The association between proton pump inhibitors and hyperparathyroidism: a potential mechanism for increased fracture-results of a large observational cohort study.

Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture; however, the mechanism is unclear. PPI users taking calcium supplements were more likely to have hyperparathyroidism compared to non-users (OR 1.56, CI 1.08-2.23, p = 0.018). This highlights the importance of monitoring PPI use, especially in older adults. PURPOSE: Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture. Hyperparathyroidism may be implicated, but few studies have considered this relationship. This study evaluated the relationship between PPI use and hyperparathyroidism in older adults. METHODS: Participants were from the TUDA study, a large cross-sectional cohort of older Irish adults. Participants with an estimated glomerular filtration rate (eGFR) < 30 ml/min and serum calcium > 2.5 mmol/l were excluded to avoid hyperparathyroidism due to chronic renal disease and primary hyperparathyroidism. Hyperparathyroidism was defined as a parathyroid hormone (PTH) > 65 pg/ml. Multivariate regression models were used to analyse the relationship between PPI use and hyperparathyroidism. RESULTS: A total of 4139 participants met the inclusion criteria, of whom 37.8% (n = 1563) were taking PPI medication. PPI use was identified in 41.4% of calcium supplement users and 35.4% of non-calcium supplement users. Overall, compared to non-users of PPIs, those taking PPIs were older (74.8 vs 72.9 years, p < 0.001) and had a higher prevalence of hyperparathyroidism (17.8 vs 11.0%, p < 0.001). In those taking calcium supplements (but not in non-users), PPI use was significantly associated with hyperparathyroidism (OR 1.56, CI 1.08-2.23, p = 0.018) after adjusting for age, sex, body mass index, serum vitamin D, eGFR, timed-up-and-go, dairy intake, medications, and comorbidities. DISCUSSION: The results are consistent with the hypothesis of PPIs reducing calcium absorption, leading to a rise in PTH which could mediate increased fracture risk. No relationship of PPI use with hyperparathyroidism was observed in non-users of calcium supplements, possibly owing to lower dietary calcium intake. These results highlight the importance of monitoring PPI use, especially in older adults at risk of fracture.

Environmental Chemicals and their Association with Hyperparathyroidism.

BACKGROUND: The incidence of hyperparathyroidism has increased in the USA. The previous work from our institution detected environmental chemicals (EC) within hyperplastic parathyroid tumors. The National Health and Nutrition Examination Survey (NHANES) is a program designed to assess the health status of people in the USA and includes measurements of EC in serum. Our aim was to determine which EC are associated with elevated parathyroid hormone (PTH) and calcium levels within NHANES. METHODS: NHANES was queried from 2003-2016 for our analysis with calcium. A separate subgroup was queried from 2003-2006 that included PTH levels. Subjects with elevated calcium, and elevated PTH and normal Vitamin D levels were identified. Wilcoxon rank sum tests were used to analyze levels of EC in those with elevated calcium, and those with elevated PTH in the subgroup. All EC with p < 0.05 were then included in separate multivariate models adjusting for serum vitamin D and creatinine for PTH and albumin for calcium. RESULTS: There were 51,395 subjects analyzed, and calcium was elevated in 2.1% (1080) of subjects. Our subgroup analysis analyzed 14,681 subjects, and PTH was elevated without deficient Vitamin D in 9.4% (1,377). Twenty-nine different polychlorinated biphenyls and the organochlorine pesticides hexachlorobenzene, transnonachlor, oxychlordane, and p,p'-dichlorodiphenyldichloroethylene (DDE) were found to be associated with elevated calcium and separately with elevated PTH (all p < 0.05). CONCLUSION: In NHANES, 33 ECs were found to be associated with elevated calcium as well as elevated PTH levels on our subgroup analysis. These chemicals may lead us toward a causal link between environmental factors and the development of hyperparathyroidism and should be the focus of future studies looking at chemical levels within specimens.

Lithium-associated hyperparathyroidism.

