Resistant hypertension after shockwave lithotripsy: the rude awakening of an adrenal incidentaloma

Abstract

A 41-year-old woman presented to the hospital because of left flank pain. CT scan of the kidneys revealed left-sided calculi and an incidental right adrenal mass, no other symptoms noted. She then underwent shockwave lithotripsy (SWL). However, immediately postoperatively, she had elevated blood pressure and remained hypertensive despite having four different medications. How SWL could have increased blood pressure could not be identified. On endocrine consult 16 months after SWL, she was found to now exhibit signs and symptoms of Cushing’s syndrome. Further workup revealed the adrenal incidentaloma to be cortisol-secreting. After undergoing right laparoscopic adrenalectomy, her blood pressure normalised, cortisol levels decreased and signs of Cushing’s syndrome gradually improved. We hypothesise that the performance of the SWL could have triggered the adenoma to ‘awaken’ from being non-functioning to cortisol-producing since this was the only intervening event. Observations of other patients are needed to validate our hypothesis.

Background

The National Institutes of Health State-of-the-Science Statement defines adrenal incidentalomas (AIs) as clinically inapparent adrenal masses measuring greater than 1 cm discovered inadvertently in the course of diagnostic testing or treatment for conditions not related to the adrenals.¹ By definition, patients serendipitously found to have an AI should not have any history, signs or symptoms of adrenal disease prior to the imaging procedure that led to its discovery. This strict definition excludes cases in which symptomatic adrenal-dependent syndromes are ‘missed’ during history taking or physical examination. In a study of 61, 054 abdominal CT scans performed from 1985 to 1990, an incidental adrenal tumour (incidentaloma >1 cm) was detected in 259 patients (0.4% of all CT scans).² Another study using higher resolution scanners reported a prevalence of adrenal incidentaloma on abdominal CT of 4.4%.³ Non-functional adenoma remains the most frequent (60%–85%), while a minority present as functional adenomas (5%–16%). Of functional masses, 6% consist of pheochromocytomas, 5% are subclinical Cushing’s syndrome, 5% are adrenal carcinoma, 2% prove to be a metastasis and the rest belong to other aetiologies, such as myelolipomas, haematomas, cysts or lymphomas.⁴

A study done to compare bilateral and unilateral AI showed that while the workup of both are similar, there are differences between them. The study showed 23 patients with bilateral incidentalomas and 112 patients with unilateral incidentalomas among a cohort of 500 patients with adrenal lesions in a tertiary hospital. Bilateral incidentalomas were associated with a significantly higher prevalence of subclinical Cushing’s syndrome and a significantly lower prevalence of pheochromocytoma compared with unilateral lesions, while rates of hyperaldosteronism were similar in both groups.⁵

According to the guidelines, both hormonal and radiographical evaluation must be performed in order to rule-out subclinical states. In general, masses ≥4 cm are removed surgically, independent of functionality. Furthermore, all functional tumours and those with malignant characteristics undergo an adrenalectomy under endocrinological supervision. Non-functional adenomas, small myelolipomas, and benign asymptomatic cysts do not require surgical intervention.⁶

This leads us to ask two primary and equally important questions:

1. Is it malignant? (Presence of malignant characteristics)

2. Is it Functional (hormonally active)? (Differentiates functional vs non-functional masses)

In this case report, we discuss a patient with left-sided obstructing nephrolithiasis and a seemingly non-functioning adrenal incidentaloma on the right which was left uninvestigated. The patient underwent a shockwave lithotripsy for her nephrolithiasis which seemingly ‘awoke’ the neighbouring adrenal incidentaloma; initially presenting with resistant hypertension and eventually showed signs of Cushing’s syndrome.

Case presentation

A 41-year-old woman with no comorbidities at the time sought to consult with her doctor due to a 2-month history of left-sided flank pain. She had no family history of any congenital condition nor malignancy. A non-contrast CT scan of the kidneys, ureters and bladder was done, which revealed three punctate obstructing nephrolithiasis measuring 0.2–0.3 cm at the left. Incidentally found was a well-defined, hypodense 3.0×2.1 cm right adrenal mass that measured 26 Hounsfield units (HU). The patient had no other symptoms then.

She was referred to a urologist and eventually underwent extracorporeal shockwave lithotripsy on the left, given 5000 shocks at a frequency of 80–90 shocks/min with a maximum energy of 3. Prior to this, she was normotensive, normoglycaemic and her serum potassium were within normal limits. Immediately postprocedure, the patient was noted to have hypertensive episodes as high as 160/90 mm Hg. She was started on amlodipine 10 mg tablet once daily and was then discharged with a follow-up schedule for blood pressure monitoring. However, she was lost to follow-up and did not monitor her blood pressure.

