Current evidence for recommendation of surgery, medical treatment and vitamin D repletion in mild primary hyperparathyroidism

Management of patients with mild primary hyperparathyroidism (PHPT) has been widely discussed because most patients today do not have specific symptoms. While surgery is always an option, the recommendations for treatment have shifted, which mostly reflects changes in clinical practice. In this study, we aimed to evaluate evidence for the current recommendations concerning operation vs observation, repletion with vitamin D (VitD) and alternative medical management. Surgery is followed by normalisation of calcium and parathyroid hormone (PTH) and a decrease in bone turnover followed by an increase in bone mass. It is not known what the consequences would be for the frequency of fractures. Randomised studies have indicated beneficial effects of operation on quality of life (QoL), but the effects have been minor and inconsistent. Operation seems not to be superior to observation for cardiovascular risk factors. Although PHPT patients in average have slightly decreased plasma 25OH VitD, severe symptomatic VitD deficiency seems not to be a characteristic of PHPT patients in Europe. However, if present, we recommend VitD substitution before final decision on surgical treatment. It is unknown whether routine VitD supplementation should be offered preoperatively to all patients with mild PHPT or as part of long-term medical treatment. Targeted medical management could be an option for patients with contraindications to surgery. Antiresorptive therapy might be appropriate for patients with a low bone mass to prevent further bone loss. Calcimimetics could be tried to control serum calcium levels although there is no evidence of an effect on the hypercalcaemic symptoms or the QoL. Combined therapy with calcimimetics and alendronate could be considered for patients with hypercalcaemia and overt bone disease.     

Nonsurgical management of mild primary hyperparathyroidism – a reasonable option

Primary hyperparathyroidism (PHPT) is a relatively common disorder which is often diagnosed incidentally and characterized in the majority of those affected by mild stable biochemical abnormalities and lack of symptoms. Nephrolithiasis and bone loss leading to an increased risk of fracture are generally accepted complications of PHPT. Some epidemiological studies report associations between PHPT and a wide range of common diseases, but these relationships may be confounded by the increased body weight observed in PHPT. Because there is a dearth of controlled clinical trial evidence in PHPT, optimal management is controversial. For individuals with mild stable PHPT, low fracture risk and no renal stones, observation without intervention is reasonable. Surgical treatment is clearly indicated for patients at risk of severe hypercalcaemia or with nephrolithiasis. For individuals with increased risk of fracture, antiresorptive therapies improve bone mineral density to a similar degree to surgical treatment. Calcimimetic agents may have a role in managing patients with symptomatic PHPT who cannot undergo, or fail, surgical treatment. There is a need for additional randomized clinical trials to inform management of PHPT.     

What medical options should be considered for the treatment of primary hyperparathyroidism?

Primary hyperparathyroidism (PHPT) is a common, often asymptomatic, endocrine disorder characterized by hypercalcaemia in the face of a nonsuppressed parathyroid hormone (PTH) level. For those with symptomatic disease or who meet surgical criteria, parathyroidectomy is the treatment of choice. However, those patients who do not meet surgical criteria or who cannot undergo or refuse surgery must be managed medically. Medical management of PHPT involves continual assessment to determine who will benefit from surgical intervention, replacement of vitamin D, treatment of parathyroid bone disease and management of hypercalcaemia and renal stone disease.     

Evaluation of acute and chronic MRI features of sacroiliitis in asymptomatic primary hyperparathyroid patients

