CALCIUM CREATININE CLEARANCE RATIO IS NOT HELPFUL IN DIFFERENTIATING PRIMARY

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Original Article EP CALCIUM CREATININE CLEARANCE RATIO IS NOT HELPFUL IN DIFFERENTIATING PRIMARY HYPERPARATHYROIDISM FROM FAMILIAL HERPERCALCEMIC HYPOCALCIURIA: A STUDY OF 1000 PATIENTS Edwina C Moore, MD, Eren Berber, MD, Judy Jin, MD, Vikram Krishnamurthy, MD, Joyce Shin, MD, Allan Siperstein, MD Running Title: Validity of CCCR in Primary Hyperparathyroidism From: Department of Endocrine Surgery, Cleveland Clinic, F/ Euclid Avenue, Cleveland, 44195, OHIO, United States Corresponding author: Edwina C Moore, MD Cleveland Clinic - Endocrine Surgery F20/9500 Euclid Avenue Cleveland Ohio edwina.bolshinsky@gmail.com / mooree@ccf.org Conflicts: There are no conflicts of interest

2 Abstract Objective: With increasing recognition of more subtle presentations of primary hyperparathyroidism (phpt), laboratory values are frequently seen in a range that would be expected for patients who have familial hypercalcemic hypocalciuria (FHH). Calcium creatinine clearance ratio (CCCR) has been advocated as a diagnostic tool to differentiate between these two disorders. However, it is limited by an indeterminate range ( ). The aim of this study is to assess the relevance of CCCR in a modern series of patients with surgically managed phpt. Methods: We performed a retrospective cohort study of 1000 patients who underwent parathyroid surgery for phpt over eleven years. CCCR was evaluated by degree of biochemical derangement, single versus multiple gland disease and interfering medications. Results: Patient demographics and resected histopathology were typical for a current series of patients with phpt. In retrospect, none of the patients were suspected to have FHH post operatively. CCCR was less than 0.01 for 19.0%, between for 43.7% and greater than 0.02 in 37.3%. Distribution of CCCR for patients free from interfering medications and different histological subtypes were the same. One third of the cohort had mild calcium elevations, more typical for FHH. Of these, almost two thirds had a CCCR in a range suspect for FHH (<0.02). Conclusion: To our knowledge this is the largest series to evaluate the validity of CCCR for patients with surgically confirmed ppht. The utility of CCCR in screening for FHH is limited, as 63% of modern patients with confirmed phpt have low values.

3 Introduction phpt is one of the most common endocrine disorders, with a disease prevalence of one case per 1000 population (1), but potentially higher as the diagnostic criteria broadens (2). Patients have hyper secretion of parathyroid hormone (PTH), usually from a single adenoma, leading to an elevation of serum calcium. Unfortunately, the clinical and biochemical profile are subject to significant individual variation, which can complicate diagnosis. One of the most critical steps for the endocrine surgeon is to exclude the potential for misdiagnosis with familial hypocalciuric hypercalcemia (FHH). First described in 1966 (3) and named by Foley in 1972 (4), FHH is a rare, autosomal dominant disorder usually caused by a heterozygous inactivating mutation in the calcium sensing receptor gene (CaSR) (5-6). Several additional genetic mutations have subsequently been associated with this disorder (7-9). The physiological defect is calcium hyposensitivity with associated hypercalcemia. It is important to identify these patients among hypercalcemic patients considering surgery, so as to avoid unnecessary surgery. Unlike patients with phpt, patients with FHH are asymptomatic with a normal phenotype and limited potential for sequelae (10). As phpt and FHH differ in their renal processing of calcium several markers of renal calcium excretion have been proposed to distinguish between the two disorders: 24 hour urine calcium

