An Ectopic Cushing’s Syndrome with Severe Psychiatric Presentation

Posted on January 12, 2024 by MaryO

an-ectopic-cushingrsquos-syndrome-with-severe-psychiatric-presentation-9744

We report a case of severe EAS in a young Tunisian man resulting from a well differentiated Neuroendocrine Tumor (NET) of the lung. Besides catabolic signs and profound hypokalemia orienting towards Cushing’s Syndrome (CS), psychiatric symptoms were particularly severe, dominant and atypical including persecutory delusions, depression and anxiety.

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Radiation-induced Undifferentiated Malignant Pituitary Tumor After 5 Years of Treatment for Cushing Disease

Posted on December 11, 2023 by MaryO

Abstract

The occurrence of a second neoplasm possibly constitutes an adverse and uncommon complication after radiotherapy. The incidence of a second pituitary tumor in patients irradiated for adrenocorticotropic hormone secreting pituitary adenoma is rare. We report a case of a 40-year-old female with Cushing disease who underwent surgical management followed by radiotherapy. After 5 years of initial treatment, an increase in tumor size was evident at the same location, with a significant interval growth of the parasellar component of the lesion. Histology revealed an undifferentiated highly malignant sarcoma. In the span of next 2 years, the patient was followed with 2 repeat decompression surgeries and radiotherapy because of significant recurrent compressive symptoms by locally invasive malignant tumor. Despite the best efforts, the patient remained unresponsive to multiple treatment strategies (eg, surgical resections and radiotherapy) and succumbed to death.

Introduction

Radiation therapy is a commonly used modality for primary or adjuvant treatment of pituitary adenoma. It is also used as an adjuvant therapy for Cushing disease with persistent or aggressive tumor growth or recurrent disease after surgery. The immediate sequelae of radiotherapy for pituitary tumors include nausea, fatigue, diminished taste and olfaction, and hair loss [1]. One frequent long-term side effect is hypopituitarism. The incidence rate of new-onset hypopituitarism after conventional radiotherapy is approximately 30% to 100% after a follow-up of 10 years, whereas after stereotactic radiosurgery or fractionated radiotherapy, the incidence is approximately 10% to 40% at 5 years [2].

The occurrence of a second neoplasm after cranial radiotherapy constitutes possibly one of the most adverse complications. Tumors such as meningioma, glioma, and sarcoma are the most frequently reported secondary neoplasms after pituitary irradiation [3]. The cumulative probability of a second brain tumor in patients irradiated for pituitary adenoma and craniopharyngioma is approximately 4% [4].

We report 1 such case with detailed clinical, histopathological, and radiological characteristics because of its rarity and associated high mortality of radiation-induced sarcoma.

Case Presentation

The patient first presented at 40 years of age with complaints of weight gain, new-onset diabetes mellitus, hypertension, and cushingoid features in 2014. She was diagnosed with Cushing disease (24-hour urinary cortisol 1384 mcg/24 hours [3819 nmol/24 hours; reference >2 upper limit of normal], low-dose dexamethasone suppression test serum cortisol 16.6 mcg/dL [457.9 nmol/L], ACTH 85 pg/mL [18.7 pmol/L; reference range, <46 pg/mL, <10 pmol/L]) caused by invasive adrenocorticotropic hormone-secreting giant adenoma. The initial imaging revealed a homogenously enhanced pituitary macroadenoma with a size of 42 × 37 × 35 mm with suprasellar extension and encasing both the internal carotid arteries with mass effect on optic chiasma and sellar erosion. The patient underwent tumor excision by endoscopic transsphenoidal transnasal approach. Partial excision of the tumor was achieved because of cavernous sinus invasion. Histopathology and immunohistochemical stains demonstrated a corticotrophin-secreting (ACTH-staining positive) pituitary adenoma with MIB labeling index of 1% to 2%. Because biochemical remission was not achieved (urinary cortisol 794 mcg/24 hours [2191 nmol/24 hours]; ACTH 66 pg/mL [14.5 pmol/L; reference range, <46 pg/mL, <10 pmol/L]), the patient was started on ketoconazole and was received fractionated radiotherapy with a dose of 5040 cGy in 28 fractions.

Diagnostic Assessment

For the next 5 years, at yearly follow-up, 400 mg ketoconazole was continued in view of insufficient control of ACTH secretion. During follow-up, the size of the tumor was stable at approximately 23 × 16 × 33 mm after radiotherapy with no significant clinical and biochemical changes.

Five years after surgery and radiotherapy, the patient developed cerebrospinal fluid rhinorrhea; imaging revealed a cystic transformation of the suprasellar component and increase in the size of the tumor to 39 × 22 × 26 mm, which included visualization of a parasellar component of size 29 × 19 × 15 mm. The patient continued on ketoconazole. The patient was also advised to undergo hypofractionated radiotherapy but did not return for follow-up.

Treatment

In 2021, 1.5 years after the last visit, the patient developed severe headache, altered sensorium, ptosis, focal seizures, and left-sided hemiparesis. During this episode, the patient had an ACTH of 66 pg/mL (14.53 pmol/L; reference range, <46 pg/mL [<10 pmol/L]) and baseline cortisol of 25 mcg/dL (689 nmol/L; reference range, 4-18 mcg/dL [110-496 nmol/L]). Repeat imaging revealed a significant decrease in the suprasellar cystic component but an increase in the size of the parasellar component to 38 × 21 × 25 mm from 29 × 19 × 15 mm, which was isointense on T1 and T2 with heterogeneous enhancement. Significant brain stem compression and perilesional edema was also visible. The patient underwent urgent frontotemporal craniotomy and decompression of the tumor. On pathological examination, the tumor tissue was composed of small pleomorphic round cells arranged in sheets and cords separated by delicate fibrocollagenous stroma. Cells had a round to oval hyperchromatic nucleus with scanty cytoplasm. Areas of hemorrhage, necrosis, and a few apoptotic bodies were seen. The tumor tissue had very high mitotic activity of >10/10 hpf and MIB labeling index of 70%. Immunohistochemistry demonstrated positivity for vimentin, CD99, and TLE-1. Dot-like positivity was present for HMB 45, synaptophysin. INI-1 loss was present in some cells. Ten percent patchy positivity was present for p53. The tumor cells, however, consistently failed to express smooth muscle actin, CD34, Myf-4, epithelial membrane antigen, desmin, LCA, SADD4, CD138, and S-100 protein. ACTH and staining for other hormones was negative. Based on the immunological and histochemical patterns, a diagnosis of high-grade poorly differentiated malignant tumor with a probability of undifferentiated sarcoma was made.

Because of the invasion of surrounding structures and surgical inaccessibility, repeat fractionated radiotherapy was given with a dose of 4500 cGy over 25 fractions at 1.8 Gy daily to the planned target volume via image-guided fractionated radiotherapy. During the next 1.5 years, patient improved clinically with no significant increase in the size of tumor (Fig. 1). The patient was gradually tapered from ketoconazole and developed hypopituitarism requiring levothyroxine and glucocorticoid replacement. There was a significant improvement in the power of the left side and ptosis.

 

Figure 1.

Contrast-enhanced T1 magnetic resonance imaging dynamic pituitary scan (A, sagittal; B, axial; C, coronal sections) reveals postoperative changes with residual enhancing tumor in the right lateral sella cavity with extension into the right cavernous sinus and parasellar region encasing the cavernous and inferiorly extends through the foramen ovale below the skull base up to approximately 1.5 cm. Anteriorly, it extends up to the right orbital apex and posteriorly extends along the right dorsal surface of clivus.

Outcome and Follow-up

After 1.5 years of reradiation in 2022, the patient again developed palsies of the abducens, trigeminal, oculomotor, and trochlear cranial nerve on the right side and left-sided hemiparesis. A significant increase in tumor size to 50 × 54 × 45 mm with anterior, parasellar, and infratentorial extension was seen (Fig. 2). Again, repeat decompression surgery was done. Two months after surgery, there was no improvement in clinical features and repeat imaging suggested an increased size of the tumor by 30%, to approximately 86 × 68 × 75 mm. Nine years after initial presentation, the patient had an episode of aspiration pneumonia and died.

 

Figure 2.

Contrast-enhanced T1 magnetic resonance imaging dynamic pituitary images (A, sagittal; B, axial; C, coronal sections) after 1.5 years of a second session of radiotherapy reveal a significant interval increase in size of heterogeneously enhancing irregular soft tissue in sellar cavity with extension into the right cavernous sinus and parasellar region when compared with previous imaging. Superiorly, it extends in the suprasellar region, causing mass effect on the optic chiasma with encasement of the right prechiasmatic optic nerve and right-sided optic chiasma. Inferiorly, the lesion extends into the sphenoid sinus. Posteriorly, there is interval increase in the lesion involving the clivus and extending into the prepontine and interpeduncular cistern. Anteriorly, mass has reached up to the right orbital apex optic nerve canal, which shows mild interval increase.