Lithium is a mood stabiliser widely used in the treatment and prophylaxis of mania, bipolar disorders and recurrent depression. Treatment with lithium can give rise to various endocrine and metabolic abnormalities, including thyroid dysfunction, nephrogenic diabetes insipidus and hypercalcaemia. Lithium may induce hypercalcaemia through both acute and chronic effects. The initial acute effects are potentially reversible and occur as a result of lithium's action on the calcium-sensing receptor pathway and glycogen synthase kinase 3, giving rise to a biochemical picture similar to that seen in familial hypocalciuric hypercalcaemia. In the long term, chronic lithium therapy leads to permanent changes within the parathyroid glands by either unmasking hyperparathyroidism in patients with a subclinical parathyroid adenoma or possibly by initiating multiglandular hyperparathyroidism. The latter biochemical picture is identical to that of primary hyperparathyroidism. Lithium-associated hyperparathyroidism, especially in patients on chronic lithium therapy, is associated with increased morbidity. Hence, regular monitoring of calcium levels in patients on lithium therapy is of paramount importance as early recognition of lithium-associated hyperparathyroidism can improve outcomes. This review focuses on the definition, pathophysiology, presentation, investigations and management of lithium-associated hyperparathyroidism.

Characterization of Calcium Homeostasis in Lithium-Treated Patients Reveals Both Hypercalcaemia and Hypocalcaemia.

INTRODUCTION: Prevalence studies demonstrate that a significant proportion of lithium-treated patients develop hypercalcaemia (3-30%). Lithium-associated hyperparathyroidism (LHPT) is poorly defined, and calcium homeostasis may be affected in a more complicated fashion than purely by elevated PTH secretion. The current study aims to examine in detail calcium homeostasis principally with regard to lithium duration. METHODS: Medical records of 297 lithium-treated patients (193 women, 104 men; median age 58 years) were examined, and information on gender, age, lithium treatment duration and calcium homeostasis was obtained. The median treatment duration with lithium was 16 (1.5-45) years. RESULTS: A total of 8504 calcium values were retrieved. Before initiation of lithium treatment, serum calcium was on average 2.33 mmol/l (2.02-2.60). During the treatment period, 178 patients (60%) remained normocalcaemic, 102 (34%) developed hypercalcaemia or were strongly suspected of LHPT, 17 (6%) had 3 or more intermittent episodes of hypocalcaemia. Forty-one per cent of patients with suspected or confirmed LHPT had low (<4 mmol) 24-h urine calcium levels. The success rate after 33 parathyroidectomies was 35%, hyperplasia being diagnosed in 75% of extirpated glands. CONCLUSIONS: The prevalence of hypercalcaemia during lithium treatment is very high. In addition, hypocalcaemic episodes appear to occur frequently, possibly reflecting a more complicated parathyroid dysfunction than previously known. Long-term surgical results are unsatisfactory. LHPT biochemical profile is different from that of primary hyperparathyroidism and is in some ways similar to familial hypocalciuric hypercalcaemia.

[Renal toxicity of lithium]. / Néphrotoxicité du lithium.

Besides its efficiency, lithium has a narrow therapeutic index and can result in considerable toxicity. Among the potential side effects, two types of renal toxicity are observed: a decreased renal concentrating ability and a chronic renal failure. Lithium-induced polyuria is frequent, estimated to affect up to 40% of patients, and develops usually early. It may be irreversible, especially if the treatment has been prescribed for more than 15 years. A chronic renal failure is observed in patients treated for more than 10 to 20 years. Its prevalence is estimated at 12% after 19 years of treatment. Some patients (0.5%) may reach end stage renal disease. The major risk factor is the duration of exposure to lithium. Discussion about stopping or not lithium in case of renal failure needs multidisciplinary expertise and depends on psychiatric status and renal function.

Use of cinacalcet in lithium-induced hyperparathyroidism.

The case of a 61-year-old female patient with a long-standing history of bipolar affective disorder treated medically with lithium therapy for the past two decades. In late 2012, the patient was diagnosed with hyperparathyroidism secondary to lithium therapy. The patient underwent parathyroidectomy in August 2013. During surgery, only two glands were conclusively located and removed. This resulted in a reduction in the patient's plasma total calcium levels and parathyroid hormone. The psychiatric management of the bipolar affective disorder was reviewed, and lithium discontinued as a result of the findings. Over the following year, a variety of different mood stabilisers were trialled, however none were found to successfully maintain the patient's mental health. In August 2014, the patient was admitted with a severe depressive relapse of her bipolar affective disorder. Her admission tests showed hypercalcaemia, which may also have contributed to her mood symptoms and mental state deterioration. The patient was reviewed by the endocrinology team and subsequently commenced on cinacalcet treatment (30 mg twice a day). Over the following months, the patient's plasma total calcium levels returned to within normal range. The patient's depressive symptomatology gradually improved with a combination of physical and pharmacological treatments.

