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Autonomic Dysfunction in Acromegaly: A Case Report

Narendra Kotwal*, Shrikant Somani*, Vimal Upreti*, Yogesh Kumar*


Abstract
Orthostatic hypotension commonly presents in patients with chronic illnesses like
hypertension, diabetes mellitus, chronic kidney disease and LV dysfunction.
Autonomic dysfunction is often overlooked as a cause for orthostatic hypotension
that can lead to increased morbidity and mortality. Though autonomic
dysfunction on electrophysiological testing has been described in patients with
acromegaly, symptomatic dysautonomia resulting in orthostatic hypotension has
not been previously reported in literature. Here we present a case of acromegaly
who presented with postural hypotension. RR variability based clinical tests
showed presence of autonomic insufficiency. His symptoms improved with
conservative measures.

Keywords: Acromegaly, Autonomic dysfunction, RR variability.


Introduction
Cardiovascular complications are the most common (70-240), non-suppressible growth hormone (GH)
cause of morbidity and mortality in patients with response (basal GH-84.2 ng/ml, post 75gm glucose
acromegaly.1 Cardiac autonomic dysfunction has suppression 60 min-78.1 ng/ml, 120 min-76.6 ng/ml;
been proposed as one of the mechanism for normal response < 1 ng/ml). Other biochemical tests
increased cardiovascular risk, however, clinically including blood glucose (FPG/ PPG-84/128 mg/dl)
symptomatic autonomic dysfunction has rarely been and hormonal profile [T4-8.16 µg/dl (5.5-13.5),
reported in acromegaly. Here we report a patient TSH-1.9 uIU/ml (0.5-6.5), prolactin-10.2 ng/ml
with acromegaly who was symptomatic with (<25), Testosterone-5.6 ng/dl (3-12), LH-5.7 IU/L
orthostatic hypotension, demonstrated to have (2.5-9.8), FSH-4.8 IU/L (1-12), basal cortisol-14
autonomic insufficiency using Ewing’s and µg/dl (12-25)] were normal. Imaging studies
Bellavere’s criteria, which was satisfactorily revealed a pituitary macroadenoma (46 x 21 x 20
managed with high salt intake, compression mm) abutting the optic chiasma (fig. 1). Transnasal
stockings and other conservative measures. transsphenoidal (TNTS) adenomectomy was tried,
however, adenoma could not be excised fully. Three
Case Report months later, repeat TNTS was tried for persistent
clinically and biochemically active acromegaly.
A 31 year old male presented with history of However, still the response was sub optimal [non
progressive increase in size of hands and feet, suppressed growth hormone nadir GH-40.4 ng/ml,
headache and weight gain over past 2 years. He also persistent pituitary macroadenoma sized 32 x 26 x
gave history of coarsening of facial features, 18 mm with normal remaining pituitary function]
hollowness in quality of voice, sweaty and sticky that was treated with external beam radiotherapy
palms and face. There was no history suggestive of (total dose of 54 Gy given as 28 cycles of 2 Gy
any other hormonal excess or deficiency or any each). After around 4 weeks of completion of
other significant illness in the past. Clinically, he radiotherapy, he presented with complaints of
had acromegaloid features. General physical and postural giddiness and lethargy. There was no
systemic examination was unremarkable and he was history suggestive of hypothalamic dysfunction,
clinically euthyroid, eucortisolemic and eugonadal. volume loss or intake of any medications known to
Evaluation showed an elevated IGF-1-912 ng/ml cause such symptoms.

*
Department of Endocrinology, Army Hospital, Research & Referral, New Delhi, India-110010.
Correspondence to: Dr Shrikant Somani, Department of Endocrinology, Army Hospital, Research & Referral, New Delhi,
India-110010.
E-mail Id:shri_somani2004@yahoo.co.in

© ADR Journals 2015. All Rights Reserved.


Kotwal N et al. 2

Figure 1.Imaging studies revealing a pituitary macroadenoma abutting the optic chiasma