Six months after the procedure, the patient developed episodes of palpitations and mild chest discomfort. She sought to consult with a cardiologist and workup included a 2D echocardiogram, 12-lead ECG, treadmill stress test and thyroid function test (thyroid-stimulating hormone, free T4, free T3) were obtained and were all unremarkable. The patient was not seen to have any remarkable physical findings during that time. The patient’s medications were then changed to amlodipine 10 mg+perindopril 10 mg tablet once daily, carvedilol 6.25 mg tablet two times per day and spironolactone 100 mg tablet two times per day. Despite the given antihypertensives, the patient’s blood pressure remained to be high at 130–140/80–90 mm Hg. She was then worked-up for other causes of hypertension.

A renal colour flow Doppler ultrasound revealed nephrolithiasis on the left but was non-obstructing, the previously incidentally detected adrenal mass on the right, and normal pulsatility index, peak systolic velocities, acceleration times and acceleration slopes in the bilateral main and segmental renal arteries which meant that there was a low probability for renal artery stenosis. The patient was then referred to the endocrinologist for further workup of the unexplained resistant hypertension (patient was already on four antihypertensives, including a diuretic) and the adrenal incidentaloma.

Sixteen months after the shockwave lithotripsy, the patient presented to the endocrinologist with a blood pressure of 130/80 mm Hg, heart rate of 70–80 beats/min and her body mass index (BMI) was 23.31 kg/m². On physical examination, she was noted to have red cheeks (facial plethora), rounded face (moon facies), fat pads on the back of the neck (buffalo hump), supraclavicular fat, plethora on the extremities and chest, a pendulous abdomen with greyish striae measuring more than 1 cm in width and thinned upper and lower extremities. The endocrinologist did an extensive investigation as to the function of the incidentaloma, as shown in table 1 and the patient’s metabolic profile.

Table 1.

Biochemical workup of the adrenal incidentaloma

Condition being tested	Test	Result	Normal values	Interpretation
Catecholamine excess	24 hours urine metanephrine	0.931 ng/24 hours	0–1 ng/24 hours	Normal
Aldosterone excess	Plasma aldosterone concentration	7.720 ng/dL	<15 ng/dL	Not elevated
	Plasma renin activity	0.38 ng/mL/hour	0.5–1.9 ng/mL/hour	Low
	Aldosterone-to-renin ratio	20.3 ng/dL per ng/mL/hour	<20 ng/dL per ng/mL/hour	Slightly elevated
Cortisol excess	08:00 hours serum cortisol after 1 mg dexamethasone suppression test	800 nmol/L	<50 nmol/L	Increased (5.8×)
	24 hours urine-free cortisol	1014.86 µg/24 hours	20–90 µg/24 hours	Increased (11×)
	Adrenocorticotropic hormone	5.0 pg/mL	9–52 pg/mL	Low
Androgen excess	Serum dehydroepiandrosterone-sulphate	0.678 µmol/L	1–6.95 µmol/L	Low

The bold values indicate that the values are not within the normal range.

Investigations

Other laboratories done were: fasting blood sugar at 104.40 mg/dL (normal value: 65.00–105.00 mg/dL), HBA1c (glycated hemoglobin) at 6.30% (normal value: 4.27%–6.07%), serum creatinine at 60.11 µmol/L (normal value: 53–115 µmol/L), total cholesterol at 3.22 mmol/L (normal value: 2.5–5.2 mmol/L), triglycerides at 1.36 mmol/L (normal value 0.34–1.7 mmol/L), high density lipoprotein at 1.11 (normal value: 0.91–1.56 mmol/L), low density lipoprotein at 1.84 mmol/L (normal value: 1.1–3.8 mmol/L) and serum potassium 4.09 mmol/L (normal value: 3.4–5.3 mmol/L).

The low renin level, in this case, can be explained by the negative feedback exerted by the elevated cortisol levels, which exhibit mineralocorticoid activity. This explains the normal aldosterone, low renin and equivocal ARR in this patient with an elevated cortisol level.⁷

A CT of the whole abdomen with triple phase-contrast study with the adrenal protocol was done. This revealed a well-defined, heterogeneous, enhancing focus measuring 2.3×2.3×2.6 cm arising in the body of the right adrenal gland with a precontrast HU of 28.8 and postcontrast HU of 86.2 (figure 1). The computed relative washout was 36.2%, and the absolute washout was 54.3%, as shown in table 2.

Figure 1.

A CT with contrast of the adrenal gland. Clockwise: precontrast HU 28.8, postcontrast HU 86.2 and delayed HU 55. HU, Hounsfield units.

