Hyperparathyroidism in multiple endocrine neoplasia (MEN) syndromes is a form of primary hyperparathyroidism in which excess parathyroid hormone (PTH) results from an inherited alteration in parathyroid growth and function, with loss of the physiological control exerted by ionised calcium on the secretory set-point. In this setting, parathyroid disease is not an isolated event but one component of a familial tumour syndrome that requires an integrated approach. Correction of hypercalcemia and its renal and skeletal consequences must proceed alongside genetic diagnosis, surveillance of at-risk organs and surgical planning aimed at preventing recurrence while minimising permanent hypoparathyroidism.
The two main clinical settings are MEN1, in which hyperparathyroidism is often the earliest and most frequent manifestation and typically involves multiple glands, and MEN2A, in which hyperparathyroidism is less common and generally milder but occurs within a syndrome dominated by medullary thyroid carcinoma and pheochromocytoma. Clinical management therefore requires early recognition of the manifestations of hypercalcemia, definition of the syndromic aetiology and adoption of a therapeutic strategy that accounts for the natural history of the disease, the risk of recurrence after surgery, interactions with other MEN components and the need for structured, continuous long-term follow-up.
The epidemiology of hyperparathyroidism in MEN syndromes is determined by the rarity of the syndromes themselves and their high penetrance for specific endocrine manifestations. In MEN1, primary hyperparathyroidism is generally the most frequent manifestation and is often the first to emerge during life, typically appearing in the third decade and showing very high penetrance by middle age. In practical terms, unlike sporadic disease, MEN1-associated hyperparathyroidism tends to be diagnosed at a younger age, often at an early or subclinical stage through surveillance programmes. However, it may have a greater cumulative impact because exposure to hypercalcemia can persist for years when the condition is not recognised or when surgical correction is incomplete.
In MEN2A, primary hyperparathyroidism is less frequent than in MEN1 and often has a milder biological phenotype, with modest hypercalcemia and a substantial proportion of patients who are minimally symptomatic or asymptomatic. Even when present, hyperparathyroidism in MEN2A is rarely the first recognised manifestation because clinical attention is usually focused on medullary thyroid disease and prevention of catecholamine crises related to pheochromocytoma. This does not reduce its clinical relevance. In a patient with MEN2A, even moderate hypercalcemia may aggravate renal vulnerability, increase the risk of nephrolithiasis and contribute to impaired quality of life, particularly when combined with complex treatments, surgical procedures and follow-up.
Strictly defined risk factors coincide with the presence of a germline mutation associated with the syndrome, together with a family history and membership of a family known to be affected by MEN. In MEN1, risk is determined by pathogenic variants of the MEN1 gene, which encodes menin, whereas in MEN2A it is associated with pathogenic variants of the RET proto-oncogene. From a clinical perspective, the most important risk factor is therefore identification of the index case and activation of a genetic counselling pathway with targeted testing of relatives. Molecular diagnosis allows biochemical surveillance to begin earlier and helps prevent target-organ damage through earlier detection of hyperparathyroidism.
Additional factors may modify severity and clinical impact without representing primary causes. Vitamin D status, calcium intake, renal function and age influence PTH levels and clinical presentation. In MEN1, multiglandular hyperparathyroidism may induce high bone turnover early in life, reducing bone mineral mass at an age when the skeleton should still be consolidating peak bone mass. The clinical epidemiology is therefore closely linked to that of early skeletal fragility. In MEN2A, hyperparathyroidism may remain undetected for longer because symptoms are less evident and clinical attention is directed towards other manifestations. Systematic surveillance of serum calcium and PTH therefore remains essential even when the absolute probability of parathyroid involvement is lower.
Finally, the observed frequency depends on the healthcare setting. In centres with structured programmes for hereditary endocrine syndromes, diagnosis often occurs before renal and skeletal complications develop, allowing milder forms to be identified. In the absence of surveillance, however, the index case may present with nephrolithiasis, osteopenia, fractures or nonspecific neurocognitive symptoms attributed to other causes. This explains why the epidemiology perceived in clinical practice varies, not necessarily because of major biological differences, but because of disparities in access to genetic diagnosis, precision medicine and dedicated multidisciplinary pathways.