Discussion

Radiation-induced tumors were initially described by Cahan et al in 1948. They also described the prerequisites for a tumor to be classified as a radiation-induced sarcoma [5]. The modified Cahan criteria state that (1) the presence of nonmalignancy or malignancy of a different histological type before irradiation, (2) development of sarcoma within or adjacent to the area of the radiation beam, (3) a latent period of at least 3 years between irradiation and diagnosis of secondary tumor, and (4) histological diagnosis of sarcoma, can be classified as radiation-induced sarcoma [5].

Our patient fulfilled the criteria for a radiation-induced sarcoma with a highly malignant tumor on histopathology. Radiation-induced sarcomas after functional pituitary tumors, especially Cushing disease, are rarely reported. One of the case reports revealed a high-grade osteoblastic osteosarcoma 30 years after treatment for Cushing disease with transsphenoidal resection and external beam radiotherapy [6]. In our case, there was a lag period of approximately 5 years before the appearance of a second highly undifferentiated, malignant, histologically distinct tumor. The cellular origin of this relatively undifferentiated tumor cannot be determined with certainty. However, the interlacing sarcomatous and adenomatous components resulting from distinct positive immunohistochemistry may indicate that the sarcomatous component may be derived from the preexisting pituitary adenoma.

A hormonally functional pituitary tumor is not itself expected to be associated with an increased risk of secondary malignancy, except in the case of GH-secreting tumors and those with a hereditary cancer syndrome. Although not proven, immunosuppression from hypercortisolism in Cushing disease has been proposed as a contributor to secondary tumor development [7]. Other mechanisms causing increased risk of secondary malignancy can be double-stranded DNA damage and genomic instability caused by ionizing radiation and germline mutations in tumor suppressor genes such as TP53 and Rb [7].

Radiation-induced intracranial tumors were studied in a multicenter, retrospective cohort of 4292 patients with pituitary adenoma or craniopharyngioma. Radiotherapy exposure was associated with an increased risk of a second brain tumor with a rate ratio of 2.18 (95% CI, 1.31-3.62, P < .0001). The cumulative probability of a second brain tumor was 4% for the irradiated patients and 2.1% for the controls at 20 years [7]. In another study including 426 patients irradiated for pituitary adenoma between 1962 and 1994, the cumulative risk of second brain tumors was 2.0% (CI, 0.9-4.4) at 10 years and 2.4% (95% CI, 1.2-5.0) at 20 years. The relative risk of a second brain tumor compared with the incidence in the normal population is 10.5 (95% CI, 4.3-16.7) [8].

The incidence of radiation-induced sarcomas has been estimated at 0.03% to 0.3% of patients who have undergone radiation therapy. The risk of radiation-induced sarcomas increases with field size and dose. In a systemic review and analysis of 180 cases of radiation-induced intracranial sarcomas, the average dose of radiation delivered was 51.4 ± 18.6 Gy and latent period of sarcoma onset was 12.4 ± 8.6 years. A total of 49 cases were developed after radiation treatment of pituitary adenomas (27.2%). The median overall survival time for all patients with sarcoma was 11 months, with a 5-year survival rate of 14.3% [9].

Our patient received approximately 50 Gy twice through fractionated radiotherapy, resulting in larger field size and significantly higher dose than one would expect with a modern stereotactic treatment. Such a high dose of radiation is indeed a risk factor for secondary malignancy. In our patient, in a period of 2 months, there was already >30% tumor growth after recent repeat decompression surgery.

The risk of secondary malignancy is thought to be much lower with stereotactic radiosurgery than conventional external beam radiation therapy, with an estimated cumulative incidence of 0.045% over 10 years (95% CI, 0.00-0.34) [10]. However, long-term follow-up data for patients receiving stereotactic radiation therapy are shorter and thus definitive conclusions cannot be made at this stage.

Our case highlights a rare but devastating long-term complication of pituitary tumor irradiation after Cushing disease. The limited response to various available treatment options defines the aggressive nature of radiation-induced malignancy.

Learning Points

  • The occurrence of a second neoplasm constitutes possibly one of the most adverse and rare complication after radiotherapy.
  • The incidence of radiation-induced sarcomas has been estimated at 0.03% to 0.3% of patients, but cases after Cushing disease are rarely reported.
  • Patients often present with advanced disease unresponsive to various treatment modalities because of aggressive clinical course.
  • New modalities with stereotactic radiosurgery and proton beam therapy are to be reviewed closely for risk assessment of secondary tumor.

Acknowledgments

The authors acknowledge Dr. Ishani Mohapatra for her support with histopathology and interpretation.

Contributors

All authors made individual contributions to authorship. G.B., S.K.M., and V.A.R. were involved in diagnosis and management of the patient. G.B. was involved in the writing of this manuscript and submission. V.P.S. was responsible for patient surgeries. All authors reviewed and approved the final draft.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Disclosures

The authors have nothing to disclose.

Informed Patient Consent for Publication

Signed informed consent could not be obtained from the patient or a proxy but was approved by the treating institute.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Filed under: Cushing's, pituitary, Rare Diseases, Treatments | Tagged: , , , | Leave a comment »

Adrenocorticotropin-Dependent Ectopic Cushing’s Syndrome: A Case Report

Posted on November 24, 2023 by MaryO

Abstract

Paraneoplastic syndromes are rare and diverse conditions caused by either an abnormal chemical signaling molecule produced by tumor cells or a body’s immune response against the tumor itself. These syndromes can manifest in a variable, multisystemic and often nonspecific manner posing a diagnostic challenge.

We report the case of an 81-year-old woman who exhibited severe hypokalemia, metabolic alkalosis, and worsening hyperglycemia. The investigation was consistent with adrenocorticotropin (ACTH)-dependent Cushing’s syndrome and, eventually, the patient was diagnosed with stage IV primary small-cell lung cancer (SCLC).

SCLC is known to be associated with paraneoplastic syndromes, including Cushing’s syndrome caused by ectopic adrenocorticotropin (ACTH) secretion. Despite being associated with very poor outcomes, managing these syndromes can be challenging and may hold prognostic significance.

Introduction

Adrenocorticotropin (ACTH)-dependent Cushing’s syndrome (CS) is caused by excessive ACTH production by corticotroph (Cushing’s disease (CD)) or nonpituitary (ectopic) tumors, leading to excessive cortisol production. Ectopic ACTH syndrome (EAS) is a rare condition, accounting for 10 to 20% of all cases of ACTH-dependent CS and 5 to 10% of all types of CS [1]. The normal glucocorticoid-induced suppression of ACTH is reduced in ACTH-dependent CS, especially with ectopic ACTH production. Studies show that a wide variety of neoplasms, usually carcinomas rather than sarcomas or lymphomas, have been associated with EAS. Most cases are caused by neuroendocrine tumors of the lung, pancreas, or thymus, in which the hypercortisolism state is not apparent clinically, resulting, all too often, in delayed diagnosis [2,3].

Current diagnostic tests for EAS aim to confirm high cortisol levels, the absence of a cortisol circadian rhythm, as well as the reduced response to negative feedback from glucocorticoid administration, and imaging to identify the site of ACTH production.

Prompt diagnosis and management are crucial in EAS, highlighting the importance of physician awareness and early recognition of this syndrome.

Treatment options depend on the underlying tumor. Surgical removal is often the primary approach, followed by radiation therapy or chemotherapy. Additionally, medications to control cortisol levels may be necessary to manage the various comorbid conditions associated with CS, such as cardiovascular disease, diabetes, electrolyte imbalances, infections and thrombotic risk [4,5].

Case Presentation

We report the case of an 81-year-old woman with a fully active performance status (ECOG 0) and a medical history of diabetes, hypertension, dyslipidemia, and depressive disorder. She was admitted to an internal medicine ward due to an acute hydroelectrolytic disorder, including metabolic alkalosis, severe hypokalemia (2 mmol/L), hypochloremia (85 mmol/L), hypocalcemia (0.95 mmol/L), hypophosphatemia (1.4 mg/dL), hypomagnesemia (0.9 mg/dL), and hyperlactatemia (5.8 mmol/L), after she reportedly self-medicated herself with higher doses of metformin (four to five pills a day) due to high blood glucose levels. The patient presented with asthenia, nausea, vomiting, and diarrhea for three days and reported uncontrolled blood glucose levels for the last eight days.

The physical examination was unremarkable, without any altered mental status or signs of infection. Arterial blood gas samples showed metabolic alkalemia (pH 7.59) and hyperlactatemia, associated with severe hypokalemia, normal bicarbonate (27 mmol/L), and mildly elevated glycemia and ketonemia (232 mg/dL and 1.7 mmol/L, respectively). Lab tests confirmed the serum potassium levels as well as the other aforementioned electrolyte disturbances. Kidney function and hepatic enzymes were normal. Considering the possible relationship between the electrolyte disorder and the gastrointestinal presentation, the patient was given intravenous (IV) fluids and received potassium and magnesium replacement therapy.

