Abstract
Objective
The diagnosis of Cushing’s disease (CD) is particularly challenging in patients with chronic kidney disease (CKD) due to abnormalities of the hypothalamo–pituitary–adrenal axis associated with the latter. This case report presents discrepant biochemical findings in a patient with CKD who was subsequently diagnosed with CD, and outlines principles which may guide the definitive diagnosis of CD in this context.
Methods
The case of a patient with Stage 4 CKD who underwent transsphenoidal surgery for pituitary-dependent CD is presented. A literature review was conducted to identify similar cases and characterise features of hypothalamo–pituitary–adrenal axis dysfunction in CKD.
Results
The patient discussed herein presented with markedly elevated plasma adrenocorticotrophic hormone (ACTH) due to a pituitary macroadenoma, with normal 24-h urine free cortisol (24-UFC) but abnormal overnight dexamethasone suppression testing and elevated midnight salivary cortisol. He experienced biochemical remission after undergoing transsphenoidal adenomectomy. A literature review revealed that CKD can be associated with elevated serum cortisol, reduced UFC and elevated plasma ACTH. Only four other cases of CD being diagnosed in a patient with CKD have been published. The loss of a circadian rhythm of cortisol secretion was the most common feature among all cases.
Conclusions
To establish a definitive diagnosis of CD in the context of pre-existing CKD, the absence of circadian rhythms of cortisol and ACTH is a more sensitive indicator than 24-UFC and low-dose dexamethasone suppression testing.
Introduction
Chronic kidney disease (CKD) can pose unique challenges in the diagnosis of Cushing’s disease (CD), especially in the presence of overlapping clinical signs or equivocal radiological abnormalities. The assessment of the hypothalamic–pituitary–adrenal (HPA) axis, including cortisol metabolism, can be particularly difficult in the context of CKD due to the important role of the kidney in cortisol excretion. As the prevalence of CKD rises in the developed world (1, 2, 3) and survival on dialysis improves (4), an informed approach to assist in the diagnosis of patients with CD on a background of CKD may become increasingly useful.
We present a case of a patient with Stage 4 CKD who was diagnosed with pituitary-dependent CD after developing progressive, severe, treatment-resistant hypertension. The patient presented discrepant biochemical findings upon HPA axis assessment, which complicated his initial diagnosis. This case also demonstrated the synergistic co-morbid burden of concomitant CD and CKD. Neurosurgical risk is elevated in cases of CKD (5, 6, 7), making it vital to ensure an accurate preoperative diagnosis of CD.
The objectives of this case report were threefold: (1) to present conflicting biochemical findings in a patient with CKD who was diagnosed with histopathologically confirmed CD, (2) to present possible explanations for discrepancies in biochemical assessment of the HPA axis in CKD and (3) to outline principles for the definitive diagnosis of CD in view of the challenging features of CKD. The literature relating to the diagnosis of CD in patients with CKD was also reviewed to support our objectives.
Case report
A 68-year-old male was referred to our centre from his nephrologist with severe, treatment-resistant hypertension in the context of long-standing, Stage 4 CKD secondary to diabetic glomerulonephropathy. His elevated blood pressure was refractory to quadruple therapy (prazosin, hydralazine, metoprolol and frusemide). Systolic blood pressures were consistently recorded between 180 and 210 mmHg, despite increasing doses of antihypertensive agents over 3 months preceding his admission for transsphenoidal pituitary adenomectomy. The patient had also been experiencing fatigue and worsening proximal muscle weakness. There was no history of osteoporosis, mood disturbance or headache.
Past medical history revealed significant vascular comorbidities including cerebrovascular disease, ischaemic heart disease and peripheral vascular disease with recent development of an ischaemic toe requiring emergency surgical intervention during investigation for CD. In addition, the patient had severe obstructive sleep apnoea and gout. There was no history of exogenous steroid use. He had a 24-pack-year smoking history and consumed an average of two standard drinks of alcohol per day. There was no family history of pituitary or other endocrine tumours. Examination revealed an obese male (body mass index 35) with mild bruising and moderate proximal myopathy but no other features of CD such as ruddy moon facies, abdominal striae or a cervico-dorsal fat pad.
