Adrenalectomy Leading to Early Diagnosis of ALECT2 Amyloidosis

Introduction

Amyloidosis is caused by the deposition of amyloid fibrils derived from endogenous proteins into tissues, leading to organ dysfunction. The clinical presentation of amyloidosis varies and depends on the type of amyloid protein, the affected tissues, and the extent of amyloid deposition. Diagnosis is made by tissue sampling and relies on clinical suspicion. ¹ Leukocyte cell-derived chemotaxin 2 (ALECT2) associated amyloidosis is the third most common renal amyloidosis in the United States, predominantly affects the kidney and liver, and most commonly presents with slowly progressive CKD which may lead to end-stage renal disease (ESRD). ² Here, we present the rare case of a patient with ALECT2-associated adrenal amyloidosis that was diagnosed after adrenalectomy for an enlarging symptomatic adrenal cyst.

Case Presentation

A 38-year-old Mexican female with a subjective remote history of nephrolithiasis presented to the emergency room with 1 day of abdominal and flank pain, urinary frequency and urgency, hematuria, and dysuria. She denied any nausea or vomiting. Physical exam was notable for an initial blood pressure of 159/98 which decreased to 121/61 after administration of IV morphine and hydromorphone. A 5 cm adrenal lesion was incidentally identified on abdominopelvic computed tomography (CT) scan performed to rule out nephrolithiasis (Figure 1A and C). Her abdominopelvic CT, transabdominal ultrasound, and transvaginal ultrasound studies were otherwise unremarkable for abnormalities of the bladder, collecting systems, kidneys, and pelvis. She was discharged on tramadol and phenazopyridine after improvement of her pain and counseled on prevention of urinary tract infections and kidney stones.

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Figure 1.

Computed tomography (CT) images showing left adrenal cyst (white arrows): (A) axial and (C) coronal views of adrenal cyst at time of discovery on non-contrast CT; (B) axial and (D) coronal views of adrenal cysts on contrast-enhanced CT 3 years and 9 months after discovery, demonstrating growth.

Further investigation with magnetic resonance imaging (MRI) and an adrenal-protocol CT demonstrated a left adrenal cyst measuring 4.2 × 4.8 × 3.7 cm. The lesion exhibited high signal intensity on T2-weighted MRI, and CT showed water attenuation with thin peripheral enhancement and no internal enhancement or enhancing soft tissue component. These imaging features were consistent with a fluid-filled cyst with low suspicion for malignancy. Follow-up imaging studies 1 year later demonstrated limited growth with no changes in the cystic appearance of the lesion. The adrenal cyst was largely asymptomatic until around 4 years after detection, when the patient developed new intermittent left abdominal and flank pain.

A repeat CT scan demonstrated interval enlargement of the left adrenal cyst to 7.4 × 5.7 × 6.3 cm (Figure 1B and D). Laboratory biochemistry values are presented in Table 1.

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Table 1.

Pre- and post-operative laboratory values.

Laboratory test	9 mo pre-op	6 mo pre-op	7 mo post-op	Reference values
Serum
Sodium (mmol/L)	140	139	135 (L)	136–145
Potassium (mmol/L)	4.0	3.7	4.0	3.5–5.1
Chloride (mmol/L)	104	104	100	98–107
Carbon dioxide (mmol/L)	27	25	25	21–31
BUN (mmol/L)	5.4	3.6	5.7	2.5–6.4
Creatinine (µmol/L)	35.4 (L)	33.6 (L)	43.3 (L)	44.2–97.2
Glucose (mmol/L)	4.72	4.83	5.16	3.89–5.49
Calcium (mmol/L)	2.2	2.2	2.4	2.1–2.6
eGFR (mL/min/1.73 m2)	126.6	127.4	119.1	⩾60
Plasma aldosterone concentration (pmol/L)	305	343	427	111–859 (upright)
Renin activity (pmol/L/min)	1.28 (L)	2.56	—	2.56–20.48
PAC:PRA ratio (in above SI units)	238 (H)	134 (H)	—	<60
DHEA sulfate (µmol/L)	1.69	—	—	0.49–6.01
Cortisol (morning after 1 mg dexamethasone) (nmol/L)	—	20	—	<55
Urine
Free cortisol, 24 h (nmol/d)	—	101.6	—	⩽124.2
Creatinine, 24 h (mmol/d)	—	8.63	—	6.19–14.14
24 h cortisol-creatinine ratio (nmol cortisol/mmol creatinine)	—	11.8 (H)	—	Female, ⩾18 y/o: ⩽7.5
Metanephrine, 24 h (nmol/d)	—	228	—	183–1161
Normetanephrine, 24 h (nmol/d)	—	1141	—	519–3549

Abnormal values relative to reference values are bolded and marked as high or low.