Asymptomatic primary hyperparathyroidism (PHPT) is characterized with autonomous overproduction of parathyroid hormone without signs or symptoms associated with hyperparathyroidism. Before symptoms become obvious, PHPT may affect structures like sacroiliac joints, which consist of bone. So, in the asymptomatic PHPT patients, structural and inflammatory changes in sacroiliac joints may lead to confusion during diagnosis workup of axial spondyloarthropathy. In this study, we evaluated active and chronic sacroiliac magnetic resonance imaging (MRI) changes relevant to sacroiliitis in the patients with asymptomatic PHPT and interpreted bone marrow edema within the scope of Assessment of SpondyloArthritis International Society–Outcome Measures in Rheumatology Clinical Trials (ASAS-OMERACT) criteria. Forty-nine patients with asymptomatic PHPT, 26 patients with newly diagnosed axial spondyloarthropathy (SpA), and 37 healthy controls were enrolled. All subjects were evaluated by sacroiliac MRI for four active (bone marrow edema, enthesitis, capsulitis, and synovitis) and four chronic (subchondral sclerosis, subchondral/periarticular erosions, periarticular fat deposition, and bony bridges/ankylosis) lesions relevant to sacroiliitis. Bone marrow edema compatible with ASAS-OMERACT active sacroiliitis criteria in sacroiliac MRI was fulfilled by 16.3 % (8/49) of the asymptomatic PHPT patients which was similar with controls but statistically lower than axial SpA. Moreover, asymptomatic PHPT patients and controls were similar for other chronic or active MRI findings. Also, we detected lower frequency of all other MRI findings, except enthesis, in asymptomatic PHPT patients according to axial SpA. Acute inflammatory including bone marrow edema fulfilling ASAS-OMERACT active sacroiliitis criteria and chronic structural sacroiliac lesions relevant to sacroiliitis in MRI were detected in asymptomatic PHPT similar frequency with controls but as expected, lower than axial SpA. But, these findings could not be attributed to excessive secretion of parathyroid hormone.     

Current Indications and Decision-making Leading to Parathyroidectomy: A Surgical Viewpoint

Primary hyperparathyroidism (PHPT) is caused by a parathyroid adenoma in 85%, parathyroid hyperplasia in 15%, and parathyroid carcinoma in less than 1% of patients. This disease is classically described by the pentad of painful bones, renal stones, abdominal groans, psychic moans, and fatigue overtones. Today about 20% of patients referred for parathyroidectomy have renal stones, 30% have osteopenia or osteoporosis, and about 2% have osteitis fibrosa cystica. There are now three different presentations for PHPT: symptomatic, minimally symptomatic, and asymptomatic. PHPT is currently diagnosed by biochemical testing with an elevated serum calcium, an elevated or non-suppressed parathyroid hormone level, and the absence of hypocalciuria. Given the wide spectrum of disease that is diagnosed based on biochemical markers, the NIH made specific recommendations for the treatment of the non-classical PHPT. Many experts in this field have challenged these recommendations because numerous long-term follow-up investigations have shown the detrimental effects of hyperparathyroidism on bone density and fracture rate, renal function, cardiovascular mortality, and neuropsychiatric function. Parathyroidectomy is the only curative treatment for PHPT with a success rate of about 95%.     

Primary hyperparathyroidism and the skeleton

Today, primary hyperparathyroidism (PHPT) in the developed countries is typically a disease with few or no obvious clinical symptoms. However, even in the asymptomatic cases the endogenous excess of PTH increases bone turnover leading to an insidious reversible loss of cortical and trabecular bone because of an expansion of the remodelling space and an irreversible loss of cortical bone due to increased endocortical resorption. In contrast trabecular bone structure and integrity to a large extent is maintained and there may be a slight periosteal expansion. Most studies have reported decreased bone mineral density (BMD) in PHPT mainly located at cortical sites, whereas sites rich in trabecular bone only show a modest reduction or even a slight increase in BMD. The frequent occurrence of vitamin D insufficiency and deficiency in PHPT and increased plasma FGF23 levels may also contribute to the decrease in BMD. The effect of smoking is unsolved. Epidemiological studies have shown that the relative risk of spine and nonspine fractures is increased in untreated PHPT starting up to 10 years before the diagnosis is made. Successful surgery for PHPT normalizes bone turnover, increases BMD and decreases fracture risk based on larger epidemiological studies. However, 10 years after surgery fracture risk appears to increase again due to an increase in forearm fractures. There are no randomized controlled studies (RCTs) demonstrating a protective effect of medical treatment on fracture risk in PHPT. Less conclusive studies suggest that vitamin D supplementation may have a beneficial effect on plasma PTH and BMD in vitamin D deficient PHPT patients. Hormone replacement therapy (HRT) and maybe SERM appear to reduce bone turnover and increase BMD. However, their nonskeletal side-effects preclude their use for this purpose. Bisphosphonates reduce bone turnover and increase BMD in PHPT as in osteoporosis and may be a therapeutical option in selected patients with low BMD. Obviously, there is a need for larger RCTs with fractures as end-points that appraise this possibility. Calcimimetics reduce plasma calcium and PTH in PHPT but has no beneficial effect on bone turnover or BMD. In symptomatic hypercalcaemic PHPT with low BMD where curative surgery is impossible or contraindicated a combination of a calcimimetic and a bisphosphonate may be an undocumented therapeutical option that needs further evaluation.     