The initial pituitary panel revealed a normal morning serum cortisol of 241 nmol/L (RR: 150–520 nmol/L), markedly elevated plasma ACTH at 57 pmol/L (RR: <12 pmol/L), hyperprolactinaemia, secondary hypothyroidism and hypogonadism (Table 1). His renal function was stable, with a serum creatinine of 289 µmol/L (reference range (RR): 60–110), estimated glomerular filtration rate (eGFR) of 16 mL/min (RR: >90) and proteinuria of 3.29 g/day (RR: <0.8). His potassium was normal, 4.7 mmol/L (RR: 3.5–5.2), with an anaemia of chronic disease, Hb 86 g/L (RR: 130–180) and he presented normal blood sugar levels on no hypoglycaemic therapy.
Preoperative pituitary hormone assessment.
| Assessment | Value | Reference range |
|---|---|---|
| ACTH (pmol/L) | 57.0 | <12.0 |
| Midnight salivary cortisol (nmol/L) | 20.0 | <8.0 |
| Baseline morning serum cortisol (nmol/L) | 241.0 | 150.0–520.0 |
| Early morning serum cortisol after DEX (nmol/L)* | ||
| 1 mg (serum DEX concentration†) | 262.0 (11.0) | <50.0 |
| 8 mg (serum DEX concentration†) | 153.0 (67.0) | N/A |
| Urine free cortisol (1st/2nd/3rd) | ||
| Volume (nmol/L/day) | 1.9/2.1/1.8 | N/A |
| Creatinine concentration (mmol/L) | 5.2/5.7/6.1 | 8.0-16.0 |
| Total creatinine (mmol/24 h) | 10.0/11.8/11.0 | 5.0-16.0 |
| Cortisol concentration (nmol/L) | 61.0/36.0/43.0 | N/A |
| Total cortisol (nmol/24 h) | 118.0/74.0/77.0 | 0-250.0 |
| IGF-1 (nmol/L) | 19.0 | 9.0-28.0 |
| GH (mIU/L) | <0.4 | 0-10.0 |
| Prolactin (mIU/L) | 2620.0 | <500.0 |
| LH (IU/L) | <0.5 | 1.7-8.6 |
| FSH (IU/L) | 1.1 | 1.5-13.0 |
| Testosterone (nmol/L) | 6.7 | 8.0-32.0 |
| TSH (mIU/L) | 0.4 | 0.3-4.0 |
| Free T3 | 2.4 | 3.0-6.2 |
| Free T4 | 8.7 | 11.0-22.0 |
*Serum cortisol was measured 9 h after the administration of dexamethasone. †Serum dexamethasone concentration was deemed to be adequate if >5.6 nmol/L.
ACTH, adrenocorticotropic hormone; DEX, dexamethasone; FSH, follicle stimulating hormone; GH, growth hormone; IGF-1, insulin-like growth factor 1; LH, luteinising hormone; TSH, thyroid-stimulating hormone.
Subsequent investigations were performed which demonstrated an elevated midnight salivary cortisol of 20 nmol/L (RR: <8 nmol/L) as well as lack of suppression on both low- and high-dose dexamethasone testing after documentation of appropriately elevated dexamethasone levels (Table 1). However, 24-UFC measurements performed on three separate occasions (and not concurrent with dexamethasone testing) were all at the lower end of the normal range, 118 nmol, 74 nmol and 77 nmol respectively (RR: <250 nmol/24 h). Urine volumes were acceptable, between 1.8–2.1 L, with normal 24-h urine creatinine excretion.
MRI of the brain revealed a lobulated, heterogeneously intense pituitary mass of 16.3 mm with suprasellar extension, mild optic chiasm compression but no cavernous sinus invasion (Fig. 1). Intravenous gadolinium was not administered in the setting of CKD. Visual fields were intact on preoperative perimetry testing.