Parathyroid hormone contributes to the down-regulation of cytochrome P450 3A through the cAMP/PI3K/PKC/PKA/NF-κB signaling pathway in secondary hyperparathyroidism.

Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models. In SHPT rats, hepatic and intestinal CYP3A expression was suppressed, but the changes were recovered by the administration of the calcimimetic cinacalcet, a PTH suppressor. Under the same experimental conditions, a pharmacokinetic study using orally administered midazolam, a substrate for CYP3A, showed that the AUC was increased by 5 times in SHPT rats, but that was partially recovered by a cinacalcet treatment. This was directly tested in rat primary hepatocytes and intestinal Caco-2 cells where the expression of the CYP3A protein was down-regulated by PTH (1-34). In Caco-2 cells, PTH (1-34) down-regulated the expression of CYP3A mRNA, but an inactive PTH derivative (13-34) had no effect. 8-Bromo-cyclic adenosine monophosphate, a membrane-permeable cAMP analog, reduced mRNA expression of CYP3A whereas the inhibitors of PI3K, NF-κB, PKC and PKA reversed the PTH-induced CYP3A down-regulation. These results suggest that PTH down-regulates CYP3A through multiple signaling pathways, including the PI3K/PKC/PKA/NF-κB pathway after the elevation of intracellular cAMP, and the effect of PTH can be prevented by cinacalcet treatment.

Tenofovir monotherapy for hepatitis B after 1 year does not produce renal dysfunction, but is associated with hyperparathyroidism not related to vitamin D.

INTRODUCTION: Viral hepatitis B (VHB) represents a major public health problem. Studies from HIV multidrug patients have associated the use of tenofovir disoproxil fumarate (TDF) with renal dysfunction and phosphate wasting. OBJECTIVE: The aim of this study was to examine the effect of year-long TDF monotherapy on renal function in VHB patients. PATIENTS AND METHODS: We evaluated adult patients diagnosed with VHB before treatment initiation (T0), and after 3 and 12 months (T3 and T12) of TDF initiation. Estimated glomerular filtration rate (eGFR) was estimated by serum cystatin C and creatinine. In addition, urinary electrolytes and tubular biomarkers (cystatin C, ß2-microglobulin and neutrophil gelatinase-associated lipocalin) were analyzed, as well as parathyroid hormone (PTH) and 25(OH)vitamin D levels. RESULTS: After 1 year, 32 patients completed the study, 22 (68.7%) men and 12 (37.5%) Whites, mean age 44.1±12.0 years. We found that serum electrolytes were similar at baseline and 3 or 12 months after initiation of TDF monotherapy. In addition, urinary fractional excretions of electrolytes as well as proteinuria, albuminuria, urinary ß2-microglobulin, and urinary cystatin C showed no significant differences across the treatment timeline. There were also no statistical differences in the eGFR. There was a statistically significant increase in the PTH (Friedman's test, P=0.012), but the 25(OH)vitamin D levels were in the normal range in the beginning and did not change at the follow-up. Moreover, there was no correlation between the initial levels of vitamin D and the corresponding increases in the PTH values. CONCLUSION: If used as monotherapy in hepatitis B patients for a 12-month period, TDF is not associated with changes in either eGFR or a panel of urinary biomarkers. Serum and urinary electrolytes also remained unchanged. Of note, a significant increase in the PTH was found, although not related to the 25(OH)vitamin D initial status.

[Lithium carbonate-induced hyperparathyroidism in a patient after removal of a parathyroid adenoma]. / Nadczynnosc przytarczyc spowodowana przez weglan litu u chorego po usunieciu gruczolaka przytarczyc.