Despite receiving 200 milliequivalents (mEq) of IV potassium chloride and 4 grams of magnesium sulfate, in the first 48 hours, the ion deficits persisted. Given the persistent electrolyte derangement, the patient was admitted to the Internal Medicine ward for etiological investigation and monitoring of ionic correction. The initial period was remarkable for refractory hypokalemia and uncontrolled diabetes under respective therapeutic measures, including 80 to 130 mEq of IV potassium chloride and progressive titration of spironolactone to 200 mg a day. Laboratory investigation revealed high parathormone levels (PTHi 167 pg/mL; reference range: 10-65 pg/mL), vitamin D deficiency (3.3 ng/mL; reference range >20 ng/mL) and apparent ACTH-dependent hypercortisolism (serum cortisol 80.20 ug/dL; ACTH 445 pg/mL), as well as high urinary potassium and glucose concentrations (190 mEq/24 h and 21161 mg/24 h). A dexamethasone suppression test was performed twice (standard low and high dose) without any changes in cortisol levels, leading to the suspicion of a CS caused by abnormally high ACTH production. Cranioencephalic computed tomography (CT) and magnetic resonance imaging (MRI) were performed, excluding the presence of pituitary anomalies. A follow-up whole-body CT scan was performed, revealing a suspicious pulmonary mass in the left lower lobe, associated with ipsilateral hilar lymphadenopathy and hepatic and adrenal gland lesions suggestive of secondary involvement. An endobronchial ultrasound bronchoscopy and biopsy were performed, documenting anatomopathological findings of small-cell lung carcinoma with a Ki67 expression of 100% (Figures 1–3).

Pulmonary-mass-(SCLC)-in-the-left-lower-lobe-with-ipsilateral-hilar-lymphadenopathy-and-pleural-effusion.
Figure 1: Pulmonary mass (SCLC) in the left lower lobe with ipsilateral hilar lymphadenopathy and pleural effusion.

SCLC: small-cell lung cancer.

Secondary-involvement-of-the-liver-with-hypodense-multilobar-hepatic-lesions-(arterial-phase).
Figure 2: Secondary involvement of the liver with hypodense multilobar hepatic lesions (arterial phase).
Bilateral-suprarenal-lesions-suggestive-of-secondary-involvement.
Figure 3: Bilateral suprarenal lesions suggestive of secondary involvement.

The patient was referred to oncology, and chemotherapy was deferred, considering the infectious risk associated with hypercortisolism.

The patient started metyrapone 500 mg every eight hours, resulting in a reduction in cortisol levels and control of hypokalemia. Later on, a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan was performed, confirming disseminated disease with additional bone involvement. Unfortunately, despite endocrinological stabilization, the patient’s condition worsened, and she ended up dying one month after the diagnosis.

Discussion

When this patient was admitted, it was assumed that the metabolic alkalosis and various electrolyte disturbances were related to the gastrointestinal presentation and hyperlactatemia secondary to metformin overdose. However, the unusual persistence and refractory hypokalaemia raised some concerns that an alternative etiology might be involved and incited subsequent testing.

The high cortisol levels were unexpected given the subclinical presentation, which seems to be more frequent in cases of EAS. In fact, because of this, the true incidence of EAS is unknown and probably underdiagnosed since patients often have subclinical presentations and do not exhibit catabolic features.

Since the patient wasn’t on any steroid medication, the association between the high cortisol and ACTH levels, non-responsive to the dexamethasone suppression test, along with the absence of a pituitary lesion, raised suspicion of a probable EAS, which was later confirmed by the body CT scan and endobronchial ultrasound (EBUS).

EAS is a rare disease with a poor prognosis. It reportedly occurs in 3.2 to 6% of neuroendocrine neoplasms, and the tumor often originates in the lung, thyroid, stomach, and pancreas. Locoregional and/or distant metastasis can be seen at the time of diagnosis in 15% of typical carcinoids and about half of atypical carcinoids with visible primaries [6,7].

The presence of a typical CS presentation, with or without electrolyte abnormalities, should raise suspicion and serum levels of both ACTH and cortisol should be assessed to determine if they are elevated and to distinguish between an ACTH-dependent (pituitary or nonpituitary ACTH-secreting tumor) and an independent mechanism (e.g., from an adrenal source). The diagnosis of CS is established when at least two different first-line tests are unequivocally abnormal and cannot be explained by any other conditions that cause physiologic hypercortisolism. Additional evaluation is performed to rule out a pituitary origin (with brain MRI) and to assess for a possible ectopic ACTH-secreting tumor.

In the aforementioned case, the production of ACTH was caused by primary neuroendocrine SCLC. The recommended approach to EAS involves the initial normalization of serum cortisol levels and the treatment of related comorbidities before performing a complete diagnostic evaluation and addressing the underlying cause [5-7]. This approach seems to improve survival and prevent complications such as sepsis following a combined steroid-induced immunosuppression and chemotherapy-induced agranulocytosis [6,7].

Direct therapies vary according to the tumor, but surgery is usually the first line of treatment (transsphenoidal surgery in cases of CD or tumor resection in cases of non-metastatic EAS). However, our patient presented with stage IV SCLC with EAS, in which chemotherapy remains the first-line treatment. SCLC patients with EAS have a poorer prognosis than those without EAS, with a life expectancy of only three to six months. This makes early diagnosis more important [2,7], as controlling the high cortisol levels and then administering systemic chemotherapy may achieve longer survival [8].

Apart from systemic chemotherapy, ketoconazole (widely accepted but highly toxic), metyrapone, mitotane (adrenocortical suppressant drug with significant side effects), and mifepristone (glucocorticoid antagonist, mainly used for the treatment of hyperglycemia in CS) can be used to reduce circulating glucocorticoids. Moreover, thromboprophylaxis and Pneumocystis jirovecii pneumonia prophylaxis should be started.

Because ketoconazole may increase the risk of chemotherapy toxicity by inhibiting cytochrome P450 3A4, metyrapone has been reported to be a better choice [5,7].

Nonetheless, administration of chemotherapy in the setting of a hypercortisolism-induced immunosuppressive state, cancerous background and metabolic disorders featuring electrolyte disturbance and hyperglycemia, aggravate the condition and can be life-threatening. Thus, a palliative approach can sometimes be reasonable.

Conclusions

The diagnosis of CS is a three-step process that includes its suspicion based on the patient’s laboratory and semiologic findings, the documentation of hypercortisolism, and the identification of its cause, which can be either ACTH-dependent or independent.

The ectopic secretion of ACTH (EAS) by nonpituitary tumors is a relatively rare cause of CS and often presents as paraneoplastic syndromes, adding therapeutic and prognostic concerns.

This case, in particular, highlights the importance of seeking alternative explanations for common electrolyte disturbances, particularly when they don’t resolve promptly. Clinicians should be aware of EAS and its frequent subclinical presentation in order to initiate the diagnostic workup as soon as suspicion arises.

References

  1. Hayes AR, Grossman AB: The ectopic adrenocorticotropic hormone syndrome: rarely easy, always challenging. Endocrinol Metab Clin North Am. 2018, 47:409-25. 10.1016/j.ecl.2018.01.005
  2. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK: Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005, 90:4955-62. 10.1210/jc.2004-2527
  3. Lacroix A, Feelders RA, Stratakis CA, Nieman LK: Cushing’s syndrome. Lancet. 2015, 29:913-27. 10.1016/S0140-6736(14)61375-1
  4. Nieman LK: Molecular derangements and the diagnosis of ACTH-dependent Cushing’s syndrome. Endocr Rev. 2022, 43:852-77. 10.1210/endrev/bnab046
  5. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A: Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015, 100:2807-31. 10.1210/jc.2015-1818
  6. Bostan H, Duger H, Akhanli P, et al.: Cushing’s syndrome due to adrenocorticotropic hormone-secreting metastatic neuroendocrine tumor of unknown primary origin: a case report and literature review. Hormones (Athens). 2022, 21:147-54. 10.1007/s42000-021-00316-z
  7. Richa CG, Saad KJ, Halabi GH, Gharios EM, Nasr FL, Merheb MT: Case-series of paraneoplastic Cushing syndrome in small-cell lung cancer. Endocrinol Diabetes Metab Case Rep. 2018, 2018:4. 10.1530/EDM-18-0004
  8. Zhang HY, Zhao J: Ectopic Cushing syndrome in small cell lung cancer: a case report and literature review. Thorac Cancer. 2017, 8:114-7. 10.1111/1759-7714.12403

From https://www.cureus.com/articles/198133-adrenocorticotropin-dependent-ectopic-cushings-syndrome-a-case-report#!/

Filed under: Cushing's, Rare Diseases, symptoms | Tagged: , , | Leave a comment »

Adrenocorticotropic Hormone-Dependent Cushing’s Syndrome Complicated With Gastric Ulcer Perforation in a 30-Year-Old Saudi Female

Posted on November 4, 2023 by MaryO

Abstract

Gastrointestinal perforation is a well-addressed complication of exogenous hypercortisolism; however, patients with endogenous Cushing’s syndrome (CS) do not usually experience this condition in clinical practice. The literature on this subject is limited and consists solely of clinical case reports/series with only 23 instances of gastrointestinal perforation occurring in individuals with endogenous Cushing’s syndrome. This is mainly attributed to the rarity of Cushing’s syndrome itself and the low chance of occurrence of such complications.

