Metachronous parathyroid adenoma characterised by recurrent nephrolithiasis

Abstract

Hyperparathyroidism is often diagnosed after identifying hypercalcaemia through routine testing in asymptomatic patients; however, many patients experience severe and painful symptoms related to their diagnosis, including nephrolithiasis and bone pain with osteoporosis. Double adenomata are an uncommon cause of hyperparathyroidism, and they occasionally occur metachronously with recurrent symptoms years apart. This case report examines a woman in her 60s with a history of parathyroid adenoma 9 years earlier who presented with recurrent nephrolithiasis. She was found to have a recurrence of primary hyperparathyroidism after more than a year of recurrent urinary tract infections, nephrolithiasis and bacteraemia. A neck exploration revealed a metachronous parathyroid adenoma, which was removed with complete resolution of symptoms. Her case demonstrates the importance of evaluating patients with nephrolithiasis for hyperparathyroidism and communicating abnormal laboratory results with the patient in a hospital setting. It also provides the opportunity to examine the rare diagnosis of a metachronous parathyroid adenoma.

Background

The parathyroid glands are responsible for regulating calcium and phosphate levels through the blood, kidneys, intestines and bones. Hyperparathyroidism is a state of excessive production of parathyroid hormone (PTH), most commonly due to a single parathyroid adenoma, which results in hypercalcaemia and hypophosphataemia (table 1).¹ The hypercalcaemia associated with a single parathyroid adenoma is typically mild and intermittent with calcium levels less than 0.25 mmol/L over normal limits.¹ This condition is most common among women aged 50–70 years old.¹

Table 1.

This table demonstrates the relative prevalence of the different aetiologies for primary hyperparathyroidism

Aetiology of primary hyperparathyroidism	Prevalence
Single parathyroid adenoma	80–85%
Double adenomata	4–5%
Parathyroid hyperplasia	10–12%
Parathyroid carcinoma	>1%

The table was created by author KBT using information from another source.¹

Double adenomata are a less common cause of hyperparathyroidism where two parathyroid glands each have an adenoma (table 1). They can occur either synchronously where both adenomata develop simultaneously or metachronously where the adenomata occur in sequence with a second adenoma developing after the removal of the first.

Primary hyperparathyroidism is often diagnosed by elevated calcium levels while the patient is asymptomatic; however, the most common symptom associated with this condition is nephrolithiasis, which is seen in 39% of patients with a parathyroid adenoma.² Other symptoms include polyuria, constipation, fatigue, bone pain and psychiatric manifestations.¹ In severe cases, patients may experience cardiac arrhythmia, coma or even death due to severe electrolyte derangements.¹

When a parathyroid adenoma is suspected, it is often identified by a sestamibi scan with single-photon emission CT (SPECT) imaging before undergoing surgical treatment. Parathyroid adenomata are more commonly observed in the inferior poles and on the right side.³ Histologically, parathyroid adenomata are typically composed of chief cells, which are either unencapsulated or have a thin fibrous capsule.¹

Four-gland exploratory surgery allows for a thorough analysis of each parathyroid gland at the time of parathyroidectomy; however, minimally invasive (focused) parathyroidectomy is becoming a common surgical option due to the high prevalence of single adenomata, the similar cure rate and complication rate, and the improved cosmetic outcome.¹ The PTH level is measured prior to parathyroidectomy, and the procedure is considered successful if PTH drops by at least 50% 10 min after parathyroidectomy.¹

Following parathyroid surgery, successful or otherwise, many patients experience brief hypocalcaemia for days or even weeks.^{1 3 4} The patient may require calcium supplementation if hypocalcaemia fails to resolve on its own.¹ Following resection of a parathyroid adenoma, some patients may develop a condition known as ‘hungry bone syndrome’ characterised by a temporary dramatic hypoparathyroidism with PTH levels below 10 pg/mL (reference range: 12–88 pg/mL) due to the affinity for calcium by depleted bone after normalisation of the PTH, as well as ongoing preoperative suppression of the normal parathyroid glands responding appropriately to the prior hypercalcaemia.⁵ Conversely, patients who experience persistent hypercalcaemia following a parathyroidectomy may have had an incomplete resection or misdiagnosed four-gland parathyroid hyperplasia.

Case presentation

The patient was a woman in her 60s with a history of parathyroid adenoma resolved by successful resection of a solitary adenoma, presenting for recurrent nephrolithiasis. Her other medical conditions include hypothyroidism, hyperlipidaemia and childhood asthma. She has a surgical history of parathyroidectomy, cholecystectomy and left mastectomy for breast cancer. Her only regular medications in 2020 and 2021 were levothyroxine 75 µg daily and rosuvastatin 20 mg daily. She was adopted, and her family medical history is unknown.