Preoperative T1-weighted magnetic resonance imaging scans showing a pituitary macroadenoma: (A) coronal and (B) sagittal views.
Citation: European Journal of Endocrinology 181, 4; 10.1530/EJE-19-0326
Preoperative T1-weighted magnetic resonance imaging scans showing a pituitary macroadenoma: (A) coronal and (B) sagittal views.
Citation: European Journal of Endocrinology 181, 4; 10.1530/EJE-19-0326
Preoperative T1-weighted magnetic resonance imaging scans showing a pituitary macroadenoma: (A) coronal and (B) sagittal views.
Citation: European Journal of Endocrinology 181, 4; 10.1530/EJE-19-0326
Despite the patient’s discordant biochemical findings, the presence of a pituitary macroadenoma on MRI facilitated the decision to proceed to transsphenoidal surgery (TSS). Postoperatively, there was a reduction in the patient’s serum cortisol levels over 4 days (Fig. 2). The patient was commenced on glucocorticoid replacement on day 5, after his serum cortisol reached a nadir 99 nmol/L. There was a significant improvement in blood pressure control postoperatively and no surgical complications encountered. His 3-month postoperative MRI demonstrated no residual tumour.
Postoperative serum cortisol values.
Citation: European Journal of Endocrinology 181, 4; 10.1530/EJE-19-0326
Postoperative serum cortisol values.
Citation: European Journal of Endocrinology 181, 4; 10.1530/EJE-19-0326
Postoperative serum cortisol values.
Citation: European Journal of Endocrinology 181, 4; 10.1530/EJE-19-0326
Pathological examination of the resected tumour revealed a corticotroph adenoma with extensive fibrosis and chronic haemorrhage (Fig. 3). Immunohistochemistry demonstrated the tumour was ACTH and T-pit positive with Ki67 index of 1.6% and the mitotic count was not elevated. A cystic component was also present, which raised the possibility of an incorporated Rathke’s cleft cyst.
Tumour histological appearance: haematoxylin and eosin stain at (A) 10× magnification and (B) 20× magnification, (C) adrenocorticotropin immunoreactivity and (D) reticular fibre staining.
Citation: European Journal of Endocrinology 181, 4; 10.1530/EJE-19-0326
Tumour histological appearance: haematoxylin and eosin stain at (A) 10× magnification and (B) 20× magnification, (C) adrenocorticotropin immunoreactivity and (D) reticular fibre staining.
Citation: European Journal of Endocrinology 181, 4; 10.1530/EJE-19-0326
Tumour histological appearance: haematoxylin and eosin stain at (A) 10× magnification and (B) 20× magnification, (C) adrenocorticotropin immunoreactivity and (D) reticular fibre staining.
Citation: European Journal of Endocrinology 181, 4; 10.1530/EJE-19-0326
Discussion
This case highlights the challenges of diagnosing CD in a patient with pre-existing CKD. Chronic renal dysfunction is known to cause physiologic hypercortisolism, which can produce a similar phenotype to that of CD (8, 9). In addition, some features of CKD can interfere with the accurate interpretation of biochemical findings that would be diagnostic of CD in patients with normal renal function (10). This is particularly troubling in the case of adenomas that are invisible on preoperative MRI, as is the case in up to 45% of patients with CD (11, 12). The contraindication of intravenous contrast in CKD may further limit the utility of imaging in this context.
A systematic literature search was conducted using MEDLINE, Embase Classic and Embase for cases of CD diagnosed in patients with CKD (search strategies are available on request from the corresponding author; Supplementary tables 1 and 2, see section on supplementary data given at the end of this article). The aim was to determine whether any clinical approaches have been used to aid diagnosis in this setting.
This revealed only four other published cases of CD diagnosed in a patient with CKD. In three cases, the presence of CD was suspected due to significantly elevated serum cortisol and loss of cortisol and ACTH circadian rhythm (13, 14, 15). In the fourth case, the diagnosis of CD was established after inferior petrosal sinus sampling revealed a central-peripheral gradient of ACTH (16). In contrast, the patient reported herein demonstrated consistently normal 24-UFC and morning serum cortisol levels but inadequate suppression following dexamethasone administration..