The aetiology of hyperparathyroidism in MEN syndromes is genetic and results from an inherited predisposition to the development of functionally active parathyroid lesions. In MEN1, the primary cause is an inactivating germline mutation of the MEN1 gene, which encodes menin, a nuclear regulator involved in transcriptional control, genomic stability and cell-cycle regulation. The pathogenic model is consistent with a tumour suppressor gene mechanism. A first germline alteration is present in all cells of the body, while a second somatic event within parathyroid tissue promotes clonal expansion and transformation into hyperfunctioning tissue. The result is typically a multiglandular, frequently asynchronous and asymmetric process in which several glands develop hyperplasia or multiple adenomas over time. This makes the disease intrinsically prone to persistence or recurrence after surgery when hyperfunctioning tissue remains.
In MEN2A, the primary cause is an activating germline mutation of the RET proto-oncogene, which encodes a receptor tyrosine kinase. In this syndrome, the pathophysiology of hyperparathyroidism occurs within a clinical picture dominated by neoplastic transformation of thyroid C cells and the risk of catecholamine-secreting tumours. Parathyroid involvement in MEN2A is generally less aggressive and is often characterised by hyperplasia or adenomas causing mild hypercalcemia. However, the common mechanism remains a loss of physiological calcium-mediated set-point regulation, resulting in PTH secretion that is inappropriate for the serum calcium and phosphate concentrations.
The final pathophysiological pathway converges on excess PTH and its coordinated effects on bone, kidney and vitamin D metabolism. In bone, PTH increases remodelling with a predominance of resorption, mediated by osteoblast activation, increased RANKL signalling and consequent stimulation of osteoclast activity. In chronic disease, particularly when MEN1 is diagnosed late, this causes loss of bone mineral density, disruption of microarchitecture and an increased risk of fractures. This skeletal profile is especially relevant because it may develop in young adulthood and interfere with the achievement of peak bone mass. In the kidney, PTH increases tubular calcium reabsorption and reduces phosphate reabsorption, promoting phosphaturia and a tendency towards relative hypophosphataemia. It also stimulates 1-alpha-hydroxylase activity and increases production of calcitriol, thereby enhancing intestinal calcium absorption. The combination of hypercalcemia, hypercalciuria and tubular abnormalities explains the increased risk of nephrolithiasis and nephrocalcinosis, as well as the possibility of progressive renal impairment when the disease persists.
Within the MEN setting, pathophysiology must also be interpreted from a syndromic perspective. In MEN1, the coexistence of pancreatic neuroendocrine tumours and pituitary adenomas may introduce additional factors affecting mineral metabolism, nutrition, body weight and exposure to therapies, making the clinical presentation more subtle or obscured by overlapping symptoms. Gastrointestinal symptoms, for example, may be attributed to enteropancreatic disease, while mood and sleep disturbances may be multifactorial. In this setting, hypercalcemia can act as an amplifier of nonspecific symptoms. In MEN2A, the presence or suspicion of pheochromocytoma changes clinical and anaesthetic priorities because neck surgery without adequate assessment of catecholamine excess may expose the patient to substantial haemodynamic risk. Pathophysiology should therefore not be viewed solely as a PTH-calcium-bone-kidney sequence, but as a node within an integrated system of risks that determines the timing, setting and strategy of treatment.
A crucial feature of MEN-associated hyperparathyroidism is its tendency to recur. In MEN1, multiglandular involvement and the possible presence of ectopic tissue, including intrathymic parathyroid tissue, make surgery highly valuable but not always definitively curative. The choice between subtotal parathyroidectomy and total parathyroidectomy with autotransplantation is therefore pathophysiological as well as technical. Removing as much at-risk tissue as possible reduces the probability of recurrence but increases the risk of permanent hypoparathyroidism if the remnant or autograft does not function adequately. This tension between control of hypercalcemia and preservation of parathyroid function lies at the centre of the management of hyperparathyroidism in MEN syndromes.
The clinical manifestations of hyperparathyroidism in MEN syndromes result from chronic hypercalcemia, hypercalciuria and increased bone remodelling. They are particularly significant because they often develop at a younger age than in sporadic disease and interact with symptoms caused by other syndromic components. In many patients, particularly when active surveillance is in place, onset is subtle. Patients may report persistent fatigue, reduced physical performance, difficulty concentrating and mood changes, which may be interpreted as stress or sleep disorders. Without screening, hyperparathyroidism may instead present with more typical features, such as renal colic, bone pain or a history of recurrent stone disease.