We report a case of a recently diagnosed adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome in a 30-years-old female who presented initially with a three-month history of progressive weight gain, generalized weakness, acne, menstrual irregularity, and severe hypokalemia, and then developed a gastric ulcer perforation only one month after her ACTH-dependent Cushing’s syndrome diagnosis and was managed through emergent surgery.

Introduction

A disorder of the endocrine system characterized by excessive cortisol production, known as Cushing’s syndrome, rarely occurs. The main causes are pituitary tumors, ectopic adrenocorticotropic hormone (ACTH)-secreting tumors, or adrenal tumors that secrete cortisol independently [1]. Patients initially present with a wide range of symptoms, including weight gain, proximal myopathy, skin thinning, and abdominal striae [1]. Additionally, several metabolic disorders, such as diabetes mellitus, hypertension, and dyslipidemia, can occur, especially when the diagnosis is not established at an early stage [2]. There is a possibility of gastrointestinal complications among patients receiving exogenous glucocorticoids. However, there is limited information on gastrointestinal complications associated with endogenous hypercortisolemia [3,4]. Thus far, only 23 instances have been published addressing the co-occurrence of gastrointestinal perforation with endogenous Cushing’s syndrome [5-17]. To the best of our knowledge, this is the first case reporting gastric perforation in an ACTH-dependent Cushing’s syndrome, while the vast majority reported diverticular, sigmoid, or duodenal perforation with Cushing’s syndrome [5-17]. Herein, we describe the medical history, physical examination, and investigatory findings of a 30-year-old female with a recent diagnosis of ACTH-dependent Cushing’s syndrome that was complicated by gastric ulcer perforation, necessitating an urgent exploratory laparotomy. The primary motivator of this case report was the rarity of the described condition, the atypical location of the perforation in such patient group, and the relatively young age of the patient.

Case Presentation

History and examination

A 30-year-old female with a history of mental retardation was admitted to our emergency department (ER) with progressive weakness and fatigue. Upon taking the history, she had been having menstrual irregularities, progressive weight gain, and generalized weakness, which was significant enough to limit her physical activity and hinder her movement for the past three months. Initial vital signs showed that the patient had a body temperature of 37°C, a pulse rate of 90 beats per minute, and a blood pressure of 130/80 mmHg. On physical examination, the patient had a moon face with supraclavicular fullness, dorsocervical fat pad, purple abdominal striae, facial signs of hirsutism, and acne all over the face, shoulders, chest, and back.

Investigations

In the initial laboratory examination, hypokalemia of 2.1 mEq/L, hyperglycemia of 12.1 mmol/L, and metabolic alkalosis were detected (Table 1). The cortisol level after 1 mg dexamethasone suppression test was 2204 nmol/L (normal range 140-690), ACTH 123 pg/mL (normal range 7.2-63.3), DHEA-S 27.85 umol/L (normal range 2.6-13.9), And 24-hour urine cortisol level was 1560 mg/day (normal range 30-350) (Table 1). No suppression was observed in cortisol level with 8 mg dexamethasone suppression test.

Parameter Initial presentation Perforation presentation Refrence range
Na+ 143 mEq/L 139 mmol/L 135-147 mEq/L
Cl- 85 mEq/L 105 mmol/L 98-108 mEq/L
K+ 2.1 mEq/L 2.8 mmol/L 3.5-5.0 mEq/L
Mg2+ 0.79 mmol/L 0.77 mmol/L 0.85-1.110 mmol/L
PO3- 0.88 mmol/L 1.23 mmol/L 0.97-1.46 mmol/L
PH 7.54 7.36 7.35-7.45
PCO2 67.5 mmHg 42.7 mmHg 35-45 mmHg
PO2 27.7 mmHg 62.2 mmHg 75-100 mmHg
HCO3 49.8 mEq/L 23.6 mEq/L 22-26 mEq/L
Random blood glucose 12.1 mmol/L 24.1 mmol/L <5.5 mmol/L
Hemoglobin 13.5 g/dL 14.9 g/dL 13.7-16.8 g/dL
White blood cells 9,720 /uL 11,100 /uL 3,300-8,600 /uL
Lymphocyte 0.48% 0.33% –
Neutrophil 8.55% 9.66% –
Eosinophil 0.0% 0.0% –
TSH 0.55 mIU/L Was not ordered 0.4-4.0 mIU/L
Cortisol 2204 nmol/L 4842 nmol/L 140-690 nmol/L
ACTH 123 pg/mL Was not ordered 7.2-63.3 pg/mL
Table 1: Laboratory findings on initial presentation and on perforation day

TSH – thyroid stimulating hormone; ACTH – adrenocorticotropic hormone

A series of CT scans for the neck, chest, abdomen, and pelvis was performed and failed to localize any tumors acting as an ectopic source. A pituitary MRI was performed, and no adenoma was found. To complete the diagnostic workup, we decided to do an inferior petrosal sinus sampling (IPSS) and PET scan with Gallium 68; however, the patient’s family refused and requested discharge and outpatient follow-ups. These results, together with the biochemical and clinical findings, supported the diagnostic hypothesis of ACTH-dependent Cushing’s syndrome.

Treatment/management

When addressing the issue of hypokalemia that the patient presented with initially, it was found to be resistant and difficult to correct. The patient was put on spironolactone 50 mg BID, and potassium chloride 20 mEq q8h, and her potassium level barely reached 3.5 mmol/L after several days. In addition, her magnesium level was corrected with magnesium oxide 800 mg every six hours. Her blood glucose level was controlled with insulin glargine 6 units daily and Novorapid as per the sliding scale. The patient was discharged on spironolactone tablets 50 mg BID (oral), potassium chloride 20 mEq q8h, cholecalciferol, calcium carbonate, insulin glargine 6 units daily, and Novorapid 4 units TID before meals.

Follow-up and outcomes

Seven days after discharge, she presented to the ER complaining of a new onset of abdominal pain, constipation, and reduced urine output. Her Glasgow Coma Scale (GCS) was 15, her blood pressure measurement was 146/90 mmHg, her pulse rate was 66 beats per minute, her respiratory rate was 21 breaths per minute, and her temperature was 36.7°C. Upon physical examination, the patient had distended non-tender abdomen without any other significant findings. Blood work was done, including renal functions, and all parameters, including potassium, were within normal limits. A chest X-ray was also performed and revealed no evidence of pneumoperitoneum. The patient was clinically stable after managing her abdominal pain with acetaminophen injection and administering fleet enema for constipation. After instructions on when to come again to the ER were given, the patient was discharged home on lactulose and paracetamol, and a close outpatient follow-up appointment was scheduled.

Five days after the ER visit, the patient presented again to the ER. She was still complaining of severe non-resolving abdominal pain, constipation, and reduced urine output. Upon physical examination in the ER, the patient was found to have developed a new onset of lower limb edema, abdominal rebound tenderness, and abdominal rigidity and guarding. She was hypotensive with a blood pressure of 91/46 mmHg, pulse rate of 80 beats per minute, respiratory rate of 16 breaths per minute, temperature of 38.2 °C, and SpO2 of 96%. The only significant laboratory finding was her potassium level dropping low to 2.8 mEq/L (Table 1). An X-ray of the chest was requested and showed a large pneumoperitoneum (Figure 1).

Posteroanterior-chest-X-ray-at-the-time-of-gastric-perforation-displaying-severe-air-under-the-diaphragm-with-bilateral-obstruction-indicating-massive-pneumoperitoneum-(red-arrow)
Figure 1: Posteroanterior chest X-ray at the time of gastric perforation displaying severe air under the diaphragm with bilateral obstruction indicating massive pneumoperitoneum (red arrow)

Abdominal CT was also urgently performed and confirmed the presence of gastric perforation likely related to an underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature (Figures 2, 3).