Primary hyperparathyroidism in the older person

Primary hyperparathyroidism (PHPT) is a common condition which may have few symptoms. One of the principal concerns in the older person with minimally symptomatic PHPT is restoration of bone mineral density and prevention of fracture. Other important considerations are cardiovascular risk and quality of life. Surgery, the traditional treatment of choice, may not always correct these factors. We present a review of the literature and advice of medical therapies which should be of benefit, with emphasis on a multifaceted approach in protecting the patient from PHPT.     

Impact of parathyroidectomy on cardiovascular risk in primary hyperparathyroidism: A narrative review

AimsPrimary hyperparathyroidism (PHPT), one of the most frequent endocrine disorders, is not only associated with bone and kidney disorders but also with increased cardiovascular risk. This cardiovascular risk is not part of the indication for surgery owing to discordant evidence of the effects of parathyroidectomy (PTX), especially in mild PHPT which is the most common presentation of PHPT. This literature review focuses on the effects of PTX on the cardiovascular risk in PHPT. The MEDLINE database was searched via the PubMed interface, selecting relevant articles published after 1990 in English.Data synthesisIn the most recent series, PTX appeared to have a positive impact on cardiovascular morbidity and mortality. Surgery improves arterial hypertension, markers of glucose homeostasis, vascular and cardiac remodeling and electrocardiographic impairments due to classical PHPT. However, the results of surgery on mild PHPT are conflicting.ConclusionsPTX seems to improve cardiovascular risk in patients presenting the classical form of PHPT. This improvement is correlated with preoperative serum calcium and/or PTH level, depending on the cardiovascular risk factor. However, many aspects of this improvement are not fully understood. Future studies should assess the effects of PTX on nocturnal hypertension, cardiac morphology and functions. The results for mild PHPT are conflicting owing to the limited size of the cohorts included in studies and the lack of randomized trials. Surgery is not currently recommended for patients presenting mild PHPT based on the cardiovascular risk and more studies are needed to better understand the interest of PTX on cardiovascular outcomes.     

Normocalcaemic primary hyperparathyroidism: An update on diagnostic and management challenges

Normocalcaemic primary hyperparathyroidism is a condition that can present with intermittent hypercalcemia or may evolve into hypercalcemic primary hyperparathyroidism. This milder biochemical entity remains incompletely understood because of a lack of long-term health outcomes regarding both medical and surgical approaches to its management. Medical therapies have shown some efficacy. A limited number of studies have found that bisphosphonates increase bone mineral density, and calcimimetics may decrease the risk of nephrolithiasis in patients with normocalcaemic primary hyperparathyroidism. Studies have also described patient outcomes after applying the same surgical criteria used for patients with hypercalcaemic primary hyperparathyroidism to those with the normocalcaemic form of the disease. These studies suggest that parathyroid surgery appears to be effective in normalizing elevated serum parathyroid hormone concentrations and decreasing adverse renal and skeletal outcomes in patients with normocalcaemic hyperparathyroidism. Given the available data and overall lack of consensus regarding the optimal management of these patients, a reasonable approach is to tailor treatment to the individual patient by considering their risk factors for new or accelerated bone loss, kidney stones, diminished quality of life, and cardiovascular disease.     