The patient first developed kidney stones 11 years earlier, at which time she was diagnosed with hyperparathyroidism. About 10 years ago, she had a focused parathyroidectomy with the resection of a left upper pole parathyroid adenoma. She continued to follow up with her endocrinologist every year, and she initially had her PTH levels checked at each yearly visit. Her PTH levels were consistently normal following her parathyroidectomy, so she started checking her PTH level less frequently. The serum calcium remained persistently normal. Since then, she had only passed one kidney stone 6 years ago without any recurrent hyperparathyroidism or abnormal calcium values. She then developed recurrent urinary tract infections starting 17 months ago. She also started experiencing recurrent flank pain about 14–15 months before her presentation. Around 14 months ago, her endocrinologist had identified a lower right parathyroid mass on ultrasonography; however, due to poor communication, this information was not shared with the patient.

She presented to the emergency room 13 months ago after waking up with severe right flank pain radiating to her abdomen, and nausea. An abdominal and pelvic CT scan showed severe right-sided hydronephrosis secondary to a 1.3×1.4 cm right ureteropelvic junction calculus, along with additional non-obstructing calculi in the mid and lower pole collecting system of the right and left kidneys. The stone was extracted by cystoscopy and stent placement with purulent drainage. She became febrile with lactic acidosis at 4.7 mmol/L. Blood cultures revealed Klebsiella pneumoniae, so she was treated with meropenem as an inpatient and then ertapenem as an outpatient. She had an elevated PTH of 124.7 pg/mL (reference range: 12–88 pg/mL) and a normal corrected calcium of 2.20 mmol/L (reference range: 2.17–2.57 mmol/L) (figure 1). Her alkaline phosphatase was normal at 102 U/L (reference range: 35–104 U/L). She was never informed of her elevated PTH levels, and this finding was not further pursued at that time.

Figure 1.

This graph shows how the patient’s PTH levels (reference range: 12–88 pg/mL) and calcium levels (reference range: 2.17–2.57 mmol/L) changed throughout her disease and treatment course. The time of her second parathyroidectomy is labelled. This figure was created by author KBT. PTH, parathyroid hormone.

She continued experiencing frequent recurrent nephrolithiasis. Another abdominal and pelvic CT scan done 12 months ago during a separate hospital stay showed moderate left hydronephrosis and hydrouterer secondary to a 7 mm mid-left ureteral calculus residing at the L5 level, along with multiple bilateral renal calculi. She underwent cystoscopic left ureteral stent insertion.

A dual-energy X-ray absorptiometry scan done 7 months ago showed osteopenia with T score −1.5 at the femoral neck. Six months ago, her PTH was elevated again at 98 pg/mL (reference range: 12–88 pg/mL) (figure 1). The vitamin D 25-OH was slightly low at 19.3 ng/mL (reference range: 20–40 ng/mL). A corrected calcium was normal at 2.22 mmol/L (reference range: 2.17–2.57 mmol/L) (figure 1). Again, the patient was not made aware of her recurrent hyperparathyroidism.

She presented to the emergency room once again for severe flank pain 4 months before her presentation. An abdominal and pelvic CT scan showed a 7 mm calculus in the proximal right ureter causing moderate to severe right-sided hydronephrosis, along with multiple non-obstructing bilateral renal calculi. She underwent cystoscopy, right ureteroscopy and laser lithotripsy with removal of stone fragments and ureteral stent insertion. She was found to have K. pneumoniae bacteraemia, which was treated with meropenem.

Her PTH was still elevated at 95 pg/mL (reference range: 12–88 pg/mL) 2 months before her presentation (figure 1). The corrected calcium was normal at 2.17 mmol/L (reference range: 2.17–2.57 mmol/L) (figure 1). One month prior to her presentation, a vitamin D 25-OH was normal at 20.7 ng/mL (reference range: 20–40 ng/mL) with a normal corrected calcium of 2.27 mmol/L (reference range: 2.17–2.57 mmol/L), and her alkaline phosphatase was normal at 65 U/L (reference range: 35–104 U/L) (figure 1). Around this time, the patient brought her substantial medical records to another endocrinologist, and they discussed her recurrent hyperparathyroidism.

Her calcium had been consistently within normal levels, and her baseline creatinine was around 0.6–0.9 mg/dL (reference range: 0.6–1.0 mg/dL). Therefore, primary hyperparathyroidism was suspected, and she underwent a repeat parathyroidectomy. A sestamibi scan with SPECT imaging showed residual activity in the right side of the neck. A preoperative baseline PTH level was not taken due to a communication error.