During the medical history, the combination of neurocognitive, renal and musculoskeletal symptoms should raise suspicion. Patients may describe polyuria and polydipsia, reflecting the reduced urinary concentrating ability induced by hypercalcemia, together with episodes of nephrolithiasis or microscopic haematuria. Gastrointestinal manifestations may include constipation, nausea and dyspepsia. In MEN1, however, abdominal symptoms and altered bowel habits must be interpreted cautiously because enteropancreatic hypersecretion syndromes may coexist. Weight loss or reduced appetite, when present, may be influenced by several factors, although hypercalcemia may contribute substantially to nonspecific symptoms. Muscular manifestations commonly include fatigue and reduced proximal muscle strength, which may limit daily activities and promote physical inactivity and deconditioning.
The physical examination often reveals few specific signs but may identify mild dehydration, reduced muscle tone and tenderness on palpation at sites consistent with skeletal fragility. In recurrent stone disease, lumbar tenderness may be intermittent and related to episodes of renal colic. In more advanced disease, indirect signs of skeletal complications may include height loss, vertebral pain and functional limitation. Within the MEN setting, physical examination should be extended in a targeted manner to organs at risk within the syndrome, including assessment for signs of pituitary disease, examination of the neck for thyroid abnormalities and cardiovascular and blood pressure evaluation when pheochromocytoma is suspected. These findings immediately alter clinical priorities and the safety of any intervention.
MEN1 has a particular clinical feature. Hyperparathyroidism may be present even when symptoms are minimal, while skeletal damage may already be substantial. In many young patients, reduced bone mineral density can be detected early and carries considerable clinical importance because it precedes expected age-related skeletal fragility by decades. In MEN1, therefore, clinical assessment includes not only what the patient reports but also what emerges from integration of laboratory findings and target-organ evaluation. In MEN2A, hyperparathyroidism is often less severe and may remain clinically silent, but it becomes relevant when neck surgery is planned or other oncological priorities are being managed. Unrecognised parathyroid dysfunction may influence the risk of perioperative metabolic complications and postoperative calcium management.
Severe acute manifestations are less common but remain possible, particularly when hypercalcemia is marked or is compounded by dehydration, immobilisation or therapies that increase serum calcium. In such circumstances, confusion, lethargy, rapid deterioration of renal function and signs of severe dehydration may occur. Even when a true emergency does not develop, MEN-associated hyperparathyroidism must be regarded as a systemic condition because its chronicity leads to cumulative renal and skeletal risk and because its management is closely intertwined with surgical and oncological decisions related to MEN syndromes.
Suspicion of hyperparathyroidism in MEN syndromes should be high in three main clinical scenarios: patients with even mild hypercalcemia and an inappropriately normal or elevated PTH, young patients with typical complications of primary hyperparathyroidism such as nephrolithiasis or early osteopenia, and individuals with a personal or family history suggestive of MEN. Because MEN-associated hyperparathyroidism may present early and with nonspecific symptoms, the threshold for suspicion should be lower than for sporadic disease, particularly when the age at presentation is younger than expected for common primary hyperparathyroidism.
A key clinical signal is the combination of subtle symptoms and consistent biochemical markers. Fatigue, mood disturbances, impaired concentration and constipation, when associated with elevated serum calcium or values near the upper limit of normal, should prompt measurement of PTH and assessment of calcium-phosphate metabolism. Similarly, recurrent nephrolithiasis, nephrocalcinosis or progressive renal impairment without an alternative explanation should lead to a complete metabolic evaluation, including albumin-corrected calcium or ionised calcium, phosphate, creatinine and urinary calcium excretion. From a skeletal perspective, substantial osteopenia at a young age, unexplained fragility fractures or suggestive vertebral pain should raise consideration of hyperparathyroidism even when systemic symptoms are minimal.
Family history is crucial when a syndromic form is suspected. A first-degree relative with MEN1 or MEN2A, or with multiple endocrine tumours, requires proactive evaluation. In MEN1, the coexistence of pituitary adenoma and enteropancreatic neuroendocrine tumours, even when diagnosed at different times, should immediately raise the possibility of MEN and include parathyroid disease in the differential diagnosis of hypercalcemia and skeletal damage. In MEN2A, a personal or family history of medullary thyroid carcinoma or suspected pheochromocytoma requires systematic assessment for hyperparathyroidism, even when it is clinically silent.
