pierre Marie coined the term
'acromegaly' in 1886

5. What is Acromegaly ?
•In most cases, acromegaly is
characterized by chronic hypersecretion
of growth hormone (GH) from a pituitary
adenoma (>95% of cases), leading to
increases in insulin-like growth factor 1
(IGF-1) levels
1,2
1
Lugo G. Int J Endocrinol. 2012;2012:540398;
2
MelmedS. N EnglJ Med. 2006;355:2558–2573;
3
Chanson P et al.
Acromegaly. Handbook ofClinicalNeurology. 2014;124:197–219:
4
Daly AF. J EndocrinolInvest. 2005;28(11 SupplInternational):67–9
RARE CAUSES
3,4
•Ectopic peripheral GHRH
hypersecretion
•Eutopichypothalamic GHRH
hypersecretion
•GH hypersecretion from ectopic
pituitary adenomas, and
peripheral tumors like pancreatic
islet tumor or lymphoma
Genetic Causes :
•McCune Albright syndrome (>20% of
patients develop acromegaly)
•Multiple endocrine neoplasia (MEN) type 1
•Carney complex (~10% of patients develop
acromegaly)
•Familial isolated pituitary adenoma (FIPA)

6. Definition of ‘Rare’ Disease
•There is no single, widely accepted definition for rare
diseases.
•In theUnited States: "any disease or condition that affects
fewer than 200,000 people in the United States",or
about 1 in 1,500 people.
•In Japan, a rare disease is one that affects fewer than
50,000 patients in Japan, or about 1 in 2,500 people.
Rare Diseases Act 2002

7. IS ACROMEGALY RARE ?

8. ACROMEGALY : More common than you think
Acromegaly –considered “Rare” disease by National Organisation of
Rare Diseases
Belgian study (2006)
1
: 125 acromegaly cases/million of general
population
(9 acromegaly / 71,972 )
Banbury study (2008)
2
: 86 acromegaly cases/million of general
population
(7 acromegaly / 81,149)
>50% higher prevalence of acromegaly than earlier estimates
1.Daly AF et al. J Clin Endocrinol Metab 2006; 91: 4769–4775
2.Fernandez A, KaravitakiN & WassJAH Endocrine Abstracts 2008; 15: P228

9. Acromegaly : The Malaysian Scenario
Global Estimated prevalence : 40-70 cases / million population
•Malaysia : 1200-2100 cases
Global Incidence: 3-4 new cases / million / year
•Malaysia: 90-120 new cases/ year
Registry 2013-2016 : 129 patients are being treated nationwide
PICK UP RATE IS
MUCH LOWER
THAN THIS !
Only 10-15% of
cases are detected

10. Late to present and often missed
•Symptoms and signs may often be subtle
•Take 6-10 yrsto get diagnosed
1,2
•Often used in advantage ?
1
Melmed S. J ClinInvest 2009;119:3189–3202;
2
Schneider HJ et al. J ClinEndocrinolMetab2011;96:2074–2080

11. Pathological types
•Pituitary adenomas are classified as
–Microadenomas(≤ 10 mm diameter), and
–Macroadenomas(> 10 mm diameter)
•Macroadenomas: may cause local anatomic compression of local
tissue ("mass effect") –headache, visual field loss or
panhypopituitarism
•Macroadenomasare found in approximately 75%of acromegaly
1. Arafah BM. Endocr Relat Cancer 2001.
2. Lugo G. Int J Endocrinol. 2012
3. MelmedS. N EnglJ Med. 2006

12. Gigantism
•5% of GH secreting pituitary
adenomas present pre-pubertallywith
increased growth velocity
•Genetic origin (MEN 1, FIPA, X-LAG)
Robert Wadlow
•At 8 years : 1.8m
•Final Height 2.72m
•Died age 22

13. WHEN TO SUSPECT ACROMEGALY ?

14. MolitchME. Clinical manifestations of
acromegaly. EndocrinolMetabClinNorth Am.
1992

15. 28 yrs 49 yrs 65 yrs55 yrs
Greenspan & Strewler, Basic & Clinical Endocrinology, 5th Ed.,
1997 From ReichlinS. Acromegaly. Med Grand Rounds 1982;1:9
The importance at looking at old photographs

16. MrSB
14 years prior
Images shown with patient consent

18. Reid TJ et al. Features at diagnosis of 324 patients with acromegaly did not
change from 1981 to 2006: acromegaly remains under-recognized and under-
diagnosed.ClinEndocrinol(Oxf).2010.
Shoe size
Ring size

19. Presentation of Acromegaly
Mass effect GH/ IGF-1 effect
Headaches-60%
Visual field defects-10%
Panhypopituitarism

20. Pathophysiology
of Morbidity In
Acromegaly

21. Acromegaly : Presenting To The Endocrinologist
30% of acromegaly have DM at diagnosis
Rapidly worsening DM
Beta cell dysfunction-require insulin early
1.Pivonelloet al. Pituitary 2017.
2.Tiroshand Shimon. Pituitary 2017
3.Wolinskiet al. PLoSOne 2014
4. Reverteret al. PLoSOne 2014
60% of acromegalicshave nodular goiter
20% are toxic
Odds for thyroid cancer : 3.0
Menstrual irregularity, ED
Hypopituitarism

