- Email: [email protected]
An Overlooked Cause of Hypokalemia
Accepted Manuscript Title: An Overlooked Cause of Hypokalemia Author: Cherng Jye Seow, William Francis Young Jr. PII: DOI: Reference:
S0002-9343(17)30635-6 http://dx.doi.org/doi: 10.1016/j.amjmed.2017.06.005 AJM 14150
To appear in:
The American Journal of Medicine
Please cite this article as: Cherng Jye Seow, William Francis Young Jr., An Overlooked Cause of Hypokalemia, The American Journal of Medicine (2017), http://dx.doi.org/doi: 10.1016/j.amjmed.2017.06.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title Page
Title of Manuscript: An Overlooked Cause of Hypokalemia
1) Cherng Jye Seow MBBS, MRCPS (Glas), FRCP (Edin) Consultant, Department of Endocrinology, Tan Tock Seng Hospital
2) William Francis Young, Jr., MD, MSc Professor of Medicine Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
Contact Information of corresponding author Cherng Jye Seow Email Address: [email protected] Department of Endocrinology 11 Jalan Tan Tock Seng Singapore 308433
Funding Source: None
Conflict of Interest: None
All authors had access to the data and a role in writing the manuscript
Article Type: Images in Radiology
Page 1 of 12
Key Words: Hypokalemia, Cushing disease
Running head: Hypokalemia and Cushing disease
An Overlooked Cause of Hypokalemia
Page 2 of 12
Seow CJ1 MBBS, MRCPS (Glas), FRCP (Edin), Young WF, Jr.2 MD, MSc 1
Department of Endocrinology, Tan Tock Seng Hospital, Singapore
2
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
PRESENTATION
Hypokalemia is a commonly encountered clinical problem. The underlying pathophysiology can be attributed to the following 3 mechanisms: insufficient potassium intake; excessive urinary or gastrointestinal losses; and transcellular shifts. While gastrointestinal losses from vomiting and diarrhea or medications such as diuretics account for the large majority of cases, we present a patient with hypokalemia from a sinister and commonly overlooked etiology.
A 57 year old woman was referred to the endocrinology clinic for poorly controlled diabetes mellitus. She was diagnosed with Type 2 diabetes mellitus 1 year previously when she presented with polyuria, polydipsia and a weight loss of 12 pounds, and was subsequently treated with metformin and glipizide. However, despite escalating doses of oral hypoglycemics, her glycemic control remained poor with a glycated haemoglobin level of 9.5%. Eventually, isophane insulin was started and she was referred by her primary care physician for further management.
Her other medical problems included chronic hepatitis B as well as hypertension and dyslipidemia: the latter 2 conditions were diagnosed around the onset of diabetes mellitus. Other medications included enalapril, simvastatin and entacavir. There was no significant family history of note and she was not taking any supplements.
ASSESSMENT
On examination, the patient had a rounded countenance, prominent truncal obesity and thin limbs. Her body mass index was 19.1 kg/m2. Her heart rate was 70 beats per minute and blood pressure 130/70mmHg. There was no radial-femoral delay, no ballotable kidneys or renal bruit. The rest of the examination was unremarkable.
Page 3 of 12
Initial laboratory results revealed an unexpected potassium level of 2.6 mmol/L (normal, 3.5-5 mmol/L) despite treatment with enalapril.
Further history was directed at elucidating the cause of the hypokalemia. There were no complaints of recent or chronic vomiting or diarrhea. She did not experience any symptoms of thyrotoxicosis and was not on any medications such as beta-adrenergic agonists which could account for transcellular potassium shifts. She had hypertension which was well controlled. She had a significant background history of hepatitis B but had never been on adefovir or tenofovir which are associated with proximal tubulopathy. There was no significant family or personal history of autoimmune disorders such as Sjogren syndrome or systemic lupus erythematosus which could result in renal tubular acidosis. She was not on long term diuretics and did not consume excessive licorice. She also denied treatment with corticosteroids.
Additional investigations of the hypokalemia suggested a renal loss of potassium: spot urine potassium level was 68 mmol/L, spot urine creatinine level was 8.4 mmol and the urinary potassium/creatinine ratio was 8.1. In addition, she was alkalotic with a bicarbonate level of 35 mmol/L (normal, 19-31 mmol/L). Magnesium was normal at 0.7 mmol/L (normal, 0.7-1.0mmol/L). Plasma renin activity and plasma aldosterone concentration were both suppressed at <0.13ng/mL/hr and 1.7 ng/dL respectively.