老年甲状旁腺功能异常诊治特点

老年甲状旁腺功能异常主要见于原发和继发性甲状旁腺功能亢进症(甲旁亢)。老年人中原发甲旁亢以女性患病为多,乏力和骨质疏松为常见症状。注意血钙的筛查,>26 mmol/L者检测甲状旁腺激素(PTH)有助于及早发现患者。无手术禁忌、能定位的选择手术治疗能更多获益。老年人继发性甲旁亢主要见于慢性终末期肾脏功能不全需血液透析或腹膜透析的患者,注意检测PTH水平、早期给予适量钙制剂和较大剂量骨化三醇有助于维持血钙和控制PTH水平。     

Therapeutic controversies in primary hyperparathyroidism.

There is little debate about the primacy of surgery in the management of classical PHPT. Rather, the question has been what to do about the many patients with nonclassical disease. A 1990 NIH consensus conference (55) clearly recommended surgery for patients with significant adverse effects of PHPT, for patients with complicating coexistent illnesses, for younger patients, and for those in whom consistent long-term follow-up could not be assured. It allowed that conscientious surveillance may be justified in patients with minimal hypercalcemia and no adverse effects, but it recognized that for many patients, the time and expense involved in rigorous follow-up would outweigh the burden of surgery. Nine years later, the demonstrated prevalence of nonclassical symptoms and their reversibility, the evidence of "asymptomatic" but harmful effects reversible by surgery, and the accumulating evidence for surgical reduction of increased long-term mortality risk substantially strengthen the argument for surgery in such patients. For these reasons, parathyroidectomy should generally be recommended for patients with a secure diagnosis of PHPT, even in the absence of classical symptoms.     

Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features

Primary hyperparathyroidism (PHPT) is characterized most commonly now as an asymptomatic disorder with hypercalcaemia and elevated levels of parathyroid hormone (PTH). The elevation in PTH is detected by both the standard immunoradiometric assays (IRMA) and a more recent IRMA that detects only the 1-84 full-length PTH molecule. The serum calcium concentration is usually <1 mg dL(-1) above normal. Recently, another variant of PHPT (normocalcaemic PHPT) has been described in which the serum calcium is normal but the serum PTH is elevated, in the absence of any secondary cause for PTH elevation. Although usually sporadic, PHPT also occurs in inherited syndromes. Skeletal manifestations are appreciated by densitometry showing a typical pattern in which cancellous bone of the lumbar spine is reasonably well preserved whilst the cortical bone of the distal third of the radius is preferentially reduced. Although reduced in incidence, renal stones remain the most common overt complication of PHPT. Other organs are theoretical targets of PHPT such as the neurobehavioural axis and the cardiovascular system. Vitamin D looms as an important determinant of the activity of the PHPT state. The 2002 NIH Workshop on asymptomatic PHPT has led to revised guidelines to help doctors determine who is best advised to have parathyroid surgery and who can be safely followed without surgery. New information about the natural history of PHPT in those who did not undergo surgery has helped to define more precisely who is at-risk for complications. At the NIH workshop, a number of items were highlighted for further investigation such as pharmacological approaches to controlling hypercalcaemia, elevated PTH levels and maintaining bone density.     

Primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is a condition that affects calcium metabolism due to parathyroid hormone (PTH) hypersecretion leading to hypercalcemia. Manifestations have changed over time, from a symptomatic disease with bone pain, fractures, nephrolithiasis, and muscle weakness, to a condition that is mainly asymptomatic (80–90%). Typical symptoms and signs occur in the bones and kidneys and atypical manifestations are cardiovascular, neuropsychiatric and cognitive, neuromuscular, rheumatological, and gastrointestinal. Diagnosis occurs, in most cases, in asymptomatic patients by a routine calcium measurement with corrected high total calcium associated with high or inappropriately abnormal PTH. If indicated, a search for the location of the involved parathyroid gland should be performed with ultrasound, scintigraphy, or 4D CT. Parathyroidectomy is the gold standard treatment. If surgery cannot be performed, clinical management is indicated. Surgical indications are osteoporosis, hypercalciuria, spine fractures, age <50 years, calcemic values above 1.0 mg/dL threshold value, creatinine clearance ≤60 mL/min, and nephrolithiasis or nephrocalcinosis.     