Lithium compounds are widely used and effective drugs in the treatment of mood disorders. However, despite their efficacy, the use of lithium salts is limited by their narrow therapeutic window. Treatment with lithium salts may be associated with the risk of development of numerous adverse effects. Endocrine complications include: thyroid dysfunction, nephrogenic diabetes insipidus and hyperparathyroidism. Because symptoms of lithium-induced hyperparathyroidism may resemble those of the underlying disorder, hyperparathyroidism sometimes remains undetected. The pathogenic mechanism for parathyroid dysfunction in lithium-treated patients is still unclear. We report a patient who had undergone removal of a parathyroid adenoma and later developed lithium-induced hyperparathyroidism. Cessation of lithium treatment normalised parathyroid function. The described case suggests that patients with pre-existing parathyroid disorders may be particularly susceptible to the development of lithium-induced hyperparathyroidism.

The prevalence of lithium-associated hyperparathyroidism in a large Swedish population attending psychiatric outpatient units.

OBJECTIVE: This retrospective study determined the prevalence of lithium-associated hyperparathyroidism (LHPT) in 2 geographically defined, equivalent populations in Sweden, with no other selection bias. METHODS: The medical journals of all patients receiving lithium treatment were examined specifically regarding their biochemistry: calcium, parathyroid hormone (PTH), creatinine, and vitamin D. The condition LHPT was defined biochemically. All patient data were noted, and the prevalence of the condition could thereby be calculated. RESULTS: A total of 423 patients were included (251 women and 172 men; 3:2), treated over a mean of 13.5 years (range, 1-46 years), aged 19 to 92. 77 patients (18%) were identified with LHTP whose median serum calcium was 2.55 mmol/L and PTH was 99 ng/L. A further 21% showed tendencies toward hypercalcemia. Forty-three percent had vitamin D insufficiency. Five patients (approximately 1%) had undergone parathyroidectomy. CONCLUSION: The prevalence of LHPT is high and often goes undetected. Vitamin D insufficiency is common as is polypharmacy. Surgery, for unclear reasons, has not been performed extensively, possibly because of limited knowledge of the underlying pathophysiology or surgery's significance. We present standard recommendations on patient management and suggest continual, specific follow-up including the monitoring of calcium, PTH, and vitamin D at least annually. Surgery should be considered with intention to improve psychiatric well-being and provide multiorgan protection.

Long-term outcome after parathyroidectomy for lithium-induced hyperparathyroidism.

BACKGROUND: The accepted management of lithium-associated hyperparathyroidism (LiHPT) is open four-gland parathyroid exploration (OPTX). This approach has recently been the subject of controversy. A recent study has shown very high long-term recurrence rates after OPTX, whereas some have promoted unilateral focused parathyroidectomy as appropriate management. The aim was to evaluate long-term outcomes after surgery for LiHPT and to assess the accuracy of preoperative imaging. METHODS: This was a retrospective cohort study that comprised all patients undergoing initial surgery for LiHPT between 1990 and 2013. The cumulative recurrence rate was calculated by the Kaplan-Meier method. The sensitivity and specificity of sestamibi scintigraphy and ultrasound imaging for identification of single-gland versus multigland disease was investigated using intraoperative assessment as reference. RESULTS: Of 48 patients, 45 had OPTX and three underwent focused parathyroidectomy. Multiglandular disease was documented in 27 patients and 21 had a single adenoma. The median follow-up was 5·9 (range 0·3-22) years and 16 patients died during follow-up. The 10-year cumulative recurrence rate was 16 (95 per cent confidence interval 2 to 29) per cent. No permanent complications occurred after primary surgery for LiHPT. Twenty-four patients had at least one preoperative ultrasound or sestamibi scan. For concordant sestamibi scintigraphy and ultrasound imaging, the sensitivity and specificity for identifying single-gland versus multigland disease was five of nine and five of eight respectively. CONCLUSION: Surgery provided a safe and effective management option for patients with LiHPT in this series, with a long-term cure rate of well over 80 per cent.

[Lithium carbonate-induced hyperparathyroidism in a patient after removal of a parathyroid adenoma]. / Nadczynnosc przytarczyc spowodowana przez wegIan litu u chorego po usunieciu gruczolaka przytarczyc.