At this juncture, the possibility of Cushing syndrome was considered. Further evaluation showed the following: baseline 8am cortisol 44.3 ug/dL (normal, 7-25 ug/dL) with paired serum corticotrophin 55 pg/mL (normal, 10-60 pg/mL). The 24 hour urinary free cortisol excretion was more than 4-fold elevated at 1811 nmol/day (normal, 59-413 nmol/day, urine volume 1000 ml). An overnight 8mg dexamethasone suppression test revealed an early morning cortisol that suppressed by 71.3% to 12.7 ug/dL.
Magnetic resonance imaging of the pituitary gland was arranged and a 3.8 x 2.5 x 4.9 cm macroadenoma was seen, with extension into the left and right cavernous sinuses and completely encasing the left intracavernous carotid artery (Figure 1). Computed tomography of the thorax, abdomen and pelvis revealed a small liver cyst but no other abnormalities. Visual field testing was normal.
At transsphenoidal surgery, a firm fibrous vascular tumour was found in the sellar and infrasellar compartments, filling the sphenoid sinus cavity. The excised tissue stained strongly positive for corticotrophin on immunohistochemistry.
Page 4 of 12
DIAGNOSIS
Hypokalemia from Cushing disease secondary to a pituitary macroadenoma was made in view of the findings of hypokalemia from renal loss, metabolic alkalosis, suppressed renin and aldosterone level, an elevated 24-hour urinary free cortisol with unsuppressed overnight dexamethasone suppression test, magnetic resonance imaging of the pituitary showing a macroadenoma as well as histology of the excised specimen staining strongly positive for corticotrophin.
MANAGEMENT
Early morning cortisol levels in the first week post-surgery remained elevated at 16.6-22.7 ug/dL which was not unexpected given that the tumour could not be entirely excised due to invasion into the cavernous sinus. In view of her background of chronic Hepatitis B, low dose ketoconazole 100mg twice a day was started and cabergoline 0.5mg twice a week was added for control of hypercortisolism. Three months after surgery, a repeated magnetic resonance imaging of the pituitary revealed marked reduction in the pituitary macroadenoma with less mass effect on the supra-sella cistern and the left intracavernous carotid artery. The slight extension to the right cavernous sinus remained stable (Figure 2). Stereotactic radiosurgery with gamma knife was subsequently arranged and the patient was followed up closely with an aim of normalisation of her 24-hour urinary free cortisol as well an early morning serum cortisol.
One year post gamma knife radiotherapy, her cortisol level remained stable at 14 ug/dL and 24-hour urinary free cortisol 99 nmol/day (59-413 nmol/day, urine volume 1325ml) on low doses of ketoconazole (50mg twice a day) and cabergoline (0.5mg twice a week). Magnetic resonance imaging of the pituitary gland (Figure 3) showed a stable sellar mass with extension to the sphenoid sinus and right cavernous sinus. Ketoconazole and cabergoline will be discontinued when the full effects of gamma knife radiotherapy become evident.
DISCUSSION
Cortisol has mineralocorticoid activity and circulates in blood at a concentration a thousand fold greater than aldosterone. Usually, the mineralocorticoid receptor in the renal tubule is protected from
Page 5 of 12
activation by cortisol by the action of 11ß hydroxysteroid dehydrogenase type 2 (11 ß-HSD2), which converts cortisol to inactive cortisone.1 At high levels of cortisol, the 11 ß-HSD2 is overwhelmed and excess cortisol can activate the mineralocorticoid receptor. The inhibitory effect of elevated levels of corticotrophin on 11 ß-HSD22 as well as elevated corticosterone and deoxycorticosteroid which possess mineralocorticoid activity could also account for hypokalemia in corticotrophin-dependent Cushing syndrome.3 Hypokalemia secondary to Cushing disease is not common: 57% of patients with ectopic Cushing syndrome in one series4 had hypokalemia compared to only 10% in Cushing disease in another series5 – the discrepancy is likely related to the severity of hypercortisolism in ectopic Cushing syndrome. In our patient with Cushing disease, hypokalemia likely occurred due to the high levels of corticotrophin from the macroadenoma.
