Thromboembolic and cerebrovascular events as initial clues to acromegaly: A clinical case series and review of pathophysiologic links

Abstract

Acromegaly is a rare endocrine disorder with an insidious onset and delayed diagnosis, and emerging evidence suggests a potential link to an increased risk of thromboembolic and cerebrovascular events. We present three cases where vascular events were the initial or incidental diagnostic clue. Case 1 involves a 52-year-old man with pulmonary embolism who was subsequently diagnosed with acromegaly. Case 2 describes a 30-year-old man with bilateral pulmonary embolism and a delayed diagnosis of acromegaly. Case 3 reports a 44-year-old man who presented with a transient ischemic attack, leading to the incidental discovery of a pituitary microadenoma and a diagnosis of acromegaly. All patients showed a clinical or biochemical response to therapy. These cases highlight the importance of considering acromegaly in patients with unexplained thromboembolic or cerebrovascular events, as early diagnosis and treatment are crucial for reducing long-term morbidity.

Key clinical message

This case links acromegaly with pulmonary embolism and ischemic stroke, emphasizing the importance of cardiovascular and thromboembolic risk management in these patients. Comprehensive evaluations are critical for early diagnosis and prevention.

Introduction

Acromegaly is an uncommon condition with an occurrence rate of 2.8–13.7 cases/100,000 individuals. It arises from excessive release of growth hormone (GH). Most patients are diagnosed at a later stage, experiencing an average delay of 4.5–5 years in diagnosis due to the gradual progression of the condition.^{1 –3} Typical clinical features of acromegaly include acral enlargement (86% of cases), changes in facial appearance (74%), excessive sweating (48%), joint pains (46%), and headaches (40%). Additional symptoms include hypogonadism, fatigue, weight gain, and galactorrhea. ⁴

Acromegaly can lead to a diverse array of complications such as high blood pressure, enlargement of the left ventricle of the heart, heart muscle disease, obstructive sleep apnea, insulin resistance, and the development of tumors (e.g. colon cancer).^2,3

Acute ischemic stroke is a prevalent cardiovascular complication, ranking second to ischemic heart disease in terms of its impact on disability and mortality in high-income countries worldwide. ⁵

Pulmonary embolism (PE) represents a significant contributor to mortality, morbidity, and the need for hospitalization on a global scale. In the year 2004, venous thromboembolism was responsible for the deaths of more than 317,000 individuals in six European nations, which collectively had a population of 454.4 million. ⁶ Rarely, acromegaly has been reported to present with PE. Here, we add weight to the theory they advocated that acromegaly may be a hypercoagulable state as we report a case from our pituitary clinic who presented with PE, which led to him being diagnosed with acromegaly.

Case history/examination

Case 1: A 52-year-old man with PE and subsequent stroke

A 52-year-old man with a history of type 2 diabetes mellitus and hypertension presented to the emergency room with sudden-onset shortness of breath and chest pain. On examination, he was tachypneic (respiratory rate 30 breaths/min) and tachycardic (heart rate 115 beats/min). There were no clinical signs of deep vein thrombosis. His D-dimer level was elevated at 40 µg/mL, while his troponin level was normal. An electrocardiogram showed no acute ischemic changes. A Computed Tomogrophy (CT) pulmonary angiogram confirmed a PE (Figure 1). A lower limb venous Doppler ultrasound was negative for deep vein thrombosis. The patient was started on anticoagulation with enoxaparin and transitioned to rivaroxaban. During his hospitalization, physical features suggestive of acromegaly were noted, including enlarged hands and feet, a prominent jaw and forehead (frontal bossing), and thickened skin with an enlarged tongue. Further investigations revealed an elevated serum insulin-like growth factor-1 (IGF-1) level of 853 µg/L (normal range 88–210 µg/L) and a GH level of 34.44 µg/L. An oral glucose tolerance test failed to suppress GH levels, confirming the diagnosis of acromegaly. A brain MRI revealed a large pituitary macroadenoma (Figure 2). The patient was referred for transsphenoidal surgery. Postoperatively, his acromegaly remained under control, with a normal IGF-1 level of 100 µg/L (normal range 61–195 µg/L). Two years later, he presented to the emergency department with sudden right-sided weakness and numbness. A neurological assessment confirmed right-sided hemiparesis and decreased sensation. A brain MRI revealed an acute infarction in the left middle cerebral artery territory, consistent with an ischemic stroke (Figure 3). A comprehensive workup for the stroke, including a transthoracic echocardiogram, 24-h Holter monitoring, and carotid Doppler ultrasound, did not reveal any cardioembolic or large vessel atherosclerotic source, suggesting a possible link to the underlying hypercoagulable state of acromegaly.