Coronal-section-CT-image-of-abdomen-and-pelvis-at-the-time-of-gastric-perforation-showing-features-of-gastric-perforation-likely-related-to-the-underlying-perforated-peptic-ulcer-with-0.8-cm-defect-at-the-distal-greater-curvature-
Figure 2: Coronal-section CT image of abdomen and pelvis at the time of gastric perforation showing features of gastric perforation likely related to the underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature
Horizontal-section-CT-image-showing-features-of-gastric-perforation-likely-related-to-the-underlying-perforated-peptic-ulcer-with-0.8-cm-defect-at-the-distal-greater-curvature
Figure 3: Horizontal-section CT image showing features of gastric perforation likely related to the underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature

The patient underwent an emergent gastric wedge resection for gastric perforation, and the pathology reported evidence of gastric ulcer with no evidence of malignancy. Furthermore, Helicobacter pylori test was performed on the sample, and it came back positive. The patient tolerated the surgery very well, and postoperative recovery was without any complications.

Later, the patient was prescribed metyrapone 250 mg Q4h, which was then increased to 500 mg Q4h four days after surgery, and her cortisol level significantly dropped to 634nmol/L. During that time, a gastrin level test was also performed to exclude the presence of gastrinomas, and the level was 45 pg/ml (normal range 13-115).

Discussion

A small percentage of the population suffers from Cushing’s syndrome, which is an endocrine disorder characterized by an endogenous overproduction of glucocorticoids, resulting in hypercortisolemia [1]. It is estimated to affect 0.7 to 2.4 people per million annually [1]. Hypercortisolemia alters psychologic, metabolic, and cardiovascular functions, resulting in increased mortality and morbidity rates, particularly if the diagnosis is delayed and long-term exposure to high cortisol levels occurs [2]. Women are more likely to suffer from this condition than men, and people in their 40s to 60s are most vulnerable to it [1]. Patients initially present with a wide range of symptoms, including weight gain, proximal myopathy, skin thinning, and abdominal striae [1]. Additionally, several metabolic disorders, such as diabetes mellitus, hypertension, and dyslipidemia, can occur [1]. Due to the rarity of this condition, there is often a significant delay in diagnosis and treatment, which could eventually lead to complications from prolonged hypercortisolism.

From another standpoint, in a systematic review, the incidence of peptic ulcer perforation ranges from 3.8 to 14 per 100,000 individuals in the general population [18]. In under-developed countries, patients are typically young, tobacco-using males [19]. However, patients in industrialized countries are typically older with multiple co-morbidities and are on long-term non-steroidal anti-inflammatory drugs (NSAIDs) or steroid use [19]. Patients may present with an abrupt onset of abdominal discomfort, abdominal rigidity, and tachycardia in the early stages of a perforated peptic ulcer [19]. Later, abdominal distention, pyrexia, hypotension, fever, and vomiting can occur [19]. Furthermore, when the diagnosis is made early, a perforated ulcer often has a good prognosis. However, the risk of adverse events increases if there is a delay in the diagnosis [20]. Therefore, making an early detection through different imaging modalities is crucial [20]. A history of peptic ulcer disease, NSAIDs, physiological stress, smoking, corticosteroids, and Helicobacter pylori are some of the well-established risk factors for a perforated peptic ulcer [20].

The prevalence of Helicobacter pylori among Saudi patients is high; in one study, the overall prevalence was 46.5% in patients with dyspepsia using gastric biopsy [21]. Several studies have explored the relationship between Helicobacter pylori and gastrointestinal perforation, but the results have been mixed. Some studies have suggested a higher prevalence of Helicobacter pylori infection among individuals with gastrointestinal perforation compared to those without, indicating a potential association. However, other studies have found no significant difference in the prevalence of Helicobacter pylori infection between perforated and non-perforated gastrointestinal ulcer cases [22]. Furthermore, they suggested that the presence of other risk factors like the use of NSAIDs, smoking, and alcohol may interact with Helicobacter pylori infection and contribute to the development of complications such as gastrointestinal perforation [22]. However, in our case, the patient did not have any established risk factors for gastric perforation, such as NSAIDs, smoking, or alcohol. Therefore, considering the low incidence of gastrointestinal perforation and high prevalence of Helicobacter pylori, the conflicting data regarding the association between Helicobacter pylori and gastrointestinal perforation, and the lack of established risk factors for gastrointestinal perforation in our patient, we suggest that prolonged excess glucocorticoids from Cushing’s syndrome may have contributed to the gastric perforation either independently or synergistically with Helicobacter pylori since hypercortisolism can lead to a weakened gastrointestinal wall integrity due to decreased collagen turnover and disruption of mucosal protection by prostacyclin [15]. In addition, because of hypercortisolism, perforation may not be contained or healed initially due to the immunosuppressive effects of hypercortisolism, whether endogenous or exogenous [15]. Additionally, high levels of cortisol may delay the diagnosis and treatment since it may mask the symptoms of the perforation [14]. Moreover, our patient was treated for severe hypokalemia with potassium supplementation for an extended period of time. Previous studies have linked potassium chloride supplementation to gastrointestinal ulceration and perforation, making this a possible additive cause of our patient’s condition [23,24].

A limited number of studies have addressed gastrointestinal perforations associated with endogenous hypercortisolemia [5-17]. The correlation between Cushing’s syndrome and gastrointestinal perforation is highlighted in our study and in the case reports that have been previously published (Table 2). Similar to our case, a female predominance was seen in gastrointestinal perforation among the reported cases of Cushing’s syndrome [6,7,12,13,15,16]. Additionally, the average age at which gastrointestinal perforation occurred in patients with endogenous hypercortisolism ranged from 45 to 80, which is a noticeably higher age range than the case we are presenting here (aged 30) [6-10,12]. Furthermore, unlike our case, in which gastrointestinal perforation occurred four months after the onset of Cushing’s symptoms, Intestinal perforation occurs approximately 9.8 months after Cushing’s symptoms first appear [15]. Furthermore, in our patient, gastric perforation occurred while she was hypercortisolemic and not in a remission state. Hence, in association with Helicobacter pylori infection, severe hypercortisolemia could have been a secondary contributing factor to gastric perforation. The complications of gastric ulceration, specifically with endogenous Cushing’s syndrome, have been addressed in two case reports [25,26]. It must be noted, however, that neither case is similar to ours. A case of gastric perforation was reported by Kubicka et al. in a patient who had a confirmed diagnosis of gastrinoma, and the patient was diagnosed with ectopic Cushing’s syndrome seven months after gastric perforation [25]. Therefore, since ectopic Cushing’s syndrome was diagnosed seven months after the perforation, it is more likely that the gastrinoma contributed to this complication. In contrast, our patient’s serum gastrin level was within the normal range, ruling out gastrinoma. Further, Hoshino et al. reported a case of gastrointestinal bleeding in a 39-year-old man with a confirmed diagnosis of Cushing’s disease secondary to pituitary adenoma [26]. He was found to have gastric ulceration and bleeding along with Helicobacter pylori infection and elevated cortisol levels [26]. In spite of the patient not developing a gastric perforation, it was suggested by the author that hypercortisolism might be a contributing factor for gastric ulcer complications by slowing down the ulcer healing process [26]

Reference Year of publication Age, gender Highest cortisol level plasma cortisol (PC, nmol/L) / UFC (nmol/L) Cause of Cushing’s syndrome Time from onset of Cushing’s symptoms to perforation (months) Reported site of gastrointestinal perforation
Current 2023 30, Female PC 4842 ACTH-dependant 4 Gastric perforation
Ishinoda et al. [17] 2023 24, Male PC 1647 Cushing’s disease 12 Sigmoid colon perforation
Wijewickrama et al. [16] 2021 32, Female PC 1147 Pituitary microadenoma 1 Diverticular perforation
Shahidi et al. [15] 2019 72, Female UFC 5296 Pancreatic neuroendocrine tumor 12 Diverticular perforation
Shahidi et al. [15] 2019 61, Female PC 1925 Metastatic medullary carcinoma of thyroid 12 Sigmoid colon and diverticular perforation
Shahidi et al. [15] 2019 68, Female UFC 410 Cushing’s disease 12 Sigmoid colon perforation
Shahidi et al. [15] 2019 71, Female UFC 1533 Cushing’s disease 4 Diverticular perforation
Shahidi et al. [15] 2019 54, Male UFC 374 Cushing’s disease 3 Sigmoid colon perforation
Shahidi et al. [15] 2019 52, Female UFC 885 Cushing’s disease 16 Diverticular perforation
Sater et al. [14] 2018 80, Female UFC 5601 Lung carcinoid 36 Diverticular perforation
Sater et al. [14] 2018 60, Female UFC 72726 Metastatic islet cell carcinoma 36 Diverticular perforation
Sater et al. [14] 2018 31, Male UFC 1297 Cushing’s disease 20 Diverticular perforation
Sater et al. [14] 2018 52, Female UFC 2371 Lung carcinoid 4 Diverticular perforation
Sater et al. [14] 2018 67, Male UFC 3836 Ectopic ACTH 10 Diverticular perforation
Sater et al. [14] 2018 51, Male UFC 13552 Metastatic thymic carcinoma 4 Diverticular perforation
Kaya et al. [9] 2016 70, Male PC 1432 Small cell lung cancer 1 Diverticular perforation
Dacruz et al. [12] 2016 60, Female UFC 4481 Metastatic parotid tumor 5 Sigmoid colon and diverticular perforation
Matheny et al. [10] 2016 67, Male UFC 11119 Metastatic medullary carcinoma of thyroid 4 Diverticular perforation
Flynn et al. [13]   2016 63, Female UFC 12465 Pheochromocytoma 1 Perforation at the splenic flexure
Balestrieri et al. [11] 2016 75, Male PC 2272 Neuroendocrine tumor 1 Intestinal perforation
Hara et al, [8] 2013 79, Male PC 1230 Cushing’s disease 6 Diverticular perforation
De Havenon et al. [7] 2011 71, Female PC 2593 Cushing’s disease 9 Diverticular perforation
Lutgers et al. [6] 2010 55, Female UFC 10152 Right pheochromocytoma 1 Sigmoid colon and diverticular perforation
Drake et al. [5] 1998 35, Male PC 1442 Islet cell tumor 4 Duodenal perforation and rupture of pancreatic pseudocyst
Table 2: Current case and previous reported 23 cases of patients with Cushing’s syndrome and gastrointestinal perforation