Primary hyperparathyroidism: controversies in surgical management.

Controversy surrounds the optimal management of patients with mild or asymptomatic primary hyperparathyroidism (PHPT). Although many new medical therapies for this disorder have emerged in the past decade, existing evidence indicates that parathyroidectomy is the only curative option and reverses not only many of the classic, but also the more subtle, manifestations of PHPT. Moreover, parathyroidectomy can be performed successfully with minimal morbidity by experienced surgeons. With the recent development and widespread use of several preoperative localization studies, various focused approaches to neck exploration and intraoperative parathyroid hormone testing, management for this disorder will need to be tailored to individual patients.     

Increased plasma N-terminal pro-B-type natriuretic peptide and markers of inflammation related to atherosclerosis in patients with primary hyperparathyroidism

OBJECTIVE: Increased risk of cardiovascular disease has been reported in patients with primary hyperparathyroidism (PHPT). The aim of this study was to evaluate novel plasma risk markers of cardiovascular disease in patients with PHPT. DESIGN: PHPT patients were evaluated with a control group. Patients who underwent parathyroidectomy were re-evaluated after 7 and 18 months. PATIENTS: Forty-five PHPT patients and 40 matched controls participated. Seventeen patients underwent parathyroidectomy. MEASUREMENTS: Plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (CRP), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha), lipids and blood pressure were measured. In 27 patients a bicycle exercise test and radionuclide angiography were performed, and repeated in those who underwent parathyroidectomy. RESULTS: Plasma NT-proBNP, CRP and TNF-alpha, but not IL-6, were higher in patients with PHPT than in controls (P < 0.01 and P = 0.17, respectively). In patients with PHPT, NT-proBNP correlated with systolic blood pressure, left ventricular end-diastolic volume, and peak oxygen uptake (all P < 0.01). Log CRP correlated with systolic and diastolic blood pressure (both P < 0.05) and log IL-6 (P < 0.01). No significant correlations were observed between PTH or calcium and risk markers of cardiovascular disease. No decrease in NT-proBNP, markers of inflammation or blood pressure was observed after parathyroidectomy. CONCLUSIONS: Our data suggest that hypertension or other factors, rather than plasma calcium or PTH, could explain the increased levels of the inflammatory markers and NT-proBNP in PHPT. We therefore suggest that aggressive treatment of hypertension should be initiated in patients with PHPT to try to reduce the increased cardiovascular mortality described in PHPT. Further prospective studies are needed to validate the suggestion that increased levels of NT-proBNP and inflammatory markers also represent strong prognostic markers of cardiovascular disease in patients with PHPT.     

Marked improvement of psychiatric symptoms after parathyroidectomy in elderly primary hyperparathyroidism

Psychosomatic symptoms in primary hyperparathyroidism (PHPT) are various and include such conditions as obsessive-compulsive disorder, depression, anxiety, and paranoia. In the elderly the clinical features of the disease are often non-specific and difficult to diagnose. To quantify subjective symptoms of patients with hyperparathyroidism in the elderly, we determined whether these clinical manifestations resolved after surgical parathyroidectomy (PTX) in three PHPT patients over eighty years old. They were diagnosed with hypercalcemia, hypophosphatemia, high PTH concentrations, and osteoporosis. A single parathyroid adenoma was confirmed in each patient by Tc-MIBI scintigram, neck ultrasonography and computed tomographic scanning. PTX was performed in these three patients. Assessments of psychologic symptoms, using the Hamilton Rating Scale for Depression (HAM-D), serum calcium, and intact PTH were obtained before and after PTX. Mean weight of the resected adenomas was 438 +/- 138 mg (mean +/- SD). After PTX, serum calcium decreased from 11.1 +/- 0.5 to 9.2 +/- 0.5 mg/dl and intact PTH from 160.0 +/- 25.2 to 45.3 +/- 22.2 pg/ml. Total HAM-D scores in each patient decreased from 45 to 9, 17 to 1 and 15 to 5, respectively. Especially, there were marked improvements in depressive mood, psychomotor inhibition, anxiety and somatic symptoms after PTX. The quality of life in those patients was also improved by PTX. We propose here that PTX in elderly PHPT patients with psychiatric symptoms should be considered instead of oral administration, such as anti-depressants or bisphosphonates.     