Figure 1.

A computed tomography pulmonary angiogram reveals extensive bilateral pulmonary embolism with filling defects in both the right and left main pulmonary arteries (indicated by arrows).

Figure 2.

A pituitary magnetic resonance imaging scan reveals the presence of a pituitary macroadenoma.

Figure 3.

Subacute left deep Middle cerebral artery (MCA) watershed infarct.

Case 2: A 30-year-old man with bilateral PE

A 30-year-old male with no prior medical history presented with acute dyspnea and pleuritic chest pain. A computed tomography pulmonary angiogram confirmed bilateral PE. He was treated with therapeutic enoxaparin and transitioned to oral warfarin for lifelong anticoagulation due to the unprovoked nature of the event. A thrombophilia screen, including tests for Factor V Leiden, prothrombin gene mutation, and antiphospholipid antibodies, was negative. Approximately 1 year later, the patient developed persistent headaches, new-onset hypertension, and diabetes mellitus. On clinical examination, he exhibited frontal bossing, coarse facial features, widened hands and feet, and thickened, oily skin. Visual field testing revealed bitemporal hemianopia. Biochemical evaluation showed elevated IGF-1 levels, and random GH levels were inappropriately elevated. A pituitary MRI revealed a sellar mass consistent with a pituitary macroadenoma compressing the optic chiasm. The patient underwent endoscopic transsphenoidal resection of the tumor. Histopathology confirmed a somatotroph adenoma. Postoperative IGF-1 levels declined significantly, indicating partial biochemical remission. However, follow-up testing 3 months later showed a marked increase in IGF-1. Long-acting octreotide (20 mg intramuscularly every 3 weeks) was initiated. Despite medical therapy, repeat testing 6 months later demonstrated persistently elevated IGF-1 levels. An MRI revealed regrowth of the pituitary lesion. The patient underwent a second transsphenoidal resection. Subsequent evaluations showed biochemical improvement and a reduction in tumor size on imaging.

Case 3: A 44-year-old man with transient ischemic attack

A 44-year-old gentleman with no significant past medical history was admitted with a suspected transient ischemic attack (TIA) after presenting to the Emergency Department with acute, transient left upper limb weakness. The episode resolved completely within an hour. On initial assessment, there was no history of dizziness, headache, or numbness. He reported a single episode of loss of consciousness 1 week prior to presentation. Neurological examination was normal. A brain MRI, performed as part of the TIA workup, incidentally revealed an oval, 9.3 × 5.2 mm pituitary microadenoma on the right side with hypointensity on contrast imaging and slight sagging into the sphenoid sinus, without suprasellar or cavernous sinus involvement. Further endocrine evaluation revealed a markedly elevated IGF-1 level of 532 ng/mL and a prolactin level >1000 mIU/L. Other pituitary hormones (TSH, FSH, LH) were within normal limits. These findings supported a diagnosis of acromegaly with concurrent hyperprolactinemia. The patient was initially managed medically with cabergoline and somatostatin analogs. However, a follow-up MRI showed an increase in tumor size, consistent with a macroadenoma, and the patient subsequently underwent successful transsphenoidal hypophysectomy on December 25, 2019. Postoperatively, he showed biochemical improvement and was maintained on long-acting somatostatin therapy (Table 1).

Table 1.

Summary of cases.

Feature	Case 1	Case 2	Case 3
Event type	PE	PE and ischemic stroke	Bilateral PE
Key vascular risk factors	Type 2 diabetes mellitus, hypertension	None	None
Clues at presentation	Enlarged hands and feet, prominent jaw and forehead, thickened skin, enlarged tongue	Frontal bossing, coarse facial features, widened hands and feet, thickened, oily skin	None (incidental finding)
Endocrine severity (IGF-1/GH)	IGF-1: 853 µg/L, GH: 34.44 µg/L	Elevated IGF-1 and random GH	IGF-1: 532 ng/mL, prolactin: >1000 mIU/L
Pituitary imaging features	Large pituitary macroadenoma	Sellar mass consistent with a pituitary macroadenoma compressing the optic chiasm	9.3 × 5.2 mm pituitary microadenoma
Treatment	Transsphenoidal surgery, anticoagulation	Endoscopic transsphenoidal resection (×2), long-acting octreotide	Cabergoline, somatostatin analogs, transsphenoidal hypophysectomy
Follow-up outcomes	Acromegaly under control, presented with stroke 2 years later	Partial biochemical remission, then regrowth of tumor, then biochemical improvement and reduction in tumor size	Biochemical improvement, maintained on long-acting somatostatin therapy

GH: growth hormone; IGF-1: insulin-like growth factor-1; PE: pulmonary embolism.