UFC – urinary free cortisol; PC – plasma cortisol; ACTH – adrenocorticotropic hormone

Conclusions

A high blood cortisol level can be associated with various clinical manifestations and diverse sets of complications. This case report sheds light on one of the less common complications of hypercortisolism in patients with Cushing’s syndrome, which is gastrointestinal perforation. Our report further supports the published evidence that gastrointestinal perforation is a rare but potentially fatal complication among patients with Cushing’s syndrome. Moreover, it highlights the possibility of developing gastric perforations in this patient group, even at younger ages than expected. This should elicit a high clinical suspicion and demand prompt investigation of Cushing’s syndrome patients in a hypercortisolism state presenting with modest gastrointestinal symptoms.

References

  1. Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A: Cushing’s syndrome. Endocrinol Metab Clin North Am. 2008, 37:135-49. 10.1016/j.ecl.2007.10.010
  2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing’s syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6
  3. Goethals L, Nieboer K, De Smet K, De Geeter E, Tabrizi NH, Van Eetvelde E, de Mey J: Cortisone associated diverticular perforation. JBR-BTR. 2011, 94:348-9. 10.5334/jbr-btr.705
  4. Piekarek K, Israelsson LA: Perforated colonic diverticular disease: the importance of NSAIDs, opioids, corticosteroids, and calcium channel blockers. Int J Colorectal Dis. 2008, 23:1193-7. 10.1007/s00384-008-0555-4
  5. Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM: Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing’s syndrome and peritonitis. J Clin Endocrinol Metab. 1998, 83:3542-4. 10.1210/jcem.83.10.5156
  6. Lutgers HL, Vergragt J, Dong PV, de Vries J, Dullaart RP, van den Berg G, Ligtenberg JJ: Severe hypercortisolism: a medical emergency requiring urgent intervention. Crit Care Med. 2010, 38:1598-601. 10.1097/CCM.0b013e3181e47b7a
  7. de Havenon A, Ehrenkranz J: A perforated diverticulum in Cushing’s disease. Int J Surg Case Rep. 2011, 2:215-7. 10.1016/j.ijscr.2011.06.009
  8. Hara T, Akutsu H, Yamamoto T, Ishikawa E, Matsuda M, Matsumura A: Cushing’s disease presenting with gastrointestinal perforation: a case report. Endocrinol Diabetes Metab Case Rep. 2013, 2013:130064. 10.1530/EDM-13-0064
  9. Kaya T, Karacaer C, Açikgöz SB, Aydemir Y, Tamer A: Severe hypokalaemia, hypertension, and intestinal perforation in ectopic adrenocorticotropic hormone syndrome. J Clin Diagn Res. 2016, 10:OD09-11. 10.7860/JCDR/2016/17198.7127
  10. Matheny LN, Wilson JR, Baum HB: Ectopic ACTH production leading to diagnosis of underlying medullary thyroid carcinoma. J Investig Med High Impact Case Rep. 2016, 4:2324709616643989. 10.1177/2324709616643989
  11. Balestrieri A, Magnani E, Nuzzo F: Unusual Cushing’s syndrome and hypercalcitoninaemia due to a small cell prostate carcinoma. Case Rep Endocrinol. 2016, 2016:6308058. 10.1155/2016/6308058
  12. Dacruz T, Kalhan A, Rashid M, Obuobie K: An ectopic ACTH secreting metastatic parotid tumour. Case Rep Endocrinol. 2016, 2016:4852907. 10.1155/2016/4852907
  13. Flynn E, Baqar S, Liu D, et al.: Bowel perforation complicating an ACTH-secreting phaeochromocytoma. Endocrinol Diabetes Metab Case Rep. 2016, 2016:10.1530/EDM-16-0061
  14. Sater ZA, Jha S, McGlotten R, Hartley I, El Lakis M, Araque KA, Nieman LK: Diverticular perforation: A fatal complication to forestall in Cushing syndrome. J Clin Endocrinol Metab. 2018, 103:2811-4. 10.1210/jc.2018-00829
  15. Shahidi M, Phillips RA, Chik CL: Intestinal perforation in ACTH-dependent Cushing’s syndrome. Biomed Res Int. 2019, 2019:9721781. 10.1155/2019/9721781
  16. Wijewickrama PS, Ratnasamy V, Somasundaram NP, Sumanatilleke M, Ambawatte SB: A challenging case of Cushing’s disease complicated with multiple thrombotic phenomena following trans-sphenoidal surgery; a case report. BMC Endocr Disord. 2021, 21:29. 10.1186/s12902-021-00701-0
  17. Ishinoda Y, Uto A, Meshino H, et al.: Bowel perforation associated with Cushing’s disease: a case report with literature review. Endocr J. 2023, 70:933-9. 10.1507/endocrj.EJ23-0110
  18. Lau JY, Sung J, Hill C, Henderson C, Howden CW, Metz DC: Systematic review of the epidemiology of complicated peptic ulcer disease: incidence, recurrence, risk factors and mortality. Digestion. 2011, 84:102-13. 10.1159/000323958
  19. Chung KT, Shelat VG: Perforated peptic ulcer – an update. World J Gastrointest Surg. 2017, 9:1-12. 10.4240/wjgs.v9.i1.1
  20. Weledji EP: An overview of gastroduodenal perforation. Front Surg. 2020, 7:573901. 10.3389/fsurg.2020.573901
  21. Akeel M, Elmakki E, Shehata A, Elhafey A, Aboshouk T, Ageely H, Mahfouz MS: Prevalence and factors associated with H. pylori infection in Saudi patients with dyspepsia. Electron Physician. 2018, 10:7279-86. 10.19082/7279
  22. Thirupathaiah K, Jayapal L, Amaranathan A, Vijayakumar C, Goneppanavar M, Nelamangala Ramakrishnaiah VP: The association between Helicobacter pylori and perforated gastroduodenal ulcer. Cureus. 2020, 12:e7406. 10.7759/cureus.7406
  23. Farquharson-Roberts MA, Giddings AE, Nunn AJ: Perforation of small bowel due to slow release potassium chloride (slow-K). Br Med J. 1975, 3:206. 10.1136/bmj.3.5977.206
  24. Payan H, Blaustein A: Potassium chloride and small bowel perforation. Gastroenterology. 1965, 48:877-8. 10.1016/S0016-5085(65)80073-7
  25. Kubicka E, Zawadzka K, Syrycka J, Kałużny M, Pawluś A, Bolanowski M: A case of gastrinoma associated with ectopic Cushing syndrome. Pol Arch Intern Med. 2020, 130:328-9. 10.20452/pamw.15201
  26. Hoshino C, Satoh N, Narita M, Kikuchi A, Inoue M: Another ‘Cushing ulcer’. BMJ Case Rep. 2011, 2011:10.1136/bcr.02.2011.3888

From https://www.cureus.com/articles/196132-adrenocorticotropic-hormone-dependent-cushings-syndrome-complicated-with-gastric-ulcer-perforation-in-a-30-year-old-saudi-female-a-case-report-and-a-review-of-the-literature#!/

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A Case Report of Cushing’s Disease Presenting With Psychosis and Muscle Weakness Postpartum

Posted on October 31, 2023 by MaryO

Abstract

Cushing’s syndrome is a condition leading to overproducing of cortisol by the adrenal glands. If the pituitary gland overproduces cortisol, it is called Cushing’s disease. Cushing’s syndrome and even Cushing’s disease during and after pregnancy are rare events. There is not enough literature and guidance for managing and treating these patients. The diagnosis of Cushing’s syndrome in pregnancy is often delayed because the symptoms overlap. We presented a thin 31-year-old woman, admitted 2 months after a normal-term delivery, with an atypical presentation of Cushing’s disease, unusual clinical features, and a challenging clinical course. She had no clinical discriminatory features of Cushing’s syndrome. Given that the patient only presented with psychosis and proximal myopathy and had an uncomplicated pregnancy, our case was considered unusual. The patients also had hyperpigmentation and severe muscle weakness which are among the less common presentations of Cushing’s syndrome. Our findings suggest that an early diagnosis of Cushing’s disease is important in pregnancy period for its prevalent fetal and maternal complications, and it should be treated early to optimize fetal and maternal outcomes as there is an increasing trend toward live births in treated participants.