He had postural fall in blood pressure [fall in control of GH excess along with conservative
Systolic blood pressure (SBP)/ Diastolic blood measures for postural hypotension.
pressure (DBP): 30/14 mmHg] with unremarkable
systemic examination. He had persistent elevated Discussion
IGF-1-578 ng/ml (70-240), non suppressed GH
(nadir GH-22.1 ng/ml) with euhormonal status for Autonomic dysfunction is commonly associated
rest of the hormones [serum cortisol (Basal/ with Diabetes mellitus (DM), spinal cord diseases,
stimulated-13.1/22.2 ug/dl), T4-11.0 (5.5-13.5) Parkinson’s disease, Multi-system atrophy, Multiple
µg/dl), LH-5.6 (2.5-9.8) IU/L, FSH-6.3(1-12) IU/L, sclerosis, Guillain Barre syndrome, pure autonomic
Testosterone-4.9 (3-12) ng/dl, Prolactin-7.2 (< 25) failure and toxic neuropathies (alcohol, porphyria,
ng/ml]. Autonomic function tests showed abnormal botulism). Out of various dysautonomic features,
response suggestive of autonomic insufficiency cardiovascular autonomic neuropathy is undoubtedly
[Heart rate variability (HRV) testing using Ewing’s the most extensively investigated aspect of
protocol: Severe CAN (Cardiovascular Autonomic autonomic neuropathy and is associated with
Neuropathy) and using Bellavere’s criteria: Definite alterations in resting heart rate, cardiovascular
CAN]; while 2D echocardiography, Holter reflexes and circadian heart rate variability (HRV).
monitoring and nerve conduction study were Patients with acromegaly commonly show
normal. MRI of brain revealed a residual pituitary cardiovascular autonomic dysfunction on
macroadenoma (32 x 26 x 18 mm) with no electrophysiological tests,1,2,3 however, symptomatic
hypothalamic involvement. Other possible causes of orthostatic hypotension has not been reported
autonomic failure including porphyria, and toxin earlier.
exposure were excluded by relevant history,
examination and laboratory evaluation. Thus, Acromegaly characterized by GH/IGF-1 excess
autonomic insufficiency was attributed to affects almost all the organ systems in the body.
acromegaly itself. He was managed conservatively Hypertension, asymptomatic left ventricular
with increased salt intake, postural exercises, diastolic dysfunction, congestive cardiac failure,
compression stockings and life style modifications arrhythmias are cardiovascular manifestations seen
like crossing legs before rising from lying down in acromegaly. Cardiovascular autonomic
position, avoidance of prolonged standing and hot dysfunction has also been demonstrated as one of
showers. He showed remarkable improvement in his the potential factors for increased cardiovascular
symptoms in 3-4 days and postural fall in blood morbidity and mortality in these patients.1 The exact
pressure also improved quantitatively (SBP/DBP pathophysiologic mechanism of autonomic
16/6 mmHg), however, HRV based autonomic dysfunction in this group of patients is not known.
abnormalities persisted even after 1 month of follow GH/IGF-1 excess per se has been considered to be
up. Presently, the patient is on injectable octreotide an important factor causing cardiovascular
LAR (30mg once a month intramuscularly) for dysfunction.1 Oz O et al.3 in their study reported

ISSN: 2349-7181 J. Adv. Res. Med. 2015; 2(2): 1-5.


3 Kotwal N et al.

presence of asymptomatic autonomic dysfunction in Similarly, in our patient, the heart rate variability
18 male acromegaly patients compared to 18 healthy tests were persistently abnormal even when
matched controls. They showed presence of both treatment measures resulted in improvement of
sympathetic and parasympathetic autonomic orthostatic hypotension. Dural et al.1 in their study
dysfunction by demonstrating abnormalities in SSR of 20 acromegaly patients reported asymptomatic
(sympathetic skin response) and RRIV (RR interval impairment of cardiac autonomic function compared
variability) respectively. Similarly, in our patient as to 32 matched controls and found significant
well, both the heart rate and the blood pressure tests negative correlations between the disease duration
were abnormal suggestive of parasympathetic and and heart rate recovery parameters (HRR1, HRR2,
sympathetic autonomic dysfunction respectively. HRR3).
Clinical tests based on heart rate variability are
useful for detecting autonomic dysfunction in First consideration in treatment of orthostatic
diabetes (table 1). An increased resting heart rate hypotension should be avoidance of situations
and loss of heart-rate variation in response to deep known to exacerbate symptoms, such as prolonged
breathing are primary indicators of parasympathetic standing, physical exercise after meals, exposure to
dysfunction. Tests for sympathetic dysfunction a warm environment, prolonged hot baths, alcohol
include measurements of heart rate and blood ingestion, large carbohydrate-rich meals and
pressure responses to standing, exercise, and avoidance of vasoactive drugs such as anti-
handgrip. The criteria for the diagnosis were laid hypertensives, tricyclic anti-depressants. Helpful
down by Ewing (table 2) and Bellavere (table 3). As physical maneuvers include crossing the legs while
to the selection of tests, the Ewing battery of five standing, squatting, abdominal compression,
tests was recommended by the San Antonio bending forward and use of external support like
conference on diabetic neuropathy, while after a elastic compression stockings. Fludrocortisone (100
consensus in 1992, the American Diabetes mcg once or twice daily) is given if non-
Association and American Academy of Neurology pharmacological measures fail. Other useful drugs
utilizes the Bellavere’s criteria for diagnosis of include midodrine, clonidine and octreotide.4 Our
CAN. Ewing’s criteria were based on tests for patient was treated along the same lines and showed
parasympathetic as well as sympathetic components good response with conservative measures alone.
(5 tests) while Bellavere’s criteria were based only
on the tests of parasympathetic components (3 Conclusion
tests).5 We used these recommended tests for
diagnosis and categorization of CAN for diabetic Patients with acromegaly are prone to have
patient in our patient as well as there are no clear cut autonomic dysfunction depending upon the duration
recommended tests in patients with acromegaly. of disease, severity of disease activity and response
to treatment. Those demonstrating signs and
Resmini et al.2 evaluated the sympathovagal balance symptoms related to dysautonomia should be tested
in acromegalic patients by performing power for presence of autonomic dysfunction. Heart rate
spectral analysis of heart rate variability in variability is standard measure for assessment of
clinostatism and orthostatism using a frequency cardiovascular autonomic dysfunction. Whether
domain method. They concluded that there is routine evaluation of all patients of acromegaly for
sympathovagal imbalance in acromegalic patients, autonomic dysfunction, for cardiovascular risk
due to vagal hypertone, and that it is difficult to stratification, is required or not is a matter of future
reverse and is not influenced by medical therapy. research.