Perioperative suspicion is particularly important. In patients with known or suspected MEN2A, the presence of pheochromocytoma must be assessed before any neck operation and therapeutic priorities must be established, because failure to diagnose catecholamine excess may make anaesthesia dangerous. In this context, suspected hyperparathyroidism should not be managed in isolation but within a pathway that includes evaluation of the other MEN manifestations and safe sequencing of interventions. Similarly, in MEN1, parathyroid surgery must be planned with consideration of the likelihood of multiglandular involvement, the possible presence of ectopic tissue and the need to preserve sufficient functional tissue to prevent chronic hypocalcaemia.
Finally, early diagnosis alters outcomes. Timely suspicion allows treatment before recurrent nephrolithiasis, renal deterioration and substantial bone loss become established. In a hereditary syndrome, suspicion in a single patient also has implications for family health. Identification of the index case enables surveillance and prevention of complications in relatives, reducing the likelihood of late and complex presentations.
The diagnosis of hyperparathyroidism in MEN syndromes begins with biochemical confirmation of primary hyperparathyroidism and is completed by defining the syndromic context, because the surgical strategy and surveillance programme depend on the type of MEN. The first step is to document persistent hypercalcemia, ideally through repeated measurements of albumin-corrected total calcium and, when available, ionised calcium, in association with non-suppressed PTH concentrations. Phosphate, creatinine, 25(OH) vitamin D and, when indicated, magnesium should also be measured because deficiencies and comorbidities may influence PTH secretion and clinical severity. Correction of vitamin D deficiency is particularly important. Deficiency may increase PTH and worsen the skeletal phenotype, but replacement must be undertaken cautiously in the presence of hypercalcemia to avoid further increases in serum calcium.
After biochemical confirmation, the diagnostic pathway should include assessment of the target organs affected by hyperparathyroidism and investigation of features suggesting MEN1 or MEN2A. Renal evaluation includes a history of stone disease, urinalysis when appropriate, estimation of renal function and renal imaging when nephrolithiasis or nephrocalcinosis is suspected. Skeletal assessment includes bone densitometry and, in selected cases, vertebral imaging for subclinical fractures. This step is not secondary. In MEN syndromes, the timing of parathyroidectomy is often determined by target-organ damage even when hypercalcemia is relatively mild.
Diagnostic assessment of hyperparathyroidism in MEN syndromes
Parathyroid imaging, although useful for planning, has a different role from that in sporadic disease. In MEN1, disease is frequently multiglandular and asynchronous, so a strategy based on localisation of a single gland risks undertreating the condition. Diagnosis is therefore always biochemical, while imaging is mainly used to define cervical anatomy, identify enlarged glands and detect possible ectopic sites, including intrathymic tissue that may influence the surgical strategy. In MEN2A, imaging may help identify abnormal glands and coordinate management with thyroid surgery, but it remains essential to recognise that the treatment sequence must be safe when pheochromocytoma is a possibility.
Diagnosis of a MEN syndrome requires a higher level of integration. In a young patient with hyperparathyroidism, multiglandular disease or recurrence after surgery, MEN1 should be given priority in the diagnostic assessment, particularly when other endocrine manifestations are present or suspected. Genetic diagnosis is not merely confirmatory but operational. It enables screening of relatives and establishment of a surveillance programme that includes both calcium-phosphate metabolism and the organs typically affected by the syndrome. In MEN2A, detection of a RET mutation is central to management of thyroid and catecholamine-related risks, while hyperparathyroidism must be considered within a pathway in which perioperative safety and thyroid oncology are major strategic determinants.
Finally, MEN-associated primary hyperparathyroidism must be distinguished from other causes of hypercalcemia. An inappropriately elevated PTH supports primary hyperparathyroidism, whereas malignancy-related or vitamin D-mediated hypercalcemia usually presents with suppressed PTH. In a patient with MEN, this distinction is particularly important because coexisting tumours may introduce alternative or concurrent causes of metabolic abnormalities. A rigorous diagnostic pathway prevents unnecessary interventions and allows appropriate surgery to be planned. In MEN syndromes, surgery must always balance adequate functional control with preservation of sufficient parathyroid reserve.