The most common cause of Cushing syndrome is the administration of supraphysiologic doses of glucocorticoids.6 Endogenous Cushing syndrome is rare, with an incidence of 0.7-2.4 per million population per year7 and can be divided into corticotrophin-dependent (80-85%) or corticotrophinindependent (10-15%) causes. It is estimated that 75-80% are due to corticotrophin production from a pituitary adenoma, 15-20% from ectopic sources and <1% from corticotrophin-releasing hormoneproducing tumours. Surgical resection of the pituitary adenoma is the recommended first-line treatment of Cushing disease, but is unfortunately associated with a remission rate8 of less than 15% in macroadenomas as in this patient. Nonetheless surgery is still recommended for debulking intent and to increase the success with radiotherapy and medical therapy. Stereotactic radiosurgery is preferred over conventional fractionated radiotherapy as it can be given over one session with a faster therapeutic response. Our patient received gamma knife radiosurgery and was started on medical therapy while waiting for effects of radiosurgery to occur.
Medical therapies for Cushing disease can be divided into agents that decrease corticotrophin release at the pituitary (eg, somatostatin analogs such as pasireotide and dopamine agonists such as cabergoline), inhibit steroidogenesis at the adrenal glands (eg, etomidate, metyrapone, ketoconazole, mitotane) and block glucocorticoid action (mifepristone)9 at the cortisol receptor level. Patients on medical therapy should be educated on symptoms of hypocortisolism and need for glucocorticoid treatment during sick days. Combination therapy, as in this patient, can reduce drug-related adverse events by using lower doses of either drug. Bilateral adrenalectomy is an option in cases of refractory Cushing disease.
In summary, Cushing disease is associated with a 2- to 5-fold increase in mortality10-11 and hypokalemia occurs if there is severe hypercortisolism, usually secondary to a macroadenoma. Thus, there needs to be a heightened index of suspicion for this possible diagnosis in the evaluation of hypokalemia. Curative treatment results in a reduction in mortality.10
Page 6 of 12
REFERENCES
1. Krozowski ZS, Funder JW. Renal mineralocorticoid receptors and hippocampal corticosterone— binding species have identical intrinsic steroid specificity. Proc Natl Acad Sci USA 1983;80:6065-6060
2. Walker BR, Campbell JC, Fraser R et al. Mineralocorticoid excess and inhibition of 11 beta hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome. Clin Endocrinol (Oxf) 1992;37(6):483-92
3. Schambelan M, Slaton PE, Jr, Biglieri EG. Mineralocorticoid production in hyperandrenocorticism. Role in pathogenesis of hypokalemic alkalosis. Am J Med 1971;51(3):299-303
4. Torpy DJ, Mullen N, IIias I et al. Association of hypertension and hypokalemia with Cuhing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci 2002;970:134-44
5. Howlett TA, PL Drury, L Perry et al. Diagnosis and management of ACTH dependent Cushing’s syndrome: comparison of the features of ectopic and pituitary ACTH production. Clin. Endocrinol (Oxf) 1986;24:699-713
6. Hopkins RL, Leinung MC. Exogenous Cushing’s syndrome and glucocorticoid withdrawal. Endocrinol Metab Clin N Am. 2005;34:371-384
7. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemol 2015;7:281-93
8. Lindsay JR, Oldfield EH, Stratakis CA et al. The postoperative basal cortisol and CRH tests for prediction of long-term remission from Cushing’s disease after transspehnoidal surgery. J Clin Endocrinol Metab 2011;96:2057-2064
Page 7 of 12
9. Molitch ME. Current approaches to the pharmacological management of Cushing’s disease. Mol Cell Endocrinol 2015;408:185-9
10. Clayton RN, Raskauskiene D, Reulen RC et al. Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab 2011;96(3):632-42
11. Feelders RA, Pulgar SJ, Kempel A et al. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol 2012;167(3):311-326
LEGEND
Figure 1: Sagittal (A) and Coronal (B) view of the magnetic resonance imaging of the pituitary gland prior to surgery showing a macroadenoma (arrows) extending into the left and right cavernous sinuses and completely encasing the left cavernous internal carotid artery.
A.
Page 8 of 12
B.
Page 9 of 12
Figure 2: Coronal view of MRI of the pituitary gland 3 months after surgery, showing decreased mass effect on the suprasellar cistern and left internal carotid artery by the remnant tumour (arrows).
Page 10 of 12
Figure 3: Coronal view of MRI of the pituitary gland 1 year after radio surgery showing a stable sellar mass (arrows) with extension to the sphenoid sinus and right cavernous sinus.