The effect of CKD on cortisol and ACTH
Plasma cortisol
Elevated levels of plasma cortisol are a well-known characteristic of CKD (17). It has been postulated that the high inflammatory state of CKD results in increased activation of the HPA axis, and subsequently, increased cortisol secretion (9, 17). The half-life of plasma cortisol and its metabolites can also be extended in CKD, a phenomenon which may be partially due to reduced renal excretion (4, 18). Furthermore, higher concentrations of glucuronide conjugates and steroids (other than cortisol) found in the serum of patients with CKD can cross-react with antisera used in cortisol immunoassays (19, 20, 21). One or more of these factors may lead to a higher likelihood of false-positive results when measuring plasma cortisol to diagnose CD.
In patients with end-stage renal disease (ESRD), plasma cortisol levels may normalise after the commencement of haemodialysis (21). In some patients, however, this correction will prove to be transient and plasma cortisol will begin to increase again after several months or years (22, 23). A factor which may confound the assessment of plasma cortisol in patients on haemodialysis is the effect of the session itself, which can transiently increase plasma cortisol for several hours (18, 24, 25). Hence, the timing of one-off cortisol measurements is important to consider in patients receiving haemodialysis, with higher levels more likely to be observed immediately post dialysis. It should also be noted that patients on haemodialysis, in the absence of underlying CD, may have reduced circadian rhythmicity or fail to achieve a discernible circadian nadir (10, 26). Studies comparing levels of plasma cortisol in haemodialysis and continuous ambulatory peritoneal dialysis (CAPD) are scarce, but levels do not appear to differ significantly between these modalities (27, 28).
Another abnormality reported in CKD, including in patients on dialysis, is inadequate suppression of plasma cortisol by dexamethasone. This is more likely to occur at lower doses or with oral administration (9, 18, 29). Possible contributing factors may be poor gastrointestinal absorption or accelerated metabolism of dexamethasone in CKD, resulting in a shortened half-life (14, 29, 30). Direct immunoassays have also been found to overestimate plasma cortisol concentrations after dexamethasone administration in patients with CKD (10). To mitigate these features, serum dexamethasone concentration should be measured during testing to confirm that adequate bioavailability has been achieved (31).
Salivary cortisol
In salivary samples of patients with CKD, the concentration of cortisol accurately reflects the level of unbound, free cortisol in the serum (10, 19, 32). Reduced levels of circulating albumin and cortisol-binding globulin can occur in CKD, which may result in an increased serum concentration of free cortisol (17, 18, 33). This limits the specificity of salivary cortisol as a test for CD in patients with CKD. However, the finding of a normal late-night salivary cortisol on several evenings in such patients makes a diagnosis of underlying CD extremely unlikely (8, 9).
Urine free cortisol
Moderate or severe renal dysfunction can lead to the reduced excretion of free cortisol into the urine despite increased plasma levels. As creatinine clearance falls below 60 mL/min, the level of UFC has been found to reduce linearly with more severe renal impairment (31, 34). This limits the sensitivity of UFC levels for detecting CD in patients with CKD, particularly those with ESRD, in whom urinary output is minimal or non-existent (35). Currently, the most widely applied method for determining UFC levels is immunoassay, which is susceptible to overestimation of UFC due to cross-reactivity with cortisol metabolites (36, 37). This has led to increasing interest in the detection of UFC using mass spectrometry (MS). Due to its specificity for cortisol alone, MS has lower sensitivity than immunoassay at low UFC concentrations (35, 38). Therefore, UFC measurement is of limited value for identifying CD in patients with CKD.