Table 2.

Washout computations using the formula by the study of Blake et al⁶

Parameters	Hounsfield units
Absolute % washout	100×(86.2−55)/(86.2−28.8)=31.2/57.4=54.3
Relative % washout	100×(86.2−55)/86.2=31.2/86.2=36.2

The patient was managed as a case of: Cushing’s syndrome secondary to a right cortisol-secreting adrenal incidentaloma with secondary hypertension and hyperglycaemic.

Differential diagnosis

The patient’s hypertension and episodes of palpitations were thought to be of thyroid in origin and thus the thyroid function tests were ordered but were unremarkable. The 12-lead ECG did not show any tachyarrhythmias; and 2D echocardiography did now show any structural heart abnormalities.

Other causes of hypertension are renal in origin. Serum creatinine and urinalysis were normal. So a renal colour flow doppler was done (to rule-out renal artery stenosis) but revealed to be unremarkable except for the presence of the adrenal mass which was already noted prior. The patient was then referred to an endocrinologist, and workup (which include extensive laboratories and imaging) revealed the cause of the patient’s resistant hypertension was the adrenal mass which was cortisol-secreting.

Treatment

She was referred to a urologist and a laparoscopic right adrenalectomy was done. There were no intraoperative and postprocedure complications. Postoperatively, the 08:00 hours serum cortisol significantly decreased to 32.47 nmol/L (low). She was started (postoperatively) on hydrocortisone 50 mg intravenously q6 for four doses only. Her blood pressure was also noted to be at around 110-120/70-80 mm Hg and capillary blood glucose monitoring to be at 104–178 mg/dL. She was discharged well and off her antihypertensive medications. She continued her antidiabetes medications and was sent home on tapering dose of prednisone starting at 10 mg/day.

Outcome and follow-up

Grossly, the removed adrenal mass was an orange-yellow irregular friable tissue (weight: 2 g) measuring 3×3×2 cm. The cut sections revealed lobulated smooth surfaces. The histopathological findings indicated microscopic focus of local invasion into the periadrenal fat, rare mitoses and more than 25% clear cells present, no atypical mitotic figures, high nuclear grade, diffuse architecture, tumour necrosis and sinusoidal invasion seen (figure 2). Histopathological diagnosis was adrenocortical adenoma. After 1 month postop, she remained normotensive on daily blood pressure monitoring and asymptomatic. Her physical features of Cushing’s syndrome were resolving and hardly noticeable. At the third month postop, a 08:00 hours serum cortisol taken 24 hours after the last intake of prednisone while at 5 mg showed 110.825 nmol/L (low), suggesting that the contralateral adrenal has not yet fully recovered from suppression. There was no adrenocorticotropic hormone (ACTH) test done yet.

Figure 2.

A histological section of the tumour showing a microscopic focus of local invasion into the periadrenal fat. There are rare mitoses; and more than 25% clear cells present. No atypical mitotic figures, high nuclear grade, diffuse architecture, tumour necrosis and sinusoidal invasion was noted. This is consistent with an adrenocortical adenoma. The image is stained with H&E.

Discussion

An electronic literature search in PubMed was done and there was no case reported of a unilateral adrenal adenoma which presented with signs and symptoms of Cushing’s syndrome and/or hyperaldosteronism after a surgical intervention was done (in this study, shockwave lithotripsy).

Adrenal incidentalomas (AI) are benign or malignant lesions that arise from the cortex, medulla or an extra-adrenal source. The most common type is the adenomatous type (a median frequency of 80%). Furthermore, adrenal adenomas are classified as: aldosterone-secreting (2.5%), autonomously cortisol-secreting (12%) and non-functioning (75%).⁸

Is it malignant?

For the differentiation of malignant from benign adrenal tumours, there are three main imaging techniques in current use: CT, MRI and positron emission tomography (PET) with F-2-deoxy-d-glucose (mostly combined with CT; FDG-PET/CT). CT and MRI are techniques mainly aiming to identify benign lesions, therefore representing tools designed for the exclusion of adrenal malignancy.⁹ Conversely, FDG-PET/CT is mainly used for the detection of malignant disease.¹⁰

CT has a high spatial and quantitative contrast resolution, which allows assessment of tissue density by measuring X-ray absorption of tissues. This allows calculation of tissue attenuation or tissue density values, which are measured in HU and quantify X-ray absorption of tissues compared with water, which is conventionally allocated an HU value of 0. For non-contrast (or ‘unenhanced’) CT, HU of ≤10 is the most widely used threshold attenuation value for the diagnosis of a lipid-rich, benign adrenal adenoma.¹¹ Contrast-enhanced washout CT uses the unique perfusion pattern of adenomas. Adenomas take up intravenous CT contrast rapidly, but also have a rapid loss of contrast—a phenomenon termed ‘contrast enhancement washout’. It is assumed that malignant adrenal lesions usually enhance rapidly but demonstrate a slower washout of contrast medium. A relative washout >40% and an absolute washout >60% is assumed to suggest that an adrenal lesion is benign.¹²

Is it functional (hormonally active)?