Classification of hyperparathyroidism in MEN syndromes has direct clinical value because it determines the type of surgery, the probability of recurrence and the follow-up strategy. The main distinction is between MEN1-associated and MEN2A-associated disease. In MEN1, hyperparathyroidism is typically multiglandular, with hyperplasia and multiple adenomas that may appear at different times. This feature makes the disease biologically diffuse and explains its strong tendency to recur over the long term. In MEN2A, parathyroid involvement is more often mild, with moderate hypercalcemia and a frequently asymptomatic presentation, but its management is influenced by the context of medullary thyroid carcinoma and the risk of pheochromocytoma.
A second classification concerns clinical presentation, distinguishing asymptomatic forms identified through screening, forms predominantly characterised by renal complications and forms with a predominantly skeletal phenotype. This distinction is useful because the timing of parathyroidectomy in MEN1 is often determined by target-organ damage rather than the absolute serum calcium concentration. In a young patient with early bone loss or recurrent nephrolithiasis, correction is more urgent even when hypercalcemia is mild. There are also forms in which neurocognitive symptoms and reduced quality of life are prominent despite the absence of evident structural complications. In these cases, treatment decisions require careful assessment because correction of hypercalcemia may substantially improve wellbeing, while surgery carries specific risks related to multiglandular disease.
Severity may also be stratified according to the probability of persistent or recurrent disease after surgery. In MEN1, the choice between subtotal parathyroidectomy and total parathyroidectomy with autotransplantation influences the risk profile. More extensive approaches reduce the risk of persistent hypercalcemia but increase the probability of permanent or prolonged hypoparathyroidism. The possible presence of supernumerary glands or ectopic tissue adds individual variability, making severity partly a property of the disease and partly the result of interactions among anatomy, genetics and surgical technique. In MEN2A, the severity of hyperparathyroidism is often lower, but the overall severity of the clinical condition is strongly influenced by the other MEN components. Classification must therefore remain syndromic and cannot be limited to the PTH-calcium axis alone.
A further useful level of classification integrates the stage of the MEN care pathway, distinguishing an index patient who has not yet undergone complete assessment, a patient enrolled in planned follow-up and a patient with recurrence or requiring reoperation. A patient with recurrent MEN1-associated hyperparathyroidism, for example, requires a different approach from that used for initial surgery because local surgical risk is higher and strategies that minimise further cervical exploration become increasingly important. In these cases, the balance between control of hypercalcemia and preservation of residual function is even more delicate and should be managed in centres with specific expertise.
Finally, severity should include familial implications. A diagnosis of MEN requires surveillance of relatives and identification of asymptomatic mutation carriers. In this sense, a clinically mild form in one individual may represent a condition of substantial severity from the perspective of family health, because failure to diagnose the syndrome can lead to late presentations and preventable complications. Modern classification must therefore combine clinical, biological and genetic dimensions, as only this integration allows coherent and sustainable long-term treatment planning.
Treatment of hyperparathyroidism in MEN syndromes aims to achieve stable correction of hypercalcemia and prevent renal and skeletal complications while preserving sufficient parathyroid function to avoid chronic hypocalcaemia. The main therapeutic intervention, particularly in MEN1, is parathyroid surgery, but the strategy must be individualised because the disease is frequently multiglandular and prone to recurrence. In MEN-associated disease, the indication for surgery does not depend solely on the absolute serum calcium concentration, but also on target-organ involvement, age, the individual risk profile and the likelihood of progressive cumulative damage. In many patients with MEN1, parathyroidectomy is considered relatively early to limit long-term skeletal and renal deterioration.
In MEN1, the most commonly used surgical strategies include subtotal parathyroidectomy, with removal of 3 or 3.5 glands and preservation of a parathyroid remnant in situ, and total parathyroidectomy with autotransplantation of parathyroid tissue, often into the non-dominant forearm to facilitate any future peripheral reintervention. The rationale for subtotal surgery is to reduce the burden of hyperfunctioning tissue while maintaining autonomous parathyroid reserve and limiting the risk of permanent hypoparathyroidism. Its limitation is the greater long-term probability of recurrence because the remnant may become hyperfunctioning. The rationale for total parathyroidectomy with autotransplantation is to maximise control of hypercalcemia and make recurrence within the graft more accessible to treatment, reducing the need for further cervical exploration. Its limitation is the risk of inadequate graft function and chronic hypocalcaemia, particularly when engraftment is incomplete or graft function declines over time.