Page 11 of 12
Page 12 of 12
S0002-9343(17)30635-6 http://dx.doi.org/doi: 10.1016/j.amjmed.2017.06.005 AJM 14150
To appear in:
The American Journal of Medicine
Please cite this article as: Cherng Jye Seow, William Francis Young Jr., An Overlooked Cause of Hypokalemia, The American Journal of Medicine (2017), http://dx.doi.org/doi: 10.1016/j.amjmed.2017.06.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title Page
Title of Manuscript: An Overlooked Cause of Hypokalemia
1) Cherng Jye Seow MBBS, MRCPS (Glas), FRCP (Edin) Consultant, Department of Endocrinology, Tan Tock Seng Hospital
2) William Francis Young, Jr., MD, MSc Professor of Medicine Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
Contact Information of corresponding author Cherng Jye Seow Email Address: [email protected] Department of Endocrinology 11 Jalan Tan Tock Seng Singapore 308433
Funding Source: None
Conflict of Interest: None
All authors had access to the data and a role in writing the manuscript
Article Type: Images in Radiology
Page 1 of 12
Key Words: Hypokalemia, Cushing disease
Running head: Hypokalemia and Cushing disease
An Overlooked Cause of Hypokalemia
Page 2 of 12
Seow CJ1 MBBS, MRCPS (Glas), FRCP (Edin), Young WF, Jr.2 MD, MSc 1
Department of Endocrinology, Tan Tock Seng Hospital, Singapore
2
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
PRESENTATION
Hypokalemia is a commonly encountered clinical problem. The underlying pathophysiology can be attributed to the following 3 mechanisms: insufficient potassium intake; excessive urinary or gastrointestinal losses; and transcellular shifts. While gastrointestinal losses from vomiting and diarrhea or medications such as diuretics account for the large majority of cases, we present a patient with hypokalemia from a sinister and commonly overlooked etiology.
A 57 year old woman was referred to the endocrinology clinic for poorly controlled diabetes mellitus. She was diagnosed with Type 2 diabetes mellitus 1 year previously when she presented with polyuria, polydipsia and a weight loss of 12 pounds, and was subsequently treated with metformin and glipizide. However, despite escalating doses of oral hypoglycemics, her glycemic control remained poor with a glycated haemoglobin level of 9.5%. Eventually, isophane insulin was started and she was referred by her primary care physician for further management.
Her other medical problems included chronic hepatitis B as well as hypertension and dyslipidemia: the latter 2 conditions were diagnosed around the onset of diabetes mellitus. Other medications included enalapril, simvastatin and entacavir. There was no significant family history of note and she was not taking any supplements.
ASSESSMENT
On examination, the patient had a rounded countenance, prominent truncal obesity and thin limbs. Her body mass index was 19.1 kg/m2. Her heart rate was 70 beats per minute and blood pressure 130/70mmHg. There was no radial-femoral delay, no ballotable kidneys or renal bruit. The rest of the examination was unremarkable.
Page 3 of 12
Initial laboratory results revealed an unexpected potassium level of 2.6 mmol/L (normal, 3.5-5 mmol/L) despite treatment with enalapril.
Further history was directed at elucidating the cause of the hypokalemia. There were no complaints of recent or chronic vomiting or diarrhea. She did not experience any symptoms of thyrotoxicosis and was not on any medications such as beta-adrenergic agonists which could account for transcellular potassium shifts. She had hypertension which was well controlled. She had a significant background history of hepatitis B but had never been on adefovir or tenofovir which are associated with proximal tubulopathy. There was no significant family or personal history of autoimmune disorders such as Sjogren syndrome or systemic lupus erythematosus which could result in renal tubular acidosis. She was not on long term diuretics and did not consume excessive licorice. She also denied treatment with corticosteroids.
Additional investigations of the hypokalemia suggested a renal loss of potassium: spot urine potassium level was 68 mmol/L, spot urine creatinine level was 8.4 mmol and the urinary potassium/creatinine ratio was 8.1. In addition, she was alkalotic with a bicarbonate level of 35 mmol/L (normal, 19-31 mmol/L). Magnesium was normal at 0.7 mmol/L (normal, 0.7-1.0mmol/L). Plasma renin activity and plasma aldosterone concentration were both suppressed at <0.13ng/mL/hr and 1.7 ng/dL respectively.