22. ACROMEGALY : OFTEN PRESENTS
TO THE NON-ENDOCRINOLOGIST
BUT

23. Acromegaly : Presenting To The Non-Endocrinologist
Hypertension –35% of acromegaly
Acromegaliccardiomyopathy –
poor prognostic indicator –40% five year
mortality
Commonest cause of death in acromegaly
1. Abreu et al. Pituitary 2016
2. Thomas et al ExpClinEndocrinolDiabetes 2017
3. van Haute et al. EurJ Endocrinol2008.
Sleep apnoea-in 80% of acromegaly
Prone to respiratory infections

24. Acromegaly : Presenting To The Non-Endocrinologist
Increased large bowel length
40% have polyps, 37% diverticular disease
Colon cancer risk (OR : 4.0)
1.Tiroshand Shimon. Pituitary 2017
2.Abreu et al. Pituitary 2016.
3.Mazziottiet al. Pituitary 2017
50% have joint disorders
Predisposed to fractures (HypovitD)
Acromegalicosteopathy
Nerve entrapment, kyphoscoliosis

25. Acromegaly : Presenting To The Non-Endocrinologist
Increased uvula and palate soft tissue
Upper airway obstruction, tongue biting
Swallowing difficulty, speech disturbance
Prognathism, bite malalignment
Difficulty chewing, Voice changes
1.Abreu et al. Pituitary 2016.
Hyperhydrosis
Skin tags
Acanthosis nigricans

26. Radiologists not spared

27. Presenting to the Psychiatrist
Don’t forget QOL : AcroQoL
Scales:
1 –Physical*
2.1 –Psychological/appearance**
2.2 –Psychological/personal relations***
Badiaet al. Health Qual Life Outcomes 2004

28. Acromegaly : Most of the time diagnosed by non-endocrinologist

29. UMMC Data : Acromegaly & Comorbidities
Cancer
Colonoscope polyp
OA
DM
HPT
Cardiomyopathy
11%
23%
17%
56%
45%
22%
unpublished

30. When to screen for acromegaly ?
•Acralenlargement are the most common presentation
•Acralenlargement + 2 or more co-morbids
Katznelsonet al. AACE guidelines for acromegaly. EndocrPrac. 2011

31. WATCH OUT : WHAT LIES AHEAD

32. Face Classification Software
Schenideret al. JCEM 2011

33. Schenideret al. JCEM 2011
Severe
Moderate
Mild
Software was better than general internists,
even expert endocrinologists

34. MORTALITY IN ACROMEGALY IS 2X
GENERALPOPULATION
Why we should not miss acromegaly

35. Acromegaly +
cardiac disease-
reduced survival >
10yrs

36. Factors Contributing to Increased Mortality in
Acromegaly Patients
1.WassJAH(ed)InHandbookofacromegaly.2001.Bioscientifica,Bristol
2.BatesASetal.QJM1993;86:293–299
3.RajasooryaCetal.ClinEndocrinol(Oxf)1994;41:95–102
4.OrmeSMetal.JClinEndocrinolMetab1998;83:2730–2734
5.WrightADetal.QJM1970;39:1–16
6.ColaoAetal.EndocrRev2004;25:102–152
7.JenkinsPJetal.ClinEndocrinol(Oxf)1997;47:17–22
8.MelmedSNEnglJMed2006;355:2558–2573
Elevated GH
concentration
2–4
Older age at
diagnosis
5
Increased risk
of colon
cancer
6–7
Diabetes at
diagnosis
3
Cardiovascular disease
or hypertension at
diagnosis
3,5
Duration
of
disease
3,5
Mortality
rate
Sleep apnea
8

37. GH matters –Mortality
•Studies in a number of
cohorts
•NZ study
•208 patients followed for
mean 13 years
•72 deaths
Holdawayet al. J ClinEndocrinolMetab2004

38. Importance of Early Diagnosis
•Milder disease-smaller tumors with better surgical
outcomes
•Reduces morbidity
•Improves mortality

39. HOW TO SCREEN FOR ACROMEGALY ?
What to do when you suspect acromegaly ?

40. Biochemical Screening
Measure IGF-1 :
•Typical facial features/ acralenlargement
•Several features : sleep apneasyndrome, type 2 diabetes mellitus,
debilitating arthritis, carpal tunnel syndrome, hyperhidrosis, and
hypertension
•Pituitary adenoma
GH is not relied upon for diagnosis, more often used for long term
monitoring
KatznelsonL et al. Acromegaly : an Endocrine Society clinical practice guideline.
J ClinEndocrinolMetab2014

