DID GOLIATH OF GATH HAVE A MEDICAL CONDITION?

Dr. Yonit Marcus

Case presentation • A 58 year-old man • Cab driver, married +2 • Family history= Mother-HTN

• Past medical history

• HTN

• 15 years • Not controlled on multiple medications • Verapamil SR 240 mg/day • Doxazosin 2mg*2 /day • Valsartan 80 mg /day

• OSA

• 5 years • Sleeps with CPAP

• Bilateral carpal tunnel syndrome per EMG

Case presentation Multinodular goiter- s/p Rt. hemithyroidectomy 2010-follicular

hyperplasia Intubation at surgery was very hard No Parathyroid tissue

Choanal atresia

2010 follow up at blood pressure clinic.

• Coarse and large hands • Large nose • Nasal voice

Suspected acromegaly

Current illness • No vision disturbance • No headache • Fatigue • PE:

• Acral enlargement • Coarse and large nose • Multiple skin tags • Large tongue with teeth marks • ↑ BP

• Lab • Blood sugar-N • Phosphor –H/N

2011 2001 1995

12/05/2011 IGF1 (7-47 nmol/L) 137 GH (0-5 ng/ml) 2.4 TSH (0.39-4 uIU/ml) 4.56 Free T4 (0.8-1.5 ng/dl) 1.1 Cortisol (mcg/dl) 10.3 Prolactin (1-18 ng/ml) 7 LH mIU/ml 2 FSH mIU/ml 6.5 Testosterone (1.81-7.72 ng/ml) 1.84

Normal response to 250 mcg ACTH stimulation test

75 gr OGTT

Time (minutes) 60 90 120

GH (ng/ml) 7.25 7.34 8.29

Glucose mg/dl 131 142 150

In normal subjects GH level falls to less than 0.3ng/ml after OGTT

Pituitary MRI

T1 with contrast •6*9 mm right pituitary mass

•Possible extension to the left

•Not in proximity with the optic chiasm

TOPICS • Introduction • Acromegalic CMP • Prevalence of HTN • Pathogenesis of HTN • Reversibility with treatment

Acromegaly : introduction

• Prevalence: 40 to >100 cases per million • Diagnosis delayed: approx. 4-10 y • Approx. 40% diagnosed by internist • Others include:

• Primary care practitioners, ophthalmologists, dentists, gynaecologists, rheumatologists and sleep disorder specialists

• At time of diagnosis >75% macroadenoma

Acromegaly : introduction

• Acromegaly is associated with a X2- to 3 increased morbidity and reduced life expectancy. • Excess mortality is mostly d/t CVS and cerebrovascular dis. and can be reduced when serum GH & IGF-I are ↓. • Determinants of mortality are cardiovascular complications, ↑GH concentrations, HTN, and heart dis.

Hypertension, cardiomyopathy, valvular disease

Glucose intolerance/

diabetes mellitus

Acromegaly comorbidities

Hypopituitarism, hypogonadism

Colon polyps

Respiratory complications,

sleep apnea

Cerebrovascular events, headache

Adaped from Colao, et al. Endocr Rev, 2004

Osteoarthritis, osteoporotic fractures

Acromegalic comorbidities

The acromegalic cardiomyopathy

• Clear-cut LVH is found in most pts. at diagnosis, overall in those with long disease history, and interstitial fibrosis constitutes the main abnormality at histology • Subsequently, gradual impairment of heart architecture by increased extracellular collagen deposition, myofibrillar derangement, areas of monocyte necrosis, and lympho- mononuclear infiltration occurs, thus configuring a pattern of myocarditis.

The acromegalic cardiomyopathy

• HTN is likely the most important factor aggravating cardiac hypertrophy and has higher prevalence in aged pt. • Studies of the coronary artery disease in acromegaly are very scant (reported between 3% and 37%).

Cardiomyopathy

• Hormonal control improves LVH and cardiac dysfunction

• SRL may cause asymptomatic bradycardia

Acromegalic

Colao, et al. JCEM, 2004. Colao, et al. JCEM, 2008. De Marinis. Pituitary, 2008. Reproduced with kind permission from Maison, et al.