Management of ectopic tissue is an important technical and clinical consideration in MEN1. The possible presence of supernumerary glands or intrathymic tissue makes complete surgical assessment important. In many protocols, a cervical thymic procedure is performed to reduce the risk of persistent disease related to ectopic tissue and, in selected settings, to address the association between MEN1 and thymic neoplasms. The decision must nevertheless be individualised, taking into account the number of glands identified, anatomy and operative risk. In all cases, surgery for MEN-associated hyperparathyroidism should be performed in experienced centres because multiglandular disease and the possibility of reoperation make surgical expertise an important determinant of outcomes and complications.
In MEN2A, treatment of hyperparathyroidism must be coordinated with management of medullary thyroid carcinoma and, above all, assessment for pheochromocytoma. When pheochromocytoma is present, catecholamine stabilisation and treatment take priority before any major surgical procedure because this substantially reduces perioperative risk. Parathyroid surgery in MEN2A is often less extensive than in MEN1 because involvement may be less diffuse. When appropriate, it may be performed at the same time as thyroid surgery, with targeted removal of enlarged glands and preservation of the remaining glands. The aim is to reduce postoperative metabolic complications in a patient who may already require an intensive oncological treatment and follow-up pathway.
Medical treatment has a supportive role and, in selected cases, may serve as a bridge or temporary alternative. Calcimimetics can reduce serum calcium by increasing the sensitivity of the calcium-sensing receptor on parathyroid cells. They are useful when surgery must be postponed, when surgical risk is high or when persistent or recurrent hypercalcemia cannot be addressed immediately through reoperation. For skeletal protection, antiresorptive therapies may be indicated, particularly when surgery is not imminent or when significant osteoporosis is present. Vitamin D deficiency should be corrected cautiously and under monitoring to avoid unwanted increases in serum calcium. Renal management includes adequate hydration, control of lithogenic factors and monitoring of renal function because reducing hypercalciuria and preventing nephrolithiasis are concrete clinical objectives even before surgery.
Finally, treatment must be syndromic. In MEN1, surgical planning should take into account possible future procedures for enteropancreatic or pituitary tumours and the need to avoid chronic metabolic instability that may impair quality of life. In MEN2A, the strategy must ensure safety in relation to pheochromocytoma and integrate the thyroid treatment pathway. In both settings, patient education, genetic counselling and establishment of shared follow-up are integral components of treatment because correction of hypercalcemia is only one part of lifelong management.
Follow-up of hyperparathyroidism in MEN syndromes must be planned for the long term and has several objectives: verifying stable control of calcium and PTH, detecting recurrence at an early stage, preventing and treating postoperative hypocalcaemia, and monitoring renal and skeletal target organs. Unlike sporadic hyperparathyroidism, in which surgery is definitively curative in most cases, MEN-associated disease, particularly MEN1, requires the assumption that a substantial proportion of patients may develop persistent or recurrent disease even many years later because of its biological nature and the presence of residual or ectopic tissue.
In the immediate postoperative period, management of serum calcium is the priority. Following parathyroidectomy, transient or prolonged hypocalcaemia may occur because of the abrupt reduction in PTH and possible hungry bone syndrome in patients with high preoperative bone turnover. Monitoring should include calcium, phosphate, magnesium and, when indicated, PTH, with calcium and active vitamin D supplementation according to clinical need. This phase is particularly important in patients with MEN because persistent hypocalcaemia may impair quality of life and complicate management of other syndromic components. A clear plan is therefore essential, including serum calcium targets and precise instructions regarding symptoms of hypocalcaemia and when urgent medical evaluation is required.
During medium-term and long-term follow-up, biochemical surveillance includes periodic measurement of calcium and PTH. A rising serum calcium trend or an inappropriately increasing PTH concentration should raise suspicion of recurrence or progression within the remnant, particularly in MEN1. Following autotransplantation, follow-up should include assessment of graft function and attention to evidence of hyperfunction within the transplanted tissue because the graft may become a site of recurrence. In some cases, this can be managed through targeted peripheral intervention, reducing the need for further cervical surgery. The frequency of monitoring depends on biochemical stability, the type of surgery performed and the presence of target-organ damage, but it should remain more intensive than in sporadic disease because of the greater probability of reactivation.