41. IGF-1 Assay
•Immunoassay
•Normal IGF-1 excludes acromegaly
•Age matched references should be used
•Caveats in interpretation
Falsely ElevateIGF-1Falsely Reduce IGF-1
Pregnancy Malnutrition
Puberty Liver/ Renal failure
Hyperthyroidism OCPs
Uncontrolled diabetes
Untreated hypothyroidism
KatznelsonL et al. Acromegaly : an Endocrine Society clinical practice guideline.
J ClinEndocrinolMetab2014

42. Mr. SB
•IGF-1 : 880 ng/ml (101-267)
•GH : 5.4 µg/L
(Random sugar : 10.5mmol/L)
•Prolactin : 210 mIU/L, testosterone: 15 nmol/L,
•FSH: 1.1 IU/L , LH :2.4 IU/L
•AM cortisol : 466 nmol/L
•ft4: 16 pmol/L, TSH: 1.2 mIU/L
•HbA1c: 8.7%, renal function : normal
Images shown with patient consent

43. CONFIRMATORY TESTS

44. Confirmatory Test
•OGTT with GH levels
•GH levels are measured at 30 minutes interval for 2 hours during
OGTT
•Failure to suppress GH to a nadir of < 1µg/L following documented
hyperglycemia on OGTT
•Pituitary MRI to locate adenoma
Others
•Anterior pituitary function : AM cortisol, fT4, TSH, LH, FSH, PRL,
estradiol, testosterone should be done as well
•Visual field testing

45. MrSB : Pituitary MRI
Primary mode of
therapy
Surgical resection
of the pituitary
tumour

46. Diagnostic Algorithm
MelmedS. N EnglJ Med 2006;355:2558–2573

47. MANAGEMENT

48. GiustinaA et al. J ClinEndocrinolMetab2010
KatznelsonL et al. J ClinEndocrinolMetab2014
Treatment goals for acromegaly
Biochemical
control
Control
tumour
mass
Goals
Maintain
pituitary
function
Reverse or
attenuate
signs and
symptoms
Manage
co-morbidities
Reduce
mortality
risk

49. Surgery is mainstay treatment for Acromegaly

50. What are the chances of surgical cure ?
63
100
75 75
63 61
55 53
0
20
40
60
80
100
Hazer Jane Campbell NomikosCampbell, 2010Hazer, 2013 Jane, 2011 Nomikos, 2005
Microadenoma Macroadenoma

51. UMMC Data : Outcomes of Primary Surgery
0
10
20
30
40
50
60
70
Cured Persistence
38.9%
61.1%
%
Disease cure : post op GH nadir on OGTT < 1ug/ L and/ or
normalisedage matched IGF-1 , 6-12 months after primary
surgery
unpublished

52. 2 2
3
4
2
5
0
1
2
3
4
5
6
7
8
9
Before 2000 2000-2010 2010-2017
Number of patients
CuredPersistent
UMMC Data : Year of Primary Surgery & Outcomes
Unpublished

53. Medical Therapy Options
•Somatostatin Receptor Ligand
Octreotide, Lanreotide
Pasireotide
•Dopamine Agonist
Cabergolline
•GH-receptor antagonist
Pegvisomant

54. HoflandLJ et al. EndocrRev 2003;24:28–47
Width of arrows represent relative binding affinities
SSTR, somatostatin receptor subtype
SSTR2 and SSTR5 are the most prevalent SSTRs on GH-secreting pituitary
adenomas
SSAs are the current standard of medical care in
acromegaly
SSTR1 SSTR4SSTR5SSTR2SSTR3
LanreotideOctreotide Pasireotide
Preferentially bind to SSTR2Multireceptor binding

55. Acromegaly : Surgery is often not enough
Treatment Success (%) TumourcontrolAdverse Events
Surgery Micro (50-85%)
Macro (20-50%)
Excellent Surgical Cx
Radiotherapy
( Conventional/
SRS)
50% after5-10 yrsGood but slowHypopituitarism
DA 10-20% Modest Nausea,Dizziness
SERMS/ Estrogen10% Modest VTE
SRL
(Octreotide/
Lanreotide)
40-60% -50% tumour
shrinkage
GI symp, gallstones,
DM
GHRA-
Pegvisomant
> 90% None Liver dysfunction

56. Medical management of Acromegaly
Guistinaet al. Nat Rev Endocrinol2014

57. UMMC Data : Mode of Secondary Therapy
0 1 2 3 4 5 6
Second surgery
RT
SRS
DA
SA
Combination
unpublished

58. It has to be Multi Disciplinary Team Approach
Neuro-
Radiologist
Endocrinologist
Neuro-
Surgeon
Oncologist
Other Specialties

59. Someone to hold your patient’s hand
[email protected]

60. Take to your clinic/ ward message
•Acromegaly : not as rare as you think
•Have a high index of suspicion
•Often presentation is due to complications –such as losing
control of diabetes or sleep apnoea
•Low threshold to screen with IGF-1
•Refer to the endocrinologist
•If left untreated, morbidity is high
•MDT input with multimodal therapy is required in most
patients

61. Thanks & I can try to answer your questions