Hormone assessment is crucial in the context of the workup for an adrenal incidentaloma. However, there are several pitfalls that have to be considered (eg diurnal rhythm, sex/age dependency, limitations of assays and drug interactions). Furthermore, normal ranges vary substantially, depending on the method used, so it is essential to interpret test results in the context of the appropriate reference range.

The patient

The adrenal incidentaloma had an HU of 28.8 on the non-enhanced contrast study; it measured 2.3×2.3×2.6 cm; and hormonal evaluation revealed the AI to be autonomously cortisol-secreting (08:00 hours serum cortisol after 1 mg dexamethasone suppression test: 800 nmol/L, 24 hours urine-free cortisol: 1014.86 µg/24 hours and ACTH: 5.0 pg/mL). We classified the AI to be functional, but could not definitely label it as benign nor malignant at this point. However, unilateral adrenalectomy/surgical excision remains to be the gold standard for management of tumours with significant hormone excess.⁸ The histopathology of the excised adrenal mass revealed an adrenocortical adenoma.

Shockwave lithotripsy

Studies have shown associations between urolithiasis and hypertension, diabetes mellitus, obesity, insulin resistance and metabolic syndrome.¹³ Shockwave lithotripsy (SWL) was introduced to the clinical setting for stone management in 1982 and became the first-line treatment for uncomplicated renal and proximal ureteral stones.¹⁴ Accompanied by endoscopic surgery, stone treatment is easier and more convenient for patients and causes less morbidity than the open surgical approach.

The pathophysiological mechanism of the interaction between hypertension and nephrolithiasis is unclear. Several hypotheses have been proposed, such as hypercalciuria, insulin resistance, chronic kidney disease and inflammatory oxidative stress, in patients with urolithiasis and hypertension.¹⁵

A recent study done showed that patients with urolithiasis who underwent an SWL had an increased risk of having hypertension by 20%. This risk was found to be directly proportional to the number of SWL treatment sessions; the more the sessions, the higher the risk.¹⁶ There are two possible mechanisms: first, shockwave is a special form of renal trauma with high incidences of intrarenal and subscapular bleeding and intrarenal ischaemia, which cause nephron loss with interstitial fibrosis in the focal zone.¹⁷ In addition, vasoconstriction with decreased renal blood flow and release of a vasoconstrictive substance might also account for hypertension after SWL.¹⁸ Second, SWL has a low stone-free rate and increased recurrent stone formation.¹⁹ Because nephrolithiasis will induce hypertension, new-onset hypertension may be attributed to recurrent stone formation in SWL-treated patients.

The patient, in this case, underwent a renal colour flow doppler ultrasound to not only rule-out renal artery stenosis but to also check for signs of intrarenal and subscapular bleeding and intrarenal ischaemia. The result was unremarkable, and the acuteness of the onset of the hypertension is not compatible with the proposed mechanisms of how SWL could have caused the hypertension.

We hypothesise that the performance of the SWL could have triggered the adenoma to ‘awaken’ from being non-functioning to cortisol-producing since this was the only intervening event. Observations of other patients are needed to validate our hypothesis.

Patient’s perspective.

I thought my only problem was my kidney stone. I already knew about the adrenal mass, but my doctor told me that it was nothing to worry about. So, I had done what I needed to do for the kidney stone. Then after I got rid of it, I had another problem. And that was my blood pressure that could not be controlled. Later on, it was found out that the adrenal mass was causing it. Something that was so small, and I thought was insignificant was actually the culprit. I now know better than to ignore minute details with regards to my health. This has also taught me to be inquisitive and ask my doctors about findings in my tests and imaging that I do not understand about.

Learning points.

• Whether the shockwave lithotripsy ‘awakened’ the initially seemingly non-functioning adrenal incidentaloma into being a cortisol-secretor or not, is still a mystery. But this was the only inciting factor that could do so and explain the whole course of the patient. Observations of other patients are needed to validate our hypothesis.

• In cases such as this, it is prudent to investigate other sources of unexplained resistant hypertension. Even a seemingly benign adrenal mass should be investigated.

• Incidentally discovered adrenal masses should be hormonally worked-up and not disregarded just because the patient does not exhibit signs or symptoms of hormonal hyperfunction.