At this juncture, the possibility of Cushing syndrome was considered. Further evaluation showed the following: baseline 8am cortisol 44.3 ug/dL (normal, 7-25 ug/dL) with paired serum corticotrophin 55 pg/mL (normal, 10-60 pg/mL). The 24 hour urinary free cortisol excretion was more than 4-fold elevated at 1811 nmol/day (normal, 59-413 nmol/day, urine volume 1000 ml). An overnight 8mg dexamethasone suppression test revealed an early morning cortisol that suppressed by 71.3% to 12.7 ug/dL.
Magnetic resonance imaging of the pituitary gland was arranged and a 3.8 x 2.5 x 4.9 cm macroadenoma was seen, with extension into the left and right cavernous sinuses and completely encasing the left intracavernous carotid artery (Figure 1). Computed tomography of the thorax, abdomen and pelvis revealed a small liver cyst but no other abnormalities. Visual field testing was normal.
At transsphenoidal surgery, a firm fibrous vascular tumour was found in the sellar and infrasellar compartments, filling the sphenoid sinus cavity. The excised tissue stained strongly positive for corticotrophin on immunohistochemistry.
Page 4 of 12
DIAGNOSIS
Hypokalemia from Cushing disease secondary to a pituitary macroadenoma was made in view of the findings of hypokalemia from renal loss, metabolic alkalosis, suppressed renin and aldosterone level, an elevated 24-hour urinary free cortisol with unsuppressed overnight dexamethasone suppression test, magnetic resonance imaging of the pituitary showing a macroadenoma as well as histology of the excised specimen staining strongly positive for corticotrophin.
MANAGEMENT
Early morning cortisol levels in the first week post-surgery remained elevated at 16.6-22.7 ug/dL which was not unexpected given that the tumour could not be entirely excised due to invasion into the cavernous sinus. In view of her background of chronic Hepatitis B, low dose ketoconazole 100mg twice a day was started and cabergoline 0.5mg twice a week was added for control of hypercortisolism. Three months after surgery, a repeated magnetic resonance imaging of the pituitary revealed marked reduction in the pituitary macroadenoma with less mass effect on the supra-sella cistern and the left intracavernous carotid artery. The slight extension to the right cavernous sinus remained stable (Figure 2). Stereotactic radiosurgery with gamma knife was subsequently arranged and the patient was followed up closely with an aim of normalisation of her 24-hour urinary free cortisol as well an early morning serum cortisol.
One year post gamma knife radiotherapy, her cortisol level remained stable at 14 ug/dL and 24-hour urinary free cortisol 99 nmol/day (59-413 nmol/day, urine volume 1325ml) on low doses of ketoconazole (50mg twice a day) and cabergoline (0.5mg twice a week). Magnetic resonance imaging of the pituitary gland (Figure 3) showed a stable sellar mass with extension to the sphenoid sinus and right cavernous sinus. Ketoconazole and cabergoline will be discontinued when the full effects of gamma knife radiotherapy become evident.
DISCUSSION
Cortisol has mineralocorticoid activity and circulates in blood at a concentration a thousand fold greater than aldosterone. Usually, the mineralocorticoid receptor in the renal tubule is protected from
Page 5 of 12
activation by cortisol by the action of 11ß hydroxysteroid dehydrogenase type 2 (11 ß-HSD2), which converts cortisol to inactive cortisone.1 At high levels of cortisol, the 11 ß-HSD2 is overwhelmed and excess cortisol can activate the mineralocorticoid receptor. The inhibitory effect of elevated levels of corticotrophin on 11 ß-HSD22 as well as elevated corticosterone and deoxycorticosteroid which possess mineralocorticoid activity could also account for hypokalemia in corticotrophin-dependent Cushing syndrome.3 Hypokalemia secondary to Cushing disease is not common: 57% of patients with ectopic Cushing syndrome in one series4 had hypokalemia compared to only 10% in Cushing disease in another series5 – the discrepancy is likely related to the severity of hypercortisolism in ectopic Cushing syndrome. In our patient with Cushing disease, hypokalemia likely occurred due to the high levels of corticotrophin from the macroadenoma.