Serum potassium, DHEA sulfate, as well as 24-hour urine metanephrines and normetanephrines were within normal limits. Serum creatinine was chronically slightly low and estimated glomerular filtration rate (eGFR) was >120 mL/min/1.73 m². 24-hour urine free cortisol was within normal limits though the cortisol-creatinine ratio was elevated. However, low-dose dexamethasone suppression testing was within normal limits which was reassuring for the absence of autonomous cortisol secretion. Notably, plasma aldosterone concentration (PAC) was 305 pmol/L (nl 111-859 upright), but plasma renin activity (PRA) was low at 1.28 pmol/L/min (nl 2.56-20.48), yielding an elevated PAC-PRA ratio of 238 (nl < 60) which raised some suspicion for primary aldosteronism (PA). However, these relatively mild derangements in laboratory values were deemed to be better explained by the compression of normal adrenal tissue by the large simple cyst seen on imaging, rather than autonomous secretion by an aldosterone-producing adenoma or PA.

Given the progressive enlargement of the cyst and new onset of symptoms, the patient was referred for surgical consultation, at which point she entered our care. At her preoperative office visit, she reported intermittent left abdominal and flank pain, and physical exam was notable for hypertension to 158/98 mmHg and BMI of 35 kg/m². There was no easy bruising, overt Cushingoid appearance, or hyperpigmentation. The decision was made to perform an adrenalectomy and forego additional workup for PA, given the size of her adrenal cyst over 4.0 cm at presentation to our practice and evidence of interval growth, both features recognized as concerning for malignancy, although imaging characteristics were not suspicious for a malignant lesion. ³

She ultimately underwent an uncomplicated laparoscopic left adrenalectomy. On surgical pathology, the resected specimen consisted of a 65 g piece of yellow-tan soft tissue measuring 13.5 × 7.5 × 1.5 cm. The adrenal gland measured 7.0 × 1.5 × 0.5 cm and had a surrounding cystic lesion that was received open, measuring 9.0 × 4.0 cm and containing approximately 10 to 20 cc of serous fluid. The specimen was serially sectioned to reveal a cystic cavity that appeared to involve the center, measuring 3.3 cm in greatest dimension. There were no other lesions present within the adrenal. The cortex was homogeneous and orange-yellow in color while the medulla was an unremarkable gray band. Histology identified the cyst as an epithelial cyst (Figure 2A). Hematoxylin and eosin staining showed deposition of eosinophilic acellular material in the adrenal cortex (Figure 2B) and Congo red staining was positive for apple-green birefringence within the adrenal cortex in polarized light, consistent with amyloid deposition (Figure 2C and D). Of note, there was no adrenal hyperplasia noted on examination of the adrenalectomy specimen.

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Figure 2.

Surgical histopathology of resected left adrenal gland and cyst: (A) low power section showing adrenal cortical parenchyma (black star) with cyst lined by single layer of epithelium (black arrow), (B) medium power showing adrenal cortex with deposition of eosinophilic acellular material (black star), compatible with amyloid, (C) adrenal tissue showing positive reaction with Congo red stain (red arrow), and (D) Congo red stain highlighting amyloid with apple green birefringence under polarized light (black arrows).

Two months following surgery, the patient was referred to a hematologist specializing in amyloidosis, where the patient endorsed several <2 cm subcutaneous masses on her arms and legs. She was evaluated for systemic versus localized amyloidosis. Serum and urine protein electrophoresis and immunofixation showed no evidence of paraprotein. Urine protein/creatinine ratio (0.1 g/g), NT-proBNP (<4.2 pmol/L [nl ⩽ 14.6 pmol/L]), liver function tests, and serum cortisol (298 nmol/L [PM cortisol: nl 69-328 nmol/L]) were unremarkable, suggesting normal function of the kidneys, heart, liver, and remaining right adrenal gland. However, abdominal fat pad biopsy revealed amyloid deposition within subcutaneous fat, confirming systemic involvement (Figure 3). Liquid chromatography tandem mass spectroscopy was performed by Mayo Clinic Laboratories (Rochester, MN) on peptides extracted from Congo red-positive sections of the resected adrenal gland, resulting in identification of the amyloid protein as LECT2 (leukocyte cell-derived chemotaxin 2), supporting the final diagnosis of systemic ALECT2 amyloidosis.

