Improved Mortality Outcomes in Primary Hyperparathyroidism: Significant Benefit of the Dedicated Indian PHPT Registry.

BACKGROUND

Primary hyperparathyroidism (PHPT) is one of the most common chronic diseases in endocrinology. It is a multisystem condition with a possible wide array of involvement, including debilitating renal and skeletal disease. Since the identification of the disease in Captain Charles Martell who presented with multiple fractures, deformity, and renal stones, PHPT has undergone a transition to a more asymptomatic phenotype following automated serum calcium measurements.[1] However, the predominant disease phenotype in India is symptomatic. While the debate on more symptomatic disease in India despite younger age at diagnosis remains unresolved, there is a paucity of evidence on the prevalence and predictors of mortality from the Southeast Asia region, and more specifically, from India. We recently analyzed mortality outcomes in patients from a single tertiary-care center in the country as part of the Indian PHPT Registry and noted an 8.8% prevalence of mortality.[2]

Insights from the Indian PHPT Registry

There were 464 patients in the cohort (following exclusion of those lost to follow-up) of which 41 patients succumbed due to disease-related or unrelated causes. The study interval was divided into two halves, the first period extending from 1997-2007 and the second interval from 2008-2018. On analyzing the trends of mortality in the cohort, there was reduced mortality in the second study interval (2008-2018). It reduced from 14.4% in the first half to 7.2% in the second interval. CKD was the most common cause of mortality overall, and on analyzing the cause-distribution of mortality, CKD emerged as the most common cause of death in both study intervals. Age at diagnosis, age at death, and male gender were not significantly different between both time intervals. Renal dysfunction, anemia, and pancreatitis were not significantly different between both groups. Serum calcium and PTH were not significantly different between both intervals. Renal parameters (creatinine and estimated glomerular filtration rate) were also similar between both time intervals. Though there was a lower eGFR and higher percentage of patients with renal dysfunction in the later interval, mortality outcomes were better in the later period.

Clinical implications

Secular trends in the behavior of the disease have been noted in the form of both increased incidence as well as the evolution from symptomatic to asymptomatic phenotype.[3] This is not only recognized in western countries but has also been reported in Indian settings.[45] However, the trends in prevalence and patterns of mortality have not been well elucidated previously. The finding of an almost halved mortality rate in the latter half of the cohort is not only encouraging but bears testimony to improved management, specifically in terms of surveillance following parathyroidectomy. The severity of disease and causes of mortality have remained unchanged with time. Despite this, there is a decrease in mortality. This is probably attributable to improvement in surveillance for complications and ensuring their timely management. Renal complications in PHPT can manifest as nephrolithiasis, nephrocalcinosis, hypercalciuria, and/or reduced eGFR. Prior experience suggests only partial resolution of these complications with curative parathyroidectomy.[67] Therefore, ensuring regular follow-up is of utmost importance for managing the collateral damage that in fact, is the major contributor to morbidity and mortality in patients with PHPT.

How do we fare as compared to the west?

Survival after parathyroidectomy has been recently reported from the US, UK, and Europe.[8910] In these contemporary reports, the common finding is comparable mortality with respect to the general population. However, higher mortality rates in patients with symptomatic (associated with complications) or severe disease (serum calcium exceeding 10.8 mg/dl) have been reported even in these countries. The mortality rate in Indian patients with PHPT is higher than in some countries but lower than others. However, the finding of reduced mortality even with similar parameters of disease complications and severity as before is both reassuring and encouraging.

Proposed line of surveillance care for PHPT in India

The Indian PHPT registry has shown the way forward in long-term active surveillance of patients following curative parathyroidectomy, so as to improve outcomes. This suggests the significant benefit of a dedicated parathyroid registry and regular surveillance in improving outcomes, despite similar severity of disease and greater preponderance of patients with symptomatic PHPT in both intervals. Though follow-up protocols may not be as stringent as for those on medical management, biannual to annual frequency of follow-up, especially for patients with renal complications at baseline is imperative. Devising a simple strategy to calculate the estimated glomerular filtration rate in all patients with PHPT can aid in risk stratification at baseline. This subset of patients should be follow-up more frequently both by the endocrinologist and urologist to provide definite management of the reversible causes such as nephrolithiasis. The non-reversibility of certain renal manifestations should be impressed upon, at each opportunity of interaction with the patient.

The way forward

Interestingly, Captain Martell succumbed to complications arising as a result of untreated nephrolithiasis.[1] As we near the centenary of the recognition of PHPT in 1926, it is only apt that we remember the statement with regard to the death of Captain Martell i.e., “he died so that others may live”. Patterns of mortality are different in India as compared to the west, and renal complications need special mention in this context. Active surveillance of these complications in patients following curative parathyroidectomy can serve as a useful first step in averting premature mortality in these patients, especially in those with reversible causes.