Acromegaly : prevalence of HTN • HTN is considered one of the most relevant negative prognostic factors for mortality in acromegaly. • The prevalence of HTN in acromegaly ranges from 18% - 60% in different series, and its incidence is higher than in the general population (ABPM? proper controls? m/p 40% vs. 8%). • Predominantly DBP, is less frequently related to a family history of HTN and is poorly related to IGF-1 levels • However, despite its importance, the physiopathological mechanisms of HTN have not yet been well clearly established.

Pathogenesis -1 • Increased plasma volume and an increase in the total exchangeable sodium pool. • Kamenicky et al , Endocrinology 2008 – found in GC rats, that GH, in concert with IGF-I, stimulates ENaC-mediated sodium transport in the late distal nephron, accounting for the pathogenesis of sodium retention in acromegaly.

Pathogenesis -2 • Reduced levels of Nitric oxide (NO) may contribute to increased vascular resistance, increased platelet aggregation, stimulation of VSMC proliferation. • Platelet NO is reduced in acromegalic pts., compared with controls. • eNOS protein concentrations were significantly reduced in the platelets of pt. compared with controls. • The NO levels are inversely correlated with GH/IGF-1 and disease duration. This low expression and availability of nitric oxide could be implicated in vascular alterations and increased atherogenic risk affecting acromegalics.

Ronconi ;Blood Pressure. 2005

Pathogenesis -3 • Aldosterone secretion and regulation are normal and so are ANP and the RAAS (Mulatero, et al JCEM 2006 – 344T/C CYP11B2 gene polymorphism is linked to the risk of HTN in pts. affected by acromegaly and so are Angiotensinogen MT and AT1R CC1166 genotype- in Turgut et al Mol Biol Rep- 2011). • There is no evidence for the activation of the adrenergic system ie plasma Epi/NE were normal both basally and after hyperinsulinemic clamp.

Pathogenesis -4 • Insulin resistance and diabetes is associated with higher BP and a non dipping effect on ABPM. • Increased cardiac output and cardiac index – SVR (both ↓

and ↑).

• Endothelial dysfunction, according to Folkow’s hypothesis- the increased BP in GH excess could directly originate from an increased thickness of wall resistance vessels. Is there a direct negative effect of GH and IGF-I hypersecretion on endothelial function? • OSA

Obstructive sleep apnea • Repetitive nocturnal desaturations are associated with arterial and pulmonary HTN, AF and right heart failure in hypoxemic subjects. • OSA may affect 60–70% of acromegalics, M>F and more in

HTN pts. • It is caused by pneumonomegaly, narrowing of the upper airways, hormonal rhinitis, nasal polyps and enlargement of the laryngeal cartilages, epiglottis, tongue (macroglossia) and pharyngeal structures. • There are contradictory results concerning OSA in pts, treated surgically and/or pharmacologically for acromegaly.

Obstructive Sleep apnea syndrome

• Degree of OSA correlates positively with the disease activity (IGF-I levels) but +/- with the duration of the disease

• The parameters of the MetSy are positively associated to the degree of OSA in acromegalic pts.

OSA only partially reversible with biochemical control of acromegaly – a reduction in soft tissue swelling?

Davi, et al. Eur J Endocrinol. 2008. & Rommler Sleep Breath (2012

Treatment effects

• Transsphenoidal adenomectomy has been reported to reduce the LVM and improve diastolic performance if dis. control is obtained . A prompt reduction in cardiac mass occurs in pts. treated with SSA • Beneficial effects of treatment with SSA were reported on HR as well (a direct effect on the conduction sys). • No significant difference in BP was demonstrated in more prolonged studies with octreotide, octreotide LAR or lanreotide or pegvisomant (Colao et al 2006).

Mortality

• Increased mortality in uncontrolled acromegaly

• Radiotherapy associated with increased mortality compared with other therapies • More data needed on

stereotactic radiation therapy • Over-replacement of

hydrocortisone can affect mortality

• Co-existing adrenal insufficiency may impact mortality

Reproduced with kind permission from Dekkers, et al. JCEM, 2008. Copyright The Endocrine Society (2008)