Stubborn hiccups as a sign of massive apoplexy in a naive acromegaly patient with pituitary macroadenoma

Background

Pituitary apoplexy is a term used for hemorrhage or infarction of pituitary adenomas. It is usually observed in patients with nonfunctioning adenomas; however, apoplexy of other tumor types, like prolactinomas and GH-secreting adenomas have been reported before (1, 2). Headache is its main symptom, and visual disturbances and/or ocular palsy can sometimes accompany (3). Apoplexy may very rarely present with hiccups, which is probably due to midbrain involvement (4).

Although PA is often followed by hypopituitarism in nonfunctioning adenomas, functioning ones occasionally demonstrate hormonal remission after an apoplectic episode. Accordingly, spontaneous remission of acromegaly due to apoplexy has been reported before (5, 6, 7).

Herein, we report the case of an undiagnosed acromegalic man with infarctive pituitary apoplexy and stubborn hiccups who demonstrated normal GH dynamics and serum insulin-like-growth factor type 1 (IGF1) level at presentation and became growth hormone deficient following decompression surgery.

Case presentation

A thirty-two-year-old man was admitted to our out-patient clinic with the story of headache, nausea, vomiting and stubborn hiccups that began five days before. On physical examination, he has most of the physical features of acromegaly; thickening of facial skin and typical acromegalic face, increased hand, finger and foot size. He had dehydration and hypotension on admission.

Investigation

His hormonal profile was thyroid-stimulating hormone: 0.007 pmol/L (0.4–4.6), free thyroxine: 12.2 pmol/L (11.5–22.7), random cortisol: 4.71 µg/dL (4.3–22.4), follicle-stimulating hormone: 2.52 IU/mL (1.42–15.4), luteinizing hormone: 1.14 IU/mL (1.24–7.8), total testosterone: 0.0 ng/mL (2.41–8.27) and prolactin: 0.43 ng/mL (2.1–17.7). His IGF1 was normal (229 ng/mL; 119–307) with random GH: 2.53 ng/mL (0.0–3.0).

Pituitary MRI demonstrated an adenoma with suprasellar extension abutting the optic chiasm, showing ring enhancement with gadolinium. The images were compatible with apoplexy (Fig. 1).

Figure 1

MRI findings of the patient on admission. (A) Pre- and post-contrast coronal T1-weighted images showing an heterogeneous pituitary mass with suprasellar extension abutting the optic chiasm and ring enhancement with gadolinium. (B) Pre and Post-contrast sagittal T1-weighted images. (C) Coronal T2 -weighted image. T1-weighted hyperintense areas and T2-weighted hypointense areas within sellar mass are consistent with pituitary apoplexy.

Diagnostic work-up for hiccups was performed, including biochemical analyses for renal and hepatic functions, electrocardiogram for ruling out myocardial infarction, X-ray of the chest and abdominal ultrasound for eliminating diaphragm irritation, neurological and otolaryngologic examination. All were found to be negative. He denied alcohol consumption or medication use.

On the third day of his admission, growth hormone suppression test with 75 g oral glucose was performed. His plasma GH levels exhibited suppression (below <1 ng/mL) at all time points.

Treatment

Urgent treatment with intravenous glucocorticoids and fluids were introduced and he dramatically improved within few hours of treatment and the frequency of hiccups decreased, although not completely disappeared.

On the sixth day of admission, he underwent transsphenoidal pituitary surgery. The tumor was removed with preservation of the surrounding gland.

Outcome and follow-up

The patient did well postoperatively, and the hiccups completely disappeared. The tumor was semi-rigid and was gray in color with no hemorrhage at gross examination. Histological work-up demonstrated an adenoma with ischemic necrosis and absence of hemorrhage. Immunohistochemical staining exhibited GH and prolactin positivity over 90% (Fig. 2).

Figure 2

Pathological and immunhistochemical work-up of the operation specimen. The histology of the tumor showed a necrotic adenoma (A) with extensive areas of necrosis (B) (hematoxylineosin stain ×100). Most of the necrotic cells were immunopositive for GH and prolactin (C, D) (immunohistochemistry ×200).

At follow-up, he demonstrated central hypogonadism and hypothyroidism with intact cortisol axis. He was GH deficient both at the first and third postoperative month (GH: 0.2 and 0.16 ng/mL, IGF1: 86.7 and 85.5 ng/mL, respectively).

Discussion

Pituitary apoplexy is a life-threatening, clinical syndrome of pituitary infarction with hemorrhage and/or necrosis. Precipitating factors cannot be identified in all cases. The most relevant clinical situations associated with PA are angiographic procedures, surgery, closed head trauma, dynamic tests and drugs (3). Most commonly presenting symptoms are headache, ophthalmoplegia, nausea and/or vomiting. The clinical manifestations of PA are related to underlying pathological mechanism, including increased intrasellar pressure, mass effect, compression of neighboring structures and nerves within the cavernous sinus and/or subarachnoid hemorrhage. Apoplexy may very rarely present with hiccups, which is probably due to midbrain involvement.

Pituitary apoplexy is usually observed in patients with nonfunctioning adenomas. When it arises in functional adenomas, it may result in spontaneous remission due to massive necrosis or hemorrhage (8). Accordingly, the potential functioning nature of the adenoma that undergoes apoplexy may not be assessed due to the extensive necrosis.

Partial or complete hypopituitarism is evident in most patients at presentation. Acute adrenal insufficiency is the most common deficit. It is also the most life-threatening hormonal complication, and corticosteroid supplementation should be given to all these patients immediately.

This is a very rare naive case of acromegaly with pituitary macroadenoma who presented with infarctive apoplexy and stubborn hiccups and normal GH dynamics. The GH secretion potential of the tumor was clearly demonstrated immunohistochemically.

Hiccups are involuntary contractions of the diaphragm. Brief episodes are usually benign and self-limiting but prolonged attacks are frequently associated with an underlying pathologic process. A reflex arc involving peripheral phrenic, vagal and sympathetic pathways and central midbrain modulation is responsible for hiccups (9). Accordingly, any physical and chemical factors, inflammation and neoplasia invading the arc may cause hiccups.

Hiccup is a rare symptom of acute apoplexy, which is attributed to the involvement of central processing unit in the midbrain. Although the exact pathophysiological mechanisms have not been clearly demonstrated till now, elevation in intrapituitary pressure due to apoplexy may be an explanation for the hiccups of this individual case (10). Hypothetically, it may be proposed to be a sign of generalized infarction of the large tumor irritating the midbrain. This infarction was so massive that he had normal GH dynamics even though he exhibited clear signs of acromegaly on admission. Surprisingly, his serum IGF1 level was low, and this might be explained by possible subclinical pituitary infarctions he experienced within the previous months. Stubborn hiccups in a patient with a pituitary macroadenoma may be a sign of massive apoplexy.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent has been obtained from the patient for publication of the case report and the accompanying images.

Author contribution statement

G S Bagir was responsible for case description, literature review and writing; S Civi and Özgür K are neurosurgeons; F K Selcuk performed histological studies and provided clinical care for the patient; M E Ertorer was responsible for case description, literature review and editing.