Introduction

Cushing’s syndrome is a condition that originates from excessive production of glucocorticoids. The condition is most common in women of childbearing age and is characterized by altered distribution of the adipose tissue to the central and upper regions of the trunk (central obesity and buffalo hump), face (moon face), capillary wall integrity (easy bruising), hyperglycemia, hypertension, mental status changes and psychiatric symptoms, muscle weakness, signs associated with hyperandrogenism (acne and hirsutism), and violaceous striae among other signs. Hypercortisolism and hyperandrogenism suppress the production of the pituitary gonadotropins, which in turn leads to menstrual irregularities and infertility.1–3 Moreover, the main common cause of developing Cushing’s syndrome is the use of exogenic steroid.3
Cushing’s disease is a form of Cushing’s syndrome with overproduction of adrenocorticotropic hormone (ACTH) due to pituitary adenoma. The diagnosis is made using clinical features and paraclinical tests including urinary free cortisol (UFC), serum ACTH, dexamethasone suppression tests (DSTs), pituitary magnetic resonance imaging (MRI), and sometimes by inferior petrosal sinus sampling (IPSS).4 Although women with Cushing’s disease are less likely to become pregnant, timely diagnosis and appropriate management are especially important during possible pregnancy, preventing neonatal and maternal complications and death. The diagnosis is challenging due to the overlap of the disease symptoms with the changes associated with a normal pregnancy. Moreover, the hormonal milieu during pregnancy has recently been proposed as a potential trigger for Cushing’s disease in some cases; hence, the term “pregnancy-associated Cushing’s disease” has been used for the disease in the recent literature. In this study, we presented a thin 31-year-old woman who was referred to our clinic 2 months after a normal delivery, with an atypical presentation of Cushing’s disease, unusual clinical features, and a challenging clinical course.

Case Presentation

Our patient was a 31-year-old woman who presented 2 months after the delivery of her second child. She had a history of type 2 diabetes mellitus and hypertension in the past 2 years prior to her presentation. She had been admitted to another center following an episode of falling and muscle weakness. Two weeks later, she was admitted to our center with an impression of pulmonary thromboembolism due to tachypnea, tachycardia, and dyspnea. During follow-up, she was found to have leukocytosis, hyperglycemia (random blood sugar: 415 mg/d; normal level: up to 180 mg/dL) and hypokalemic metabolic alkalosis (PH: 7.5, HCO3 [bicarbonate]: 44.7 mEq/L, paO2 [partial pressure of oxygen]: 73 mm Hg, pCO2: 51.7 mm Hg, potassium: 2.7 mEq/L [normal range: 3.5-5.1 mEq/L]), which was refractory to the treatment; therefore, an endocrinology consultation was first requested. On physical examination, the patient was agitated, confused, and psychotic. Her vital signs were: blood pressure 155/100 mm Hg, heart rate: 130 bpm, and respiratory rate: 22 bpm, temperature: 39°C. As it has shown in Figure 1A, her face is not typical for moon face of Cushing’s syndrome, but facial hirsutism (Figure 1A) and generalized hyperpigmentation is obvious (Figure 1A-C). She was a thin lady and had a normal weight and distribution of adiposity (Body Mass Index [BMI] = 16.4 kg/m2; weight: 40 kg, and height: 156 cm). Aside from thinness of skin, she did not have the cutaneous features of Cushing’s syndrome (e.g. purpura, acne, and violaceous striae) and did not have supraclavicular and dorsocervical fat pad (buffalo hump), or plethora. In other words, she had no clinical discriminatory features of Cushing’s syndrome despite the high levels of cortisol, as confirmed by severely elevated UFC (5000 μg/24 h and 8000 μg/24 h; normal level: 4-40 μg/24 h). In addition, as will be mentioned later, the patient had axonal neuropathy which is a very rare finding in Cushing’s syndrome.
Figure 1. Clinical finding of our case with Cushing’s disease. (A) Hirsutism, (B) muscle atrophy seen in proximal portion of lower limbs, and (C) hyperpigmentation specially on the skin of the abdominal region.

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She had a markedly diminished proximal muscle force of 1 out of 5 across all extremities; the rest of the physical examinations revealed no significant abnormalities (Figure 1B). On the contrary, based on her muscle weakness, hirsutism, psychosis and hyperpigmentation and refractory hypokalemic alkalosis, hyperglycemia, and hypertension, Cushing’s syndrome was suspected; therefore, 24-hour UFC level was checked that the results showed a severely elevated urinary cortisol (5000 μg/24 h and 8000 μg/24 h; normal level: 4-40 μg/24 h). Serum ACTH level was also inappropriately elevated (45 pg/mL; normal range: 10-60 pg/mL). High-dose dexamethasone failed to suppress plasma cortisol level and 24-hour urine cortisol level. A subsequent pituitary MRI showed an 8-mm pituitary mass, making a diagnosis of Cushing’s disease more probable. Meanwhile, the patient was suffering from severe muscle weakness that did not improve after the correction of hypokalemia. Then, a neurology consultation was requested. The neurology team evaluated laboratory data as well as EMG (Electromyography) and NCV (Nerve Conduction Velocity) of the patient, and based on their findings, “axonal neuropathy” was diagnosed for her weakness; so they ruled out the other neuromuscular diseases. A 5-day course of intravenous immunoglobulin (IVIG) was started for her neuropathy; however, the treatment did not improve her symptoms and the patient developed fungal sepsis and septic shock. Therefore, she was processed with broad-spectrum antibiotics and antifungal agents and recovered from the infection.
Mitotane was started for the patient before definitive surgical treatment to suppress hormonal production due to her poor general condition. Despite the 8-mm size of the pituitary mass which is likely to be a source of ACTH, our patient was underweight and showed the atypical clinical presentation of Cushing’s disease, making us suspect an ectopic source for the ACTH. Therefore, a Gallium dotatate scan was performed to find any probable ectopic sources; however, the results were unremarkable. The patient underwent Trans-Sphenoidal Surgery (TSS) to resect the pituitary adenoma because it was not possible to perform IPSS in our center. Finally, the patient’s condition including electrolyte imbalance, muscle weakness, blood pressure, and hyperglycemia started to improve significantly. The pathologist confirmed the diagnosis of a corticotropic adenoma. Nevertheless, the patient suddenly died while having her meal a week after her surgery; most likely due to a thromboembolic event causing a cardiac accident.

Discussion

Our patient was significantly different from other patients with Cushing’s disease because of her atypical phenotype. She was unexpectedly thin and had psychosis, hyperpigmentation, proximal myopathy, axonal neuropathy and no clinical discriminatory features of Cushing’s syndrome such as central adiposity, dorsocervical or supraclavicular fat pad, plethora or striae. She had also a history of type 2 diabetes and hypertension 2 years before her admission. The patient was diagnosed with Cushing’s later. From what was presented, the patient did not know she had Cushing’s until after her delivery and despite the highly elevated UFC, and she completed a normal-term delivery. Given that she only presented with psychosis and proximal myopathy, her pregnancy was considered unusual. Her clinical features such as hyperpigmentation and severe muscle weakness are among less common presentations.5
11β-hydroxysteroid dehydrogenase type 1 (11-βHSD1) is an enzyme responsible for converting cortisone (inactive glucocorticoid) into cortisol (active). It is speculated that this enzyme has a role in obesity (Figure 2).6,7
Figure 2. The enzymatic actions of 11β-hydroxysteroid dehydrogenase on its substrate interconverting inactive and active glucocorticoid.