Lithium compounds are widely used and effective drugs in the treatment of mood disorders. However, despite their efficacy, the use of lithium salts is limited by their narrow therapeutic window. Treatment with lithium salts may be associated with the risk of development of numerous adverse effects. Endocrine complications include: thyroid dysfunction, nephrogenic diabetes insipidus and hyperparathyroidism. Because symptoms of lithium-induced hyperparathyroidism may resemble those of the underlying disorder, hyperparathyroidism sometimes remains undetected. The pathogenic mechanism for parathyroid dysfunction in lithium-treated patients is still unclear. We report a patient who had undergone removal of a parathyroid adenoma and later developed lithium-induced hyperparathyroidism. Cessation of lithium treatment normalised parathyroid function.The described case suggests that patients with preexisting parathyroid disorders may be particularly susceptible to the development of lithium-induced hyperparathyroidism.

Mono- and polyphosphates have similar effects on calcium and phosphorus metabolism in healthy young women.

PURPOSE: Phosphate (Pi) salts, often mono- (MP) or polyphosphates (PP), are commonly used as additives in the food industry. Previous studies have shown that the effects of MP and PP on calcium (Ca) and phosphorus (P) metabolism may differ. The aim of this study was to determine whether the effects of MP and PP salts differ on markers of Ca and P metabolism in young women. METHODS: Fourteen healthy women 19-31 years of age were randomized into three controlled 24-h study sessions, each subject serving as her own control. During each session, the subjects received three doses of MP, PP or a placebo with meals in randomized order. Both Pi salts provided 1,500 mg P/d, and the diet during each session was identical. Markers of Ca and P metabolism were followed six times over 24 h. RESULTS: During both MP and PP sessions, we found an increase in serum phosphate (S-Pi, p = 0.0001), urinary phosphate (U-Pi, p = 0.0001) and serum parathyroid hormone (S-PTH, p = 0.048 MP, p = 0.012 PP) relative to the control session. PP decreased U-Ca more than did MP (p = 0.014). CONCLUSIONS: The results suggest that PP binds Ca in the intestine more than does MP. Based on the S-Pi, U-Pi and S-PTH results, both Pi salts are absorbed with equal efficiency. In the long run, increased S-PTH, caused by either an MP or PP salt, could have negative effects on bone metabolism.

Vitamin D and primary hyperparathyroidism (PHPT).

Vitamin D deficiency and primary hyperparathyroidism (PHPT) are two common conditions, especially in postmenopausal women. Vitamin D deficiency is said to be even more frequent in PHPT patients than in the general population due to an accelerated conversion of 25-hydroxy vitamin D (25OHD) into calcitriol or 24-hydroxylated compounds. Although several studies have reported worsening of PHPT phenotype (larger tumours, higher parathyroid hormone [PTH] levels, more severe bone disease) when vitamin D deficiency coexists whereas vitamin D supplementation in PHPT patients with a serum calcium level less than 3 mmol/L has been shown to be safe (no increase in serum or urinary calcium) and to decrease serum PTH concentration, many physicians are afraid to give vitamin D to already hypercalcemic PHPT patients. It is possible that, in some patients, a persistent vitamin D deficiency induces, in the long-term, an autonomous secretion of PTH (i.e. tertiary hyperparathyroidism). The mechanism by which this could occur is unclear however. Finally, as many, otherwise normal, subjects with vitamin D insufficiency may have an increased serum PTH level we believe that those with vitamin D insufficiency should be excluded from a reference population for serum PTH levels. By doing that, we found that the upper normal limit for serum PTH was 25-30% lower than in the whole population.

[Lithium-induced hyperparathyroidism]. / Lithium-geïnduceerde hyperparathyreoïdie.

Lithium is a medication successfully being used for the treatment of bipolar disorder. Lithium-induced hyperparathyroidism (LIH) is a little known complication that may arise due to the use of lithium. Symptoms of LIH are often similar to the underlying psychiatric illness for which lithium was indicated. It is thus difficult to differentiate between these, resulting in significant 'doctors' delay' in the diagnosis of LIH. The authors present three cases in this article. In the first case concerning a 51-year-old woman, they illustrate that LIH and subsequent hypercalcaemia are often diagnosed by coincidence. In the second case concerning a 47-year-old woman, they show that it can be quite complicated to locate the underlying aberration of the parathyroid and that medication may be an eligible alternative to surgery. In the third case, a 56-year-old woman, they show the need for cogency regarding appropriate surgical strategy as recurrences are quite common.

