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  1. Loh HH, Yee A, Loh HS, Sukor N, Kamaruddin NA
    Minerva Endocrinol., 2015 Dec 23.
    PMID: 26698544 DOI: 10.23736/S0391-1977.16.02394-4
    INTRODUCTION: Long-term outcome of patients with adrenal incidentaloma (AI) is unknown. The aim of this study was to systematically summarize the follow-up and outcome of clinically silent AI who do not undergo surgery.
    EVIDENCE ACQUISITION: All major databases and medical literature in English-language, published from 1998 to May 2015, were systematically searched for publications on AI. Primary endpoint was hormonal hyper function; secondary endpoints were time from diagnosis to study endpoint and the outcome of adrenalectomy. Meta-analysis was performed using both qualitative and quantitative approach.
    EVIDENCE SYNTHESIS: A total of 11 publications were included. Total sample size was 1298 patients. Mean follow-up duration was 44.2 months. There were 82 patients confirmed to have subclinical Cushing's syndrome at diagnosis, with 1.79% new cases at the end of follow up (95% CI, 0.002 to 0.045). Incidence of Cushing's syndrome was 0.7% (95% CI, 0.001 to 0.013) and pheochromocytoma 0.4% (95% CI, 0.001 to 0.008). The mean tumor size was 2.52cm, with mean increment of 0.03cm to 2.9cm at the end of follow up. About 3% of patients ended up with surgery (95% CI, 0.01 to 0.05) but none were due to primary adrenal malignancy. Time of greatest risk of developing Cushing's syndrome and pheochromocytoma was between months 36 and 42 (hazard rate 14%), and between months 48 and 54 (hazard rate 7%) respectively.
    CONCLUSIONS: Malignant change in non-functioning AI is rare. The risk of developing overt disease over the follow-up period is low. A less stringent imaging and functional work-up interval can be considered.
  2. Loh HH, Kamaruddin NA, Zakaria R, Sukor N
    Minerva Endocrinol., 2018 Jun;43(2):117-125.
    PMID: 28001017 DOI: 10.23736/S0391-1977.16.02553-0
    BACKGROUND: Recent studies showed association between hyperaldosteronism and low bone density among patients with primary aldosteronism (PA) due to secondary hyperparathyroidism. Our objective is to assess bone turnover markers (BTM) and bone mineral density (BMD) of PA patients compared to essential hypertension.

    METHODS: This was an open-label, prospective, case-controlled study, conducted over 12 months. Fifty-two consecutive patients referred for secondary hypertension were screened. Eighteen patients with confirmed PA (diagnosis based on the Endocrine Society clinical guideline) and seventeen matched controls with essential hypertension were recruited. BTM (CTX and P1NP), BMD, intact parathyroid hormone (iPTH), and bone profile were assessed at baseline and three months following treatment among the PA patients. Calcium intake was assessed using a validated questionnaire. Primary outcomes were the changes of bone markers and BMD following treatment of PA, and their relation to other parameters.

    RESULTS: PA patients had significantly lower serum calcium and higher iPTH despite comparable vitamin D levels with control group. Both BTM were significantly higher among the PA group. BMD of lumbar spine, neck of femur and distal radius did not differ between groups. Three months following treatment, there were significant: 1) reduction in BTM; 2) improvement in the lumbar spine BMD; 3) reduction in iPTH level; and 4) increment of serum 25-OH vitamin D level.

    CONCLUSIONS: Our findings support that bone loss and potential fracture risk among PA patients are likely a result of aldosterone-mediated secondary hyperparathyroidism. Patients with early PA may already exhibit increased bone turnover despite no significant changes in BMD.

  3. Loh HH, Lim LL, Yee A, Loh HS, Vethakkan SR
    Minerva Endocrinol., 2019 Jun;44(2):221-231.
    PMID: 28294593 DOI: 10.23736/S0391-1977.17.02584-6
    INTRODUCTION: We conducted a meta-analysis to assess the effects of vitamin D replacement on biochemical and skeletal parameters in subjects with mild primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency.

    EVIDENCE ACQUISITION: A systematic search of all English-language medical literature published from 1980 till May 2016 using PubMed, Embase and Ovid was performed. Nine observational studies were evaluated after fulfilling the inclusion and exclusion criteria.

    EVIDENCE SYNTHESIS: A total of 547 patients were examined. All studies used vitamin D2/D3 or calcifediol (25-hydroxyvitamin D3), There was significant improvement of serum 25(OH)D with unchanged serum iPTH level after vitamin D replacement, with pooled d+: 3.10 (95% CI 2.25 to 3.95), P<0.01 and pooled d+: 0.82 (95% CI -0.35 to 1.98), P=0.16 respectively. There was neither worsening of the pre-existing hypercalcemia (pooled d+: -0.27 [95% CI -1.09 to 0.64, P=0.56]) nor hypercalciuria (pooled d+: 3.64 [95% CI -0.55 to 7.83, P=0.09]). Two studies assessed in this meta-analysis reported unchanged bone density with vitamin D replacement.

    CONCLUSIONS: Vitamin D replacement in subjects with mild PHPT and coexistent vitamin D deficiency improved serum 25(OH)D level without worsening of pre-existing hypercalcemia or hypercalciuria. Well-designed multicenter randomized controlled trials examining pre- and postoperative outcomes of vitamin D therapy in patients with different severities of PHPT and vitamin D inadequacy are warranted to elucidate the most appropriate vitamin D treatment protocol and determine the long-term safety concerns.

  4. Loh HH, Yee A, Loh HS
    Minerva Endocrinol., 2019 Dec;44(4):387-396.
    PMID: 30482008 DOI: 10.23736/S0391-1977.18.02867-5
    INTRODUCTION: Recent studies showed a possible association between hyperaldosteronism and secondary hyperparathyroidism leading to reduced bone health, however results are conflicting.

    EVIDENCE ACQUISITION: We conducted a meta-analysis to evaluate the relationship between primary aldosteronism (PA) with bone biochemical markers and to assess bone mineral density in patients with primary aldosteronism.

    EVIDENCE SYNTHESIS: A total of 939 subjects were examined (37.5% with PA). Patients with PA had significantly higher serum parathyroid hormone, lower serum calcium, higher urine calcium excretion and higher serum alkaline phosphatase compared to patients without PA, with no significant difference in serum vitamin D between both groups. Bone mineral density of lumbar spine, femoral neck and total neck of femur were similar between two groups. With PA treatment, there was a significant increment in serum calcium and reduction in serum parathyroid hormone.

    CONCLUSIONS: PA is associated with hypercalciuria with subsequent secondary hyperparathyroidism. This potentially affects bone health. We recommend this to be part of complication screening among patients with PA.

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