A sestamibi injection 1 hour preoperatively allowed the use of a gamma probe for an intraoperative localisation of the adenoma. Hyperactive parathyroid tissue was identified by high gamma activity during surgery. A nodular mass was identified in the right lower pole area with a gamma count of 1452. This suspected adenoma was removed with a reduction in the gamma count to 400–500. An intraoperative PTH 10 min after its removal was 75.6 pg/mL (reference range: 12–88 pg/mL) (figure 1). A frozen section demonstrated an enlarged 167 mg hypercellular parathyroid gland with a caput of normal parathyroid tissue. The left lower lobe parathyroid gland was also identified, and it was grossly normal. A small fragment was evaluated with frozen section to confirm this.

Therefore, a left upper pole adenoma had previously been removed, a metachronous right lower pole parathyroid adenoma was removed, and a normal left lower parathyroid gland was identified and confirmed. The right upper pole parathyroid gland could not be clearly identified, but the intraoperative PTH was in a normal range and the gamma activity was no longer elevated, consistent with removal of the sole remaining parathyroid adenoma.

Outcome and follow-up

The patient has been doing well since her parathyroidectomy for recurrent metachronous parathyroid adenoma, and she denies recurrent nephrolithiasis since the surgery. Four months after her presentation, she appeared to have developed secondary hyperparathyroidism due to a vitamin D deficiency with an elevated PTH 105 pg/mL (reference range: 12–88 pg/mL), a low vitamin D 16.8 ng/mL (reference range: 20–40 ng/mL) and a low corrected calcium 1.97 mmol/L (reference range: 2.17–2.57 mmol/L) (figure 1). Her alkaline phosphatase was normal at 78 U/L (reference range: 35–104 U/L). She started taking calcitriol 0.25 µg daily, but her PTH remained elevated at 94 pg/mL (reference range: 12–88 pg/mL) 7 months after her presentation (figure 1). She then discontinued calcitriol and started calcifediol 30 µg daily. Ten months after her parathyroidectomy, her PTH was still elevated at 129 pg/mL (reference range: 12–88 pg/mL) with a normal vitamin D level of 29.8 ng/mL (reference range: 20–40 ng/mL) and a normal calcium of 2.25 mmol/L (reference range: 2.17–2.57 mmol/L) (figure 1). Her creatinine levels have remained normal throughout. She has been asymptomatic since her parathyroidectomy.

Discussion

Prior to her most recent surgery, the patient’s hyperparathyroidism with normal calcium was consistent with primary hyperparathyroidism with the histological confirmation of a parathyroid adenoma at the right lower pole. Additionally, her frequent recurrent nephrolithiasis completely resolved after this adenoma was removed by parathyroidectomy. Therefore, her recurrent parathyroid adenoma was likely responsible for her nephrolithiasis; however, confirmation of a solitary parathyroid adenoma cannot be obtained by intraoperative PTH levels in this case because a preoperative baseline PTH level was not taken. Her intraoperative PTH level was found to be in the normal range at 75.6 pg/mL (reference range: 12–88 pg/mL) 10 min after the adenoma was removed, but this value has little meaning without knowing the per cent reduction from the preoperative level, which cannot be determined.

A parathyroid adenoma is an uncommon cause of nephrolithiasis; however, nephrolithiasis is a common symptom of parathyroid adenoma.⁶ This condition’s rarity among patients with nephrolithiasis means it is often overlooked as a diagnosis. Another patient described in a 2010 case report experienced 10 years of recurrent nephrolithiasis before her parathyroid adenoma was discovered and removed.⁶ Patients with nephrolithiasis require additional assessment beyond the immediate treatment of an acute kidney stone to determine if there is any underlying cause that could be resolved to prevent recurrent episodes.

This patient did actually receive PTH testing during multiple hospital stays for nephrolithiasis, but no one ever informed her of these abnormal laboratory values or treated her for hyperparathyroidism. Her case demonstrates the importance of determining the root cause of a patient’s medical issues in addition to treating current symptoms. Her frequent hospital visits show how her acute pain, infections, and kidney stones were treated and resolved, but the underlying cause of her recurrent problems was not addressed for over a year.