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Figure 3.

Fine-needle aspiration specimen of abdominal fat pad stained with Congo-red. Positive staining presented as orangiophilia around blood vessels within adipose tissue (blue arrows), at (A) low magnification and (B) high magnification. (C) and (D) Congo red stain highlighting amyloid deposits in abdominal fat pad specimen with apple green birefringence under polarized light (red arrows).

The patient had an uneventful postoperative course. On follow-up with hematology, she reported mild fatigue, but otherwise was doing well with no post-operative pain or other significant symptoms. Seven months postoperatively, there was no evidence of adrenal insufficiency with ACTH 49.4 ng/L (nl 7.2-63.3 ng/L) and cortisol 375 nmol/L (AM cortisol: nl 221-607 nmol/L). Her PAC was 427 pmol/L (nl 111-859 pmol/L upright), but unfortunately PRA was not obtained. Her kidney function remained normal, with a serum creatinine of 43.3 µmol/L (nl 44.2-97.2) and eGFR of 112.5 mL/min/1.73 m² (nl ⩾ 60). There was no evidence of proteinuria. At a subsequent follow-up visit with hematology about a year postoperatively, the patient reported mild fatigue which had improved. She reported that her home systolic blood pressures were controlled. She was counselled on dietary and lifestyle changes to prevent the development of hypertension and diabetes with the overall goal to maintain her renal health, given the known complication of progressive kidney disease with ALECT2 amyloidosis. Additionally, the option of prophylactic low-dose angiotensin converting enzyme inhibitor (ACEi) therapy was discussed with the involvement of a nephrologist. The patient opted against starting this therapy prophylactically, and a plan was made to start ACEi or angiotensin II receptor blocker therapy if she developed worsening hypertension, proteinuria, or elevated creatinine.

Discussion

ALECT2 amyloidosis is the third most common renal amyloidosis after immunoglobulin light chain (AL) amyloidosis and amyloid A (AA) amyloidosis. It is caused by deposition of amyloid fibrils derived from leukocyte cell-derived chemotaxin 2, although the pathogenesis of the disease is not well established. ⁴ ALECT2 amyloidosis most commonly presents with slowly progressive CKD, with up to 39% of patients progressing to ESRD, and is typically diagnosed in older patients on renal biopsy.^2,5 There have also been several incidental diagnoses of hepatic ALECT2 amyloidosis by liver biopsy. ⁶ There are currently no specific treatment options for ALECT2 amyloidosis. Patients are monitored for progression of CKD and accordingly treated with supportive measures such as dietary modifications, blood pressure control, dyslipidemia management, and organ transplantation.

ALECT2 amyloidosis predominantly affects the kidney and liver, but other organs and tissues including the adrenal gland, parathyroid glands, heart, lungs, gallbladder, pancreas, spleen, small bowel, and prostate can be clinically or subclinically involved.^2,7 One case series of 18 ALECT2 cases among 1001 decedents in New Mexico noted that out of 5 ALECT2 cases in which the adrenal glands were investigated, all had LECT2 deposition in the adrenal cortex and medulla. Consistently uninvolved tissues included the brain, myocardium, subcutaneous and perinephric fibroadipose tissue, and pancreas. Subcutaneous fibroadipose tissue was sampled in 3 ALECT2 cases with none showing LECT2 deposition. ⁸ The positive abdominal fat pad involvement by ALECT2 in the present case is the first reported to our knowledge.