Renal manifestations of primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is associated with nephrolithiasis and nephrocalcinosis. Hypercalciuria is one of the multiple factors that is implicated in the complex pathophysiology of stone formation. The presence of a renal stone (symptomatic or asymptomatic) categorizes PHPT as symptomatic and is an indication for parathyroid adenomectomy. Progression of nephrocalcinosis is largely reversible after successful surgery, but the residual risk persists. PHPT is also associated with declining renal function. In case of asymptomatic mild PHPT, annual renal functional assessment is advised. Guidelines suggest that an estimated glomerular filtration rate (eGFR) < 60 ml / minute / 1.73 m(2) is an indication for parathyroid adenomectomy. This article discusses how to monitor and manage renal stones and other related renal parameters in case of PHPT.     

Normalized dyslipidaemia after parathyroidectomy in mild primary hyperparathyroidism: population-based study over five years

OBJECTIVE: Postmenopausal women are at increased risk of primary hyperparathyroidism (pHPT). Secondary dyslipidaemia in pHPT has attracted little attention, although morbidity and mortality associated with cardiovascular diseases have been reported to be increased in these patients. DESIGN: A population-based screening programme was used to recruit postmenopausal women with mild, asymptomatic pHPT (mean serum calcium 2.57 +/- 0.12 mmol/l) and matched controls. MEASUREMENTS AND PATIENTS: Serum lipids, lipoprotein fractions and influences of treatment for the parathyroid disease were studied in 87 case-control pairs (mean age 67 years), 69 of whom completed a 5-year follow-up period. RESULTS: pHPT was characterized by decreased serum high-density lipoprotein (HDL)-cholesterol, increased total triglycerides, very-low-density lipoprotein (VLDL)-triglycerides and VLDL-cholesterol levels and an elevated atherogenic index. The differences were more pronounced in the cases with serum parathyroid hormone levels in the normal range and were inversely correlated to the serum parathyroid hormone level. Parathyroidectomy, with or without additive hormone replacement therapy, normalized the dyslipidaemia. Five-year surveillance of pHPT without treatment was associated with a maintained increase in total triglycerides and the atherogenic index and a decrease in HDL-cholesterol levels. CONCLUSION: Proatherosclerotic dyslipidaemia characterizes mild pHPT and is effectively reversed by parathyroidectomy. As dyslipidaemia might contribute to the increased risk of cardiovascular diseases and death observed in pHPT, the findings favour operative intervention rather than conservative surveillance in mild, asymptomatic pHPT in postmenopausal females.     

Diagnosis and management of growth hormone deficiency in adults.

In adults, GHD is a clinical syndrome that occurs in patients with pituitary or hypothalamic disease. It may be asymptomatic or present with relatively nonspecific constitutional symptoms. Most patients have abnormal body composition, consisting of increased fat mass and decreased lean mass. Life expectancy is significantly decreased in hypopituitary patients with GHD, with cardiovascular disease a common cause of death. Treatment with growth hormone reverses abnormalities in body composition and may reduce cardiovascular risk factors; however, the long-term treatment outcomes regarding mortality, the incidence of cardiovascular disease, bone fractures, tumor development, and recurrence are not known. Longer prospective clinical studies are needed. The major manufacturers of growth hormone have initiated postmarketing surveillance databases to monitor the safety of growth hormone treatment.