Her history of parathyroid adenoma may have led her providers to discount recurrent parathyroid adenoma as a possibility; however, in rare cases, a patient may experience several years of euparathyroidism following removal of a parathyroid adenoma only to then experience recurrent hyperparathyroidism due to a metachronous parathyroid adenoma.^{3 4} Both synchronous and metachronous double adenomata cause about 4%–5% of primary hyperparathyroidism.¹ One study found that 9% of their participants with double adenomata were metachronous.² The average time interval from removing a primary parathyroid adenoma to identifying a second parathyroid adenoma is 8 years, which is consistent with this patient’s 9-year latency period.⁴

There is no known risk factor or predisposition that separates these patients from those who never experience recurrent parathyroid adenoma; however, the most common symptom for patients with recurrent parathyroid adenoma is bone manifestations, compared with nephrolithiasis for patients with primary parathyroid adenoma.³ This patient experienced both recurrent nephrolithiasis and osteopenia at the time of her second parathyroid adenoma.

It is theorised that recurrent parathyroid adenomata may have developed from a second small and imperceptible parathyroid adenoma that was unrecognised at the time of their original parathyroidectomy but grew to clinical significance over several years.³ This patient initially had a single parathyroidectomy without four-gland exploration, so it is possible she already had a second minuscule parathyroid adenoma, which was chemically and grossly not identifiable at that time.

Some patients experience recurrent hyperparathyroidism because the original adenoma was not completely resected or was fragmented, the remnant of which took several years to grow back to clinical significance.³ This was not the scenario for this patient whose initial adenoma was at the left upper pole with a metachronous adenoma at the right lower pole.

Multiple endocrine neoplasia type 1 (MEN1) was considered by the patient’s endocrinologist prior to surgical consultation as a potential cause for recurrent primary hyperparathyroidism; however, this condition typically has simultaneous multiglandular parathyroid enlargement instead of a single adenoma as the source of primary hyperparathyroidism.⁷ Additionally, the age of onset of primary hyperparathyroidism is 20–25 years old for 90% of patients with MEN1, and they almost always develop hypercalcaemia before the age of 50 years.⁷ This patient developed primary hyperparathyroidism in her 50s and 60s due to metachronous parathyroid adenomata without simultaneous multiple parathyroid gland enlargement. Her presentation was not consistent with MEN1, and she did not undergo genetic testing for this condition.

Initially following her second parathyroidectomy, her low vitamin D and low calcium levels suggested a secondary hyperparathyroidism from vitamin D deficiency. She had borderline low-normal vitamin D values throughout her frequent hospital visits associated with the recurrent parathyroid adenoma; however, her calcium levels were consistently normal prior to parathyroidectomy. Parathyroid adenomata can be associated with normal calcium values, which are associated with high PTH values.¹ This combination of laboratory values could be consistent with normocalcemic primary hyperparathyroidism, but her vitamin D values suggest instead a concurrent primary and secondary hyperparathyroidism due to parathyroid adenoma and vitamin D deficiency, respectively. Each condition may have counteracted the other’s calcium derangement to maintain normocalcemia, so the patient did not become hypocalcaemic until after the adenoma was removed. Concurrent primary and secondary hyperparathyroidism can be particularly difficult to diagnose in normocalcemic patients due to the lack of reflex PTH testing for hypercalcaemia, which can delay the diagnosis.

Her case is further complicated by the persistently elevated PTH levels she has been experiencing in the months following her second parathyroidectomy in spite of treatment with calcitriol and calcifediol. Pathology confirmed that a parathyroid adenoma was removed, and a sample of a remaining parathyroid gland from this patient contained normal tissue without hyperplasia. Additionally, she has no renal impairment, evidenced by consistently normal creatinine levels. Studies indicate 8%–40% of patients have persistently elevated PTH levels with normocalcemia following successful parathyroidectomy for hyperparathyroidism.⁸ The underlying cause of this phenomenon is unknown, but some controversial theories include renal resistance to PTH, impending recurrent hyperparathyroidism or impaired renal function.^{5 8}

One study suggests a significant association between musculoskeletal symptoms and persistently elevated PTH level following successful parathyroidectomy.⁵ It hypothesises that an increased calcium demand for bone remineralisation following an extended hyperparathyroidism causes elevated PTH levels for approximately 1–2 years after a parathyroidectomy before PTH values normalise.⁵ This theory could apply to this patient, who was found to have osteopenia.

Learning points.

• Nephrolithiasis should always prompt an investigation for hyperparathyroidism to avoid a recurrence of this painful problem.

• Physicians should always make an effort to identify the underlying cause of a patient’s recurrent medical issues in order to prevent future episodes.

• Recurrent hyperparathyroidism secondary to a metachronous parathyroid adenoma is a rare condition that can cause patients to present with recurrent symptoms associated with hyperparathyroidism years after having an initial parathyroid adenoma removed.

• Successful parathyroidectomies for hyperparathyroidism sometimes result in persistently elevated parathyroid hormone levels with normocalcemia, which might be caused by an increased calcium demand for bone remineralisation following an extended period of hyperparathyroidism.

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