The most common cause of Cushing syndrome is the administration of supraphysiologic doses of glucocorticoids.6 Endogenous Cushing syndrome is rare, with an incidence of 0.7-2.4 per million population per year7 and can be divided into corticotrophin-dependent (80-85%) or corticotrophinindependent (10-15%) causes. It is estimated that 75-80% are due to corticotrophin production from a pituitary adenoma, 15-20% from ectopic sources and <1% from corticotrophin-releasing hormoneproducing tumours. Surgical resection of the pituitary adenoma is the recommended first-line treatment of Cushing disease, but is unfortunately associated with a remission rate8 of less than 15% in macroadenomas as in this patient. Nonetheless surgery is still recommended for debulking intent and to increase the success with radiotherapy and medical therapy. Stereotactic radiosurgery is preferred over conventional fractionated radiotherapy as it can be given over one session with a faster therapeutic response. Our patient received gamma knife radiosurgery and was started on medical therapy while waiting for effects of radiosurgery to occur.
Medical therapies for Cushing disease can be divided into agents that decrease corticotrophin release at the pituitary (eg, somatostatin analogs such as pasireotide and dopamine agonists such as cabergoline), inhibit steroidogenesis at the adrenal glands (eg, etomidate, metyrapone, ketoconazole, mitotane) and block glucocorticoid action (mifepristone)9 at the cortisol receptor level. Patients on medical therapy should be educated on symptoms of hypocortisolism and need for glucocorticoid treatment during sick days. Combination therapy, as in this patient, can reduce drug-related adverse events by using lower doses of either drug. Bilateral adrenalectomy is an option in cases of refractory Cushing disease.
In summary, Cushing disease is associated with a 2- to 5-fold increase in mortality10-11 and hypokalemia occurs if there is severe hypercortisolism, usually secondary to a macroadenoma. Thus, there needs to be a heightened index of suspicion for this possible diagnosis in the evaluation of hypokalemia. Curative treatment results in a reduction in mortality.10
Page 6 of 12
REFERENCES
1. Krozowski ZS, Funder JW. Renal mineralocorticoid receptors and hippocampal corticosterone— binding species have identical intrinsic steroid specificity. Proc Natl Acad Sci USA 1983;80:6065-6060
2. Walker BR, Campbell JC, Fraser R et al. Mineralocorticoid excess and inhibition of 11 beta hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome. Clin Endocrinol (Oxf) 1992;37(6):483-92
3. Schambelan M, Slaton PE, Jr, Biglieri EG. Mineralocorticoid production in hyperandrenocorticism. Role in pathogenesis of hypokalemic alkalosis. Am J Med 1971;51(3):299-303
4. Torpy DJ, Mullen N, IIias I et al. Association of hypertension and hypokalemia with Cuhing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci 2002;970:134-44
5. Howlett TA, PL Drury, L Perry et al. Diagnosis and management of ACTH dependent Cushing’s syndrome: comparison of the features of ectopic and pituitary ACTH production. Clin. Endocrinol (Oxf) 1986;24:699-713
6. Hopkins RL, Leinung MC. Exogenous Cushing’s syndrome and glucocorticoid withdrawal. Endocrinol Metab Clin N Am. 2005;34:371-384
7. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemol 2015;7:281-93
8. Lindsay JR, Oldfield EH, Stratakis CA et al. The postoperative basal cortisol and CRH tests for prediction of long-term remission from Cushing’s disease after transspehnoidal surgery. J Clin Endocrinol Metab 2011;96:2057-2064
Page 7 of 12
9. Molitch ME. Current approaches to the pharmacological management of Cushing’s disease. Mol Cell Endocrinol 2015;408:185-9
10. Clayton RN, Raskauskiene D, Reulen RC et al. Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab 2011;96(3):632-42
11. Feelders RA, Pulgar SJ, Kempel A et al. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol 2012;167(3):311-326
LEGEND
Figure 1: Sagittal (A) and Coronal (B) view of the magnetic resonance imaging of the pituitary gland prior to surgery showing a macroadenoma (arrows) extending into the left and right cavernous sinuses and completely encasing the left cavernous internal carotid artery.
A.
Page 8 of 12
B.
Page 9 of 12
Figure 2: Coronal view of MRI of the pituitary gland 3 months after surgery, showing decreased mass effect on the suprasellar cistern and left internal carotid artery by the remnant tumour (arrows).
Page 10 of 12
Figure 3: Coronal view of MRI of the pituitary gland 1 year after radio surgery showing a stable sellar mass (arrows) with extension to the sphenoid sinus and right cavernous sinus.
Page 11 of 12
Page 12 of 12