Discussion

Acromegaly is a chronic, debilitating disease that, in addition to its classic features, is associated with a number of comorbidities that increase mortality. While cardiovascular and metabolic complications are well recognized, the association with thromboembolic events is less established but of growing concern. ⁷ This case series highlights the varied presentation of thromboembolic events as the initial or incidental finding in patients with acromegaly, underscoring the importance of a high index of suspicion for this endocrine disorder in patients with unexplained vascular events.

Venous thromboembolism in acromegaly

Our first two cases presented with unprovoked PE, a life-threatening condition. The association between acromegaly and Venous Thromboembolism (VTE) was first suggested by Coffey and Cummins (1912).^8,9 More recent studies have provided evidence for a hypercoagulable state in acromegaly, characterized by abnormalities in coagulation factors. For instance, Erem et al. found elevated levels of fibrinogen and tissue plasminogen activator, and reduced levels of protein S and tissue factor pathway inhibitor in patients with acromegaly compared to controls.^10,11 These findings suggest a prothrombotic state that could predispose patients to VTE. The presentation of PE in our first two cases, in the absence of other identifiable risk factors in the second case, supports the notion that acromegaly itself is a risk factor for VTE. The diagnostic delay in the second case, where the patient was diagnosed with acromegaly a year after his PE, further emphasizes the need for clinicians to consider acromegaly in the differential diagnosis of unprovoked VTE, especially in younger patients. The management of VTE in patients with acromegaly follows standard clinical practice guidelines, including the use of anticoagulation. ¹² However, the underlying acromegaly should also be addressed to potentially reduce the long-term risk of recurrence.

Arterial thromboembolism and cerebrovascular events in acromegaly

Our third case presented with a TIA, and the first case developed an ischemic stroke 2 years after his initial presentation with PE. The association between acromegaly and cerebrovascular events is multifactorial. The local effects of the pituitary adenoma, such as compression of the cavernous sinus or the induction of aneurysms, can contribute to stroke risk.^13,14 However, systemic factors are also at play. Acromegaly is associated with several cardiovascular risk factors, including hypertension and diabetes mellitus, which were present in our first case. Furthermore, acromegaly is associated with endothelial dysfunction, inflammation, and oxidative stress, all of which can contribute to the development of atherosclerosis and arterial thrombosis. ¹⁵ The relationship between IGF-1 levels and thrombosis risk is complex and not fully understood, with some studies suggesting a positive correlation and others a negative one.^16,17 In our third case, the TIA led to the incidental discovery of the pituitary microadenoma, highlighting the importance of thorough investigation of even transient neurological symptoms. The workup for stroke and TIA in these patients should include a comprehensive evaluation for traditional risk factors, as well as an assessment for acromegaly if clinical suspicion is high. The management of cerebrovascular events in patients with acromegaly follows established guidelines for stroke and TIA, ¹⁸ with the addition of specific treatment for the underlying acromegaly.

Clinical lessons from the cases

This case series offers several important clinical lessons. First, it demonstrates that thromboembolic events can be the presenting feature of acromegaly, even in the absence of the classic physical stigmata of the disease. This was particularly evident in our second and third cases. Second, it highlights the importance of considering acromegaly in the differential diagnosis of unprovoked thromboembolic events, especially in younger patients. Third, it underscores the need for a comprehensive evaluation for acromegaly in patients with cerebrovascular events, even when other risk factors are present. The incidental finding of a pituitary adenoma in our third case is a testament to this. Finally, these cases illustrate the importance of a multidisciplinary approach to the management of patients with acromegaly and thromboembolic events, involving endocrinologists, hematologists, and neurologists.

Limitations

This is a small, retrospective case series, and as such, it has several limitations. The small number of cases limits the generalizability of our findings. The retrospective nature of the study means that we were unable to collect all the data we would have liked, such as measurements of inflammatory markers or assessments for sleep apnea. Furthermore, we cannot definitively establish a causal link between acromegaly and the thromboembolic events in our patients, although the temporal association and the absence of other identifiable causes in some cases are suggestive.

Conclusion

In conclusion, hypercoagulability is a significant and often overlooked complication of acromegaly, potentially leading to serious outcomes. Future research in acromegaly should address this issue, aiming to determine its prevalence, underlying pathophysiological mechanisms, and effective preventive measures.