Renal follow-up includes monitoring renal function, enquiring about renal colic, assessing lithogenic risk and performing imaging when indicated. The aim is to prevent progression to nephrocalcinosis and reduce recurrent stone formation, particularly in patients who had nephrolithiasis before surgical correction. Skeletal follow-up includes repeat bone densitometry and, in high-risk patients, evaluation for vertebral fractures because recovery of bone mineral density may take time and may remain incomplete when disease has been prolonged or recurrence occurs. Nutritional and physical activity strategies should be integrated, with attention to maintaining adequate calcium and vitamin D intake without promoting hypercalcemia and with exercise programmes compatible with the clinical condition and any comorbidities.
Within the MEN setting, follow-up of hyperparathyroidism cannot be separated from syndromic surveillance. In MEN1, monitoring for enteropancreatic and pituitary tumours must be coordinated with assessment of mineral metabolism because symptoms, therapies and procedures may affect nutritional status, electrolyte balance and adherence to treatment. In MEN2A, surveillance for medullary thyroid carcinoma and pheochromocytoma must be integrated because clinical priorities may change and calcium stability may influence perioperative management and quality of life. A well-structured follow-up programme reduces the risk of late diagnosis of recurrence, limits renal and skeletal complications and allows patients to manage a complex chronic syndrome within a predictable, safe and organised care pathway.
The prognosis of hyperparathyroidism in MEN syndromes depends on achieving stable control of hypercalcemia and successfully preventing renal and skeletal complications, but it is also strongly influenced by the overall burden of the syndrome. Considered in isolation, MEN-associated hyperparathyroidism can be effectively controlled through appropriate surgical strategies and careful follow-up. In MEN1, however, the multiglandular natural history makes recurrence relatively frequent over the long term. In MEN2A, hyperparathyroidism is often mild but must be managed within an oncological and catecholamine-related context that may determine different clinical priorities.
The most important complications of MEN-associated hyperparathyroidism are related to chronic exposure to PTH and hypercalcemia. The main renal complication is nephrolithiasis, which is often recurrent and may lead to nephrocalcinosis and progressive renal impairment. Persistent hypercalciuria, even after partial correction of serum calcium, may maintain lithogenic risk and therefore requires monitoring and preventive interventions. In the skeleton, increased remodelling causes osteopenia and osteoporosis with a higher risk of fractures. This is particularly important in MEN1 because skeletal involvement may occur early and affect quality of life and physical function during working age. Myopathy and reduced strength also increase the risk of falls, further amplifying fracture risk.
At a systemic level, hypercalcemia may cause neurocognitive and gastrointestinal symptoms that, although not strictly defined as target-organ complications, have a substantial impact on performance, sleep and wellbeing. In patients with MEN, these manifestations may be underestimated because they overlap with other endocrine abnormalities. Their persistence may nevertheless reduce adherence to surveillance programmes and therapies, indirectly worsening the overall prognosis. In more severe forms or in facilitating conditions such as dehydration and immobilisation, hypercalcemia may lead to acute deterioration in renal function and altered mental status, requiring urgent treatment.
Treatment-related complications are central and must be anticipated. The main postoperative risk is transient or permanent hypoparathyroidism, resulting in hypocalcaemia and a need for long-term supplementation. In MEN1, the chosen surgical strategy directly affects this risk. More extensive approaches reduce the probability of persistent hypercalcemia but may increase the risk of chronic hypocalcaemia, particularly when the remaining tissue or autograft provides insufficient function. Recurrence, on the other hand, may require complex reoperations associated with a greater risk of cervical complications and a need for highly specialised planning. This balance between recurrence and hypocalcaemia is the most important determinant of the specific prognosis of MEN-associated hyperparathyroidism.
Finally, prognosis must be interpreted from a syndromic perspective. In MEN1, long-term mortality and morbidity are also influenced by neuroendocrine tumours and multiple endocrine complications. In MEN2A, prognosis is strongly determined by the course of medullary thyroid carcinoma and the management of pheochromocytoma. Optimal control of hyperparathyroidism nevertheless improves the patient's overall resilience, reduces hospital admissions and renal and skeletal complications, and makes surgical and oncological pathways safer. Prognosis is therefore favourable when the patient is managed through a dedicated multidisciplinary pathway incorporating genetic diagnosis, appropriate treatment, continuous monitoring and structured prevention of complications.