As reinforced by this case, ALECT2 amyloidosis predominantly affects Hispanic patients, with two large case series observing 88% to 92% of all cases occurring in Hispanic patients.^5,9 In one study, all Hispanic patients with ALECT2 who disclosed their ancestry were of Mexican descent. ⁵ It has also been diagnosed in geographically diverse populations including Punjabis, First Nations people of British Columbia, Native Americans, and Egyptians. ² It is also a potentially underdiagnosed cause of CKD in these populations. ⁸ These strong racial and ethnic associations, as well as evidence of familial case clustering suggest a genetic component to the development of ALECT2 amyloidosis, but no single gene has been implicated and no germline genetic testing is routinely used clinically. ¹⁰

It is unclear whether the adrenal cyst and ALECT2 amyloidosis were related in this patient. Very few cases of adrenal amyloidosis associated with an adrenal cyst or mass have been reported in the literature. To our knowledge, this is the first reported case of adrenal amyloidosis that was diagnosed in the setting of a nonfunctional benign adrenal lesion. Rauschecker et al. ¹¹ described a diagnosis of adrenal ALECT2 amyloidosis after a total left adrenalectomy to treat PA. Thakur et al. ¹² presented a case of adrenal AA amyloidosis associated with an adrenal mass, where the diagnosis was made by endoscopic ultrasound-guided fine needle aspiration biopsy. In both above cases, adrenal amyloidosis was diagnosed in patients with adrenal masses with malignant features (hormone excess or elevation in tumor markers).

Initial diagnosis of ALECT2 amyloidosis by its detection within the adrenal gland is rare, as most diagnoses are made by renal biopsy in patients presenting with CKD. Eletta et al. ⁷ described the case of a Hispanic patient who had undergone renal transplantation for ESRD, who on autopsy was found to have ALECT2 amyloid deposition in the native kidneys, adrenal glands, spleen, as well as the liver, myocardium, and intramyocardial vessels. Tariq and Sharkey ¹³ similarly report the autopsy finding of ALECT2 amyloidosis in a Hispanic patient with involvement of multiple organs.

There have also been reports of patients with AA or AL renal amyloidosis who developed symptomatic primary adrenal insufficiency, some of whom had confirmed amyloid infiltration of the adrenal glands on autopsy. However, developing such symptoms from adrenal amyloid deposition is rare as a significant portion of the adrenal cortex must be destroyed to produce symptoms. ¹⁴ To our knowledge, there are no reports of primary adrenal insufficiency associated with ALECT2 amyloidosis. As recommended for the general population, patients with ALECT2 amyloidosis for adrenal insufficiency should be screened if they present with symptoms of fatigue, anorexia, gastrointestinal symptoms, weight loss, hyperpigmentation, hypotension, and/or hyponatremia. A lower clinical threshold to screen for adrenal insufficiency may be reasonable in situations where screening may or may not be necessary, given the theoretical risk factor of adrenal amyloidosis. Acute adrenal crises should be prevented, and hormone replacement treatment can be effective.

There are very few reported cases of ALECT2 without evidence of kidney involvement. Schwartz et al. ¹⁵ describe a Hispanic patient with reportedly isolated hepatic ALECT2 amyloidosis, but it is unclear whether renal involvement was ruled out with clinical or laboratory findings. The present case is among the first reported cases of confirmed systemic ALECT2 amyloidosis without clinical or laboratory signs of renal involvement, though this is limited by the absence of a renal biopsy which is not indicated. This case may provide insight into the natural history of the disease and presents an opportunity to intervene with preventative measures prior to development of CKD in ALECT2 amyloidosis.

As mentioned previously, the patient’s aldosterone and renin values led to consideration of possible PA. However, there was no histological evidence of adrenal hyperplasia on examination of the resected adrenal gland. These abnormal findings may be attributable to the enlarging cyst causing mass effect, or possibly to the irritation or stimulation of amyloid deposits on normal adrenal cells.

While this case report is limited by the lack of immunohistochemistry confirmation of LECT2 amyloid protein deposition in the adrenal and abdominal fat pad aspiration tissue, the diagnosis is strongly supported by its identification by mass spectrometry of the adrenal specimen in addition to Congo red staining.

Conclusion

This case of ALECT2 amyloidosis diagnosed incidentally after surgical treatment of an adrenal cyst is an interesting and rare presentation of the disease, demonstrating that patients may have subclinical involvement of the adrenal glands, subcutaneous fat, and other tissues before manifestation of renal amyloidosis as CKD, which prompts most diagnoses. The abdominal fat pad involvement by ALECT2 is the first reported to our knowledge and is an important finding as abdominal fat pad biopsy is a less invasive procedure for diagnosing amyloidosis, though less sensitive. These findings present opportunities to identify disease and intervene with preventative measures prior to development of CKD. Patients with ALECT2 amyloidosis should be regularly monitored for signs of kidney disease and appropriately counseled to manage modifiable risk factors for kidney disease including hypertension, diabetes mellitus, heart disease, obesity, and smoking.