[Renal side effects of long-term lithium therapy]. / Nephrologische Nebenwirkungen einer Langzeittherapie mit Lithium.

Lithium is widely used in the treatment of bipolar disorders. Long-term administration of lithium often leads to side effects concerning the subjects: nephrology, endocrinology and surgery. This review emphasizes nephrotoxicity.Lithium treatment may disturb responsiveness to antidiuretic hormone (ADH), causing a nephrogenic diabetes insipidus. Furthermore long-term lithium therapy may trigger hyperparathyreoidism with hypercalcemia and chronic interstitial nephritis with development of microcysts. Long-term patients have an increased risk to develop impaired renal function. Lithium-induced endstage renal disease is rare. Termination of lithium treatment may decrease the risk of progression.To ensure security of lithium treatment regular controls of urine osmolarity, lithium-, creatinine- , thyroid stimulating hormone- and calcium-levels are essential. Patients with decreased renal function should be referred to a specialist early.

Sunitinib-induced hyperparathyroidism: a possible mechanism to altered bone homeostasis.

BACKGROUND: Sunitinib malate is an orally bioavailable tyrosine kinase inhibitor that is active against many tyrosine kinase receptors involving crucial pathways in both healthy tissues and malignant tissues. Because its use in clinical practice is quite recent, many of its possible side effects remain unknown. In this report, the authors describe the incidence of new-onset hyperparathyroidism in a cohort of patients with metastatic renal cell carcinoma who received treatment with sunitinib. METHODS: Twenty-six patients who received first-line sunitinib for metastatic renal cell carcinoma were enrolled in this study for a mineral and parathyroid function assessment. Plasma levels of intact parathyroid hormone; serum levels of calcium, phosphorus, 25-hydroxyvitamin D(3), and 1,25-dihydrovitamin D(3); and urinary 24-hour calcium and phosphorus excretion all were measured in each patient. Biochemical evaluations were performed before the beginning of treatment and at the end of each sunitinib treatment period. RESULTS: Eighteen of 26 patients (69.2%) developed hyperparathyroidism with normal serum calcium levels, and 6 of them developed hypophosphatemia. Patients presented with a mean elevation of parathyroid hormone after 2.2 cycles of sunitinib. The levels of 25-OH vitamin D(3) were stable over the course of treatment, whereas 1,25-OH vitamin D(3) levels were increased in 5 hyperparathyroid patients. Those who presenting with elevated parathyroid hormone levels had low or undetectable urinary calcium levels. Parathyroid hormone elevation usually persisted but did not progress during long-term therapy with sunitinib. Permanent treatment interruption resulted in a resolution of hyperparathyroidism. CONCLUSIONS: Hyperparathyroidism developed in an high percentage of patients on sunitinib. Therefore, the authors concluded that sunitinib may affect parathyroid function and bone mineral homeostasis, possibly resulting in abnormal bone remodeling.

A profile of patients with hyperparathyroidism undergoing lithium therapy for affective psychiatric disorders.

BACKGROUND: Our objective was to evaluate whether lithium-induced hyperparathyroidism (LIHPT) is caused by single-gland versus multigland disease. METHODS: Medical records of 7 patients who underwent parathyroidectomy for LIHPT were reviewed. RESULTS: The mean preoperative calcium was 11.1 ± 0.7 mg/dL. Six of 7 patients were rendered eucalcemic with surgery. Of the 6 patients successfully treated with surgery, 4 had single-gland disease, 1 had double adenomas, and 1 had 4-gland hyperplasia. Intraoperative intact serum parathyroid hormone (iPTH) accurately predicted resolution of hyperparathyroidism in 6 of 7 patients. One patient then subsequently developed persistent hyperparathyroidism refractory to further surgery. Localization studies defined the extent of disease in 5 of 7 patients. CONCLUSION: LIHPT presents with a spectrum of disease ranging from single-gland to multigland disease. The utility of preoperative localization studies and intraoperative iPTH in this population is uncertain. Bilateral exploration may be best to achieve a resolution of LIHPT.