J. Adv. Res. Med. 2015; 2(2): 1-5. ISSN: 2349-7181


Kotwal N et al. 4

S. No. Test Parameter Criteria Category Score


1. Deep breathing test Delta heart rate >15 Normal 0
11-14 Borderline 1
<10 Abnormal 2
2. Valsalva Maneuver Valsalva Ratio >1.21 Normal 0
1.11-1.20 Borderline 1
<1.10 Abnormal 2
3. Handgrip test Change in diastolic pressure >16 Normal 0
11-15 Borderline 1
<10 Abnormal 2
4. Cold pressor test Change in diastolic pressure >16 Normal 0
11-15 Borderline 1
<10 Abnormal 2
5. Lying to standing test/ Fall in systolic pressure <10 Normal 0
Head-up tilt (mmHg)*
11-20 Borderline 1
>20 Abnormal 2
30:15 ratio >1.04 Normal 0
1.01-1.03 Borderline 1
<1.01 Abnormal 2
*
Ewing’s original criteria for abnormal was fall more than 30 mmHg. The criteria were modified in line with current
definition of orthostatic hypotension.
Table 1.Test for assessment of autonomic function with cut-off limits5

Tests used with scoring as mentioned in table 1  Deep breathing test (delta heart rate)
 Valsalva maneuver (Valsalva ratio)
 Lying to standing (30:15 ratio)
CAN classification as per total score 0-1 = no CAN
2-3 = early CAN
4-6 = definite CAN
Table 2.Categorization as per Bellavere criteria5

Tests used with scoring as mentioned All the above mentioned tests in table 1 except the cold pressor
in table 1 test
CAN classification as per total score Normal = all tests normal or 1 test borderline.
Early = one of the three heart rate tests abnormal or two
borderline.
Definite = two heart rate tests abnormal.
Severe = two heart rate tests abnormal + one or both BP tests
abnormal.
Table 3.Categorization as per Ewing’s method5

References Electrophysiological assessment of the


autonomic nervous system in male patients with
1. Dural M, Kabakci G, Cinar N et al. Assessment acromegaly. Eur Neurol 2011; 66(1): 1-5.
of cardiac autonomic functions by heart rate 4. Vinik AI, Erbas T. Recognizing and treating
recovery, heart rate variability and QT diabetic autonomic neuropathy. Cleveland
dynamicity parameters in patients with Clinic Journal of Medicine 2001; 68(11): 928-
acromegaly. Pituitary 2014; 17: 163-70. 44.
2. Resmini E, Casu M, Patrone V et al. 5. Khandelwal E, Jaryal A, Deepak KK. Pattern
Sympathovagal imbalance in acromegalic and prevalence of cardiovascular autonomic
patients. J Clin Endocrinol Metab 2006; 91: neuropathy in diabetics visiting a tertiary care
115-20. referral centre in India. Indian J Physiol
3. Oz O, Taslipinar A, Yucel M et al. Pharmacol 2011; 55(2): 119-27.

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Appendix
Abbreviations
DM-Diabetes Mellitus

CAN-Cardiovascular Autonomic Neuropathy

GH-Growth Hormone

LH-Luteinizing hormone

FSH-Follicle stimulating hormone

T4-Tetra-iodo thyronine

TSH-Thyroid stimulating hormone

HRV-Heart rate variability

IGF-1-Insulin like growth factor 1

HRR1-Heart rate recovery at 1 second

HRR2-Heart rate recovery at 2 second

HRR3-Heart rate recovery at 3 second

FPG-Fasting plasma glucose

PPG-Post prandial plasma glucose

MRI-Magnetic resonance imaging

Gy-Gray

J. Adv. Res. Med. 2015; 2(2): 1-5. ISSN: 2349-7181