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In a case reported by Tomlinson, a 20-year-old female was diagnosed with Cushing’s disease despite not having the classical features of the disease. It has been suggested that the mechanism is a partial defect in 11β-HSD1 activity and concomitant increase in cortisol clearance rate. Thus, the patient did not have a classic phenotype; the defect in the conversion of cortisone to cortisol rises cortisol clearance and protects the patient from the effects of cortisol excess. This observation may help explain individual susceptibility to the side effects of glucocorticoids.6
Further studies of Tomlinson et al showed that a deficit in the function of (and not a mutation related to) 11β-HSD2 might have been responsible for the absence of typical Cushing’s symptoms. 11-HSD2 keeps safe the mineralocorticoid receptor from excess cortisol. Mutation in the HSD11B2 gene explains an inherited form of hypertension, apparent mineralocorticoid excess syndrome, in which Cushing’s disease results in cortisol-mediated mineralocorticoid excess affecting the kidney and leads to both hypokalemia and hypertension.8
It is frequent in Cushing’s syndrome that the patients usually have no mineralocorticoid hypertension; however, it is still proposed that a defect in 11β-HSD1 can be responsible for the presence of mineralocorticoid hypertension in a subgroup of patients. In fact, 11β-HSD1 is expressed in several tissues like the liver, kidneys, placenta, fatty tissues and gonads,9 meaning that this enzyme may potentially affect the results of cortisol excess in Cushing’s syndrome/disease. Abnormality in the function of this enzyme could explain the absence of the symptoms like central obesity, easy bruising, and typical striae during Cushing’s disease. Several factors affect the action of glucocorticoids. In this regard, the impact of the different types and levels of impairment in glucocorticoid receptors have been highlighted in some studies, as it can lead to different levels of response to glucocorticoids10 as well as a variety in the symptoms observed in Cushing’s disease.
The predominant reaction of the NADP(H)-dependent enzyme 11-Tukey’s honestly significant difference (HSD)1 happens through the catalysis of the conversion of inactive cortisol into receptor-active cortisol. The reverse reaction is mediated through the unidirectional NAD-dependent 11-HSD type 2 (Figure 2).11
In another case reported by Ved V. Gossein, a 41-year-old female was evaluated for hirsutism and irregular menstrual cycles. Her BMI was 22.6 kg/m2. The patient had no signs or symptoms of overnight recurrent Cushing’s syndrome, the 48-hour DST failed to suppress cortisol levels, and 24-hour urinary cortisol levels were persistently elevated on multiple occasions. Adrenocorticotropic hormone levels were unreasonably normal, suggesting ACTH-dependent hypercortisolism. Despite these disorders, she had 2 children. Magnetic resonance imaging (MRI) of the pituitary did not show any abnormalities. Moreover, abdominal MRI did not show adrenal mass or enlargement. Genetic testing to determine glucocorticoid resistance syndrome showed no mutation.12
Primary generalized glucocorticoid resistance is a rare genetic disorder characterized by generalized or partial insensitivity of target tissues to glucocorticoids.13–17 There is a compensatory increase in hypothalamic-pituitary activity due to decreased sensitivity of peripheral tissues to glucocorticoids systems.13–17 Excessive ACTH secretion leads to high secretion of cortisol and mineralocorticoids and/or androgens. However, the clinical features of Cushing’s syndrome do not develop after resistance to the effects of cortisol. Generalized glucocorticoid resistance is a rare condition characterized by high cortisol levels but no scarring of Cushing’s syndrome.18
An important aspect of our case was her pregnancy. Our patient had a history of hypertension and diabetes type 2, 2 years before her presentation to our center that could be because of an undiagnosed Cushing’s disease. The patient’s pregnancy terminated 2 months prior the admission and she had a normal vaginal delivery. So, we suspect that she become pregnant while involved with the disease. Aside from focusing on how this can happen in a patient with such high levels of glucocorticoids, more attention should be paid to occurring pregnancy in the background of Cushing’s disease. In fact, up to 250 patients were reported, of which less than 100 were actively treated.19–22
Cushing’s disease is associated with serious complications in up to 70% of the cases coinciding with pregnancy.21 The most frequent maternal complications reported in the literature are hypertension and impaired glucose tolerance, followed by preeclampsia, osteoporosis, severe psychiatric complications, and maternal death (in about 2% of the cases). Prematurity and intrauterine growth retardation account for the most prevalent fetal complications. Stillbirth, intrauterine deaths, intrauterine hemorrhage, and hypoadrenalism have also been reported.23 Early diagnosis is especially challenging during pregnancy because of many clinical and biochemical shared features of the 2 conditions.23,24 These features include an increase in ACTH production, corticosteroid-binding globulin (CBG) 1 level, level of cortisol (urinary, plasma and free), hyperglycemia, weight gain, and an increased chance for occurrence of bruising, hypertension (mistaken with preeclampsia), gestational diabetes mellitus, weight gain, and mood swings.3 There are some suggestions proposed in the studies that help in screening and differentiation of Cushing’s from the normal and abnormal effects of pregnancy and Cushing’s disease from Cushing’s syndrome in suspected pregnant patients. Contrary to Cushing’s syndrome, the nocturnal minimum level of cortisol is preserved in pregnancy.23,25 There is not yet a diagnostic cut-off determined on mentioned level; however, a few studies elucidate the evaluation of hypercortisolemia in a pregnant patient.26–28
Urinary free cortisol, a measure that reflects the amount of free cortisol in circulation, normally increases during pregnancy, and it can increase up to 8 times the normal level with Cushing’s disease during the second and the third trimesters,23,29 which is a useful tool to evaluate cortisol levels in a suspected pregnant woman. Because the suppression of both UFC and plasma cortisol is decreased in pregnancy,23,30 a low-dose DST is not very helpful for screening Cushing’s disease in pregnant patients. However, a high-dose DST with a <80% cortisol suppression might only indicate Cushing’s disease.3,31 Thus, it helps differentiating between ectopic ACTH syndrome and Cushing’s disease.32 The use of high-dose DST can distinguish between adrenal and pituitary sources of CS in pregnancy. Owing to the limited evidence available and the lack of data on normal pregnancies, the use of corticotropin-releasing hormone (CRH), desmopressin, and high-dose DST in pregnancy is not recommended yet.33 More timely diagnosis as well as timely intervention may have saved the life of our patient.
To differentiate between ectopic ACTH syndrome and Cushing’s disease, adrenal imaging should be considered. For higher plasma levels, combined employment of CRH stimulation test and an 8-mg DST can be helpful.3 Bilateral inferior petrosal sinus sampling (B-IPSS) might be needed when the findings are not in accordance with other results, but it is recommended to perform B-IPSS only if the noninvasive studies are inconclusive and only if there is enough expertise, experience, and technique for its performance.3
Although axonal neuropathy has been reported as a rare syndrome associated with paraneoplastic ectopic Cushing’s syndrome and exogenous Cushing’s syndrome, its association with Cushing’s disease has not been reported.5,32 Our patient had severe muscle weakness that we initially attributed it to myopathy and hypokalemia associated with Cushing’s syndrome. In our study, the diagnosis of axonal neuropathy was made based on electrophysiological studies by a neurology consultant and then IVIG was administered; however, the patient’s weakness did not improve after this treatment. The co-occurrence of Guillain-Barré syndrome which may also be classified as axonal neuropathy has also been reported in a pregnant woman with ectopic Cushing’s syndrome.34,35 Whether this finding is coincidental or the result of complex immune reactions driven by Cushing’s disease, or the direct effect of steroids, these results cannot be deduced from current data.36 Some data suggest that the fluctuations and inferior petrosal sinus sampling may trigger the flare of autoimmune processes, specifically when the cortisol levels start to decline during the course of Cushing’s syndrome.35,8 Also, due to COVID-19 pandemic affecting vital organs like kidney, paying attention to COVID-19 is suggested.37–40

Conclusions

We presented a thin young female with psychosis, proximal myopathy, and axonal neuropathy with Cushing’s disease who had a recent pregnancy that was terminated without any fetal or maternal complications despite the repeated elevated serum cortisol and 24-hour UFC; therefore, we suggest that she might have glucocorticoid resistance. Glucocorticoid resistance is a rare disease in which the majority, but not all, of patients have a genetic mutation in the hGR-NR3C1 gene. As we did not perform genetic testing for our patient, the data are lacking.
Another clue to the absence of the classic Cushing’s disease phenotype in our case is the role of isoenzymes of 11-HSD1 and 11-HSD2. Other mechanisms, such as the defect somewhere in the glucocorticoid pathway of action such as a decreased number of receptors, a reduction in ligand affinity, or a postreceptor defect, play an important role in nonclassical clinical manifestations of Cushing’s syndrome.

Acknowledgments

The authors thank the patient for allowing us to publish this case report. The authors show their gratitude to the of the staff of the Rasool Akram Medical Complex Clinical Research Development Center (RCRDC) specially Mrs. Farahnaz Nikkhah for its technical and editorial assists.

Ethics Approval

Our institution does not require ethical approval for reporting individual cases or case series.

Informed Consent

Written informed consent was obtained from the patient and for her anonymized information to be published in this article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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