Plasma ACTH
Plasma ACTH is typically increased in CKD, possibly due to increased stimulation of the HPA axis by the hyper-inflammatory state associated with this condition (9, 10, 28, 39, 40). In patients with ESRD, plasma ACTH may be transiently increased for several hours following each session of haemodialysis (24, 25). As with plasma cortisol, levels of plasma ACTH do not appear to differ significantly between haemodialyzed patients and those receiving CAPD (28). In addition to increased plasma ACTH in CKD, a corticotroph adenoma may secrete biologically inactive ACTH, which often has higher molecular weight than its active counterpart (41, 42). The loss of glomerular membrane size selectivity due to the accumulation of renal damage may be offset by the steric hindrance of these higher molecular weight molecules, extending their plasma half-life. As these molecules compete with normal ACTH at its binding site, the secretion of inactive ACTH may explain our patient’s normal levels of serum cortisol despite substantially elevated plasma ACTH.
Principles for diagnosing CD in pre-existing CKD
The pathological sequelae of CKD can interfere with biochemical assays and produce abnormalities of the HPA axis that mirror findings characteristic of CD. However, differing patterns of HPA axis dysfunction may be identified in patients with CD and CKD compared with CKD alone. These differences can facilitate the diagnosis of underlying CD (Table 2). The feature that most commonly differentiates underlying CD is lost circadian rhythmicity of both cortisol and ACTH (10, 13, 14, 15, 18). Nonetheless, it is important to note that the loss of circadian rhythm can still occur in CKD, particularly in patients receiving dialysis. This abnormality is associated with higher levels of circulating inflammatory markers, such as C-reactive protein (10).
Biochemical findings that may distinguish underlying Cushing’s disease in patients with pre-existing chronic kidney disease.
| Assessment | Findings in patients with pre-existing CKD | |||||
|---|---|---|---|---|---|---|
| Without CD | With CD* | |||||
| Case 1 (13) | Case 2 (14) | Case 3 (15) | Case 4 (16) | Case 5 (reported herein) | ||
| Morning serum cortisol | Increased (10, 34) | Increased | Increased | Increased | NR | Normal |
| 24-h UFC | Decreased (31, 34) | Decreased | NR | Decreased | Normal | Normal |
| Circadian rhythm | ||||||
| Cortisol | Preserved (10, 18, 29) | Lost | Lost | Lost | NR | Lost |
| ACTH | Preserved (10) | Lost | NR | Lost | NR | NR |
| Oral dexamethasone suppression of serum cortisol† | ||||||
| Low dose | Not suppressed (18, 29) | Not suppressed | Not suppressed | Not suppressed | Not suppressed | Not suppressed |
| High dose | Suppressed (18, 29) | Not suppressed | Suppressed | Suppressed | NR | Not suppressed |
*Expected findings are based on cases reported in the literature to date, including the case described herein. †Normal response: plasma cortisol ≤50 nmol/L after dexamethasone administration.
ACTH, adrenocorticotropic hormone; CD, Cushing’s disease; CKD, chronic kidney disease; NR, not reported; UFC, urine free cortisol.
Another distinguishing feature of CD in CKD is failure to suppress cortisol to <50 nmol/L in response to a higher dose of dexamethasone, such as 8 mg (usually performed in patients without CKD, in whom Cushing’s syndrome has been confirmed but differentiation between a pituitary and ectopic source of ACTH is being sought) (13). In CKD without underlying CD, cortisol suppression should be seen (13, 18, 29).
Conclusions
This is the first known case report of successful transsphenoidal adenomectomy for CD in a patient with CKD. This case highlights the difficulty of using biochemical assessments to diagnose CD in patients with CKD and provides insight into the contextual significance of tests used. To guide a definitive diagnosis of CD in this context, the circadian rhythms of cortisol and ACTH are likely to be the most accurate indicators. The use of 24-UFC, nadir serum cortisol levels and low-dose dexamethasone suppression testing should be avoided, due to the likelihood of false positives or false negatives. Meticulous attention should be paid to signs, symptoms and clinical history. Further research will be needed to more accurately assess the sensitivity and specificity of circadian rhythms of cortisol and ACTH as diagnostic criteria for CD in patients with CKD.
Supplementary data
This is linked to the online version of the paper at https://doi.org/10.1530/EJE-19-0326.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
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