4 excretion, fasting urinary calcium excretion, calcium creatinine ratio and CCCR (5,11-19). Classically, urinary calcium is low in FHH, but despite its name this is not universally the case (20-21). In 2008, Christensen et al proposed a two-step diagnostic algorithm to exclude FHH from patients with suspected phpt. This includes calculating CCCR followed by genetic testing for all patients with CCCR<0.02. This two-step algorithm is reportedly associated with a sensitivity of 98% (17). The CCCR diagnostic cutoffs (<0.01 is FHH and >0.02 is phpt) dates from the first published series in 1981 (13). To our knowledge, no large scale study has confirmed the efficacy of CCCR in a modern series of patients surgically treated (and cured) for phpt, using the cutoffs previously described. Our primary aim was to evaluate the validity of CCCR, as a diagnostic test for FHH, amongst patients with suspected phpt. Secondary aims were to assess its utility for particular subgroups including patients with mild biochemical derangement, patients free from medications known to interfere with urine calcium excretion and histological variants of hyperparathyroidism. Methods Patients Over an eleven year period (Jan Jan ), 1847 patients were managed in a tertiary referral center for parathyroid disease. Preoperative workup and surgery was performed by one

5 of five staff surgeons. Indications for surgery followed the guidelines of the American Association of Endocrine Surgeons (22). Specific inclusion criteria were adult patients with biochemically proven primary hyperparathyroidism. Exclusion criteria were re-operative surgery. The study was approved by the Cleveland Clinic Institutional Review Board. Data collection The institution database, which is prospectively maintained, was accessed for patients surgically treated for phpt. Basic demographics (gender, age, primary complaint, medication history), preoperative biochemical markers (serum calcium, serum creatinine, serum phosphorus, PTH, Vitamin D, 24hour urine calcium and 24hour urine creatinine), indications for surgery, histology and postoperative biochemistry (serum calcium and PTH) were extracted. CCCR was calculated as [24hour urine calcium (mg/24hrs)/total serum calcium (mg/dl)]/[24 hour urine creatinine (mg/24hrs)/total serum creatinine (mg/dl)]. Statistical analysis The data was retrospectively analyzed. Metric variables are described by median and interquartile range (IQR) and categorical variables by absolute and relative frequencies. Regression analyses were completed using Excel and SPSS. Results We identified 1000 patients out of 1847, who had primary hyperparathyroidism and a complete set of biochemistry to calculate CCCR, over 11 years. All of these patients underwent parathyroid surgery and none, in retrospect, were suspected of having FHH.

6 The majority of patients were female (79.7%) and the mean age was 60.7 years. Twenty-six patients had a history of prior neck radiation. Almost one in four patients (23.7%) used medications known to affect calcium excretion (thiazide 181, cinacalcet 6, bisphosphonate 62, lithium 10, biotin 6) at the time of surgery. The mean preoperative serum calcium was 10.8 mg/dl and PTH was 111 pg/ml parathyroid glands were excised from 1000 patients. Of these, 624 patients had single adenomas (624 adenomas, 62.4%), 186 patients had double adenomas (372 adenomas, 18.6%) and 190 patients had four gland hyperplasia (760 parathyroid glands, 19.0%). The distribution of CCCR for the total study population was 19.0% for CCCR<0.01, 43.7% for CCCR between and 37.3% for CCCR >0.02. A similar distribution was seen for each histological subtypes. (Inset Table 1 and Figure 1) When patients using medications known to interfere with calcium excretion were excluded (n=237) from the analysis, the distribution of CCCR was unchanged from the total population. More than two thirds of this subset of patients with histologically confirmed and biochemically cured primary hyperparathyroidism were still found to have a preoperative CCCR less than (CCCR< %, CCCR %, CCCR > %). (Inset Figure2) There were 303 patients with mild biochemical derangement (defined as serum Ca <10.8mg/dL and PTH <100pg/mL). Distribution of CCCR for this subgroup showed that 18% (n=137) had a

7 value less than 0.01 and 68.0% (n=206) had a value less than (Inset Figure 3). The distribution of CCCR was unaffected gender. On regression analysis, there was no correlation between PTH and Ca with CCCR. Figure 4 compares the regression analysis of Ca and CCCR for the total population and the subset with four gland hyperplasia. The proportion of patients with hyperplasia who had a low CCCR and a borderline serum calcium, was not statistically different to the proportion of patients in the entire population with a similar biochemical profile (19% v/v 31%). population. (Inset Figure 4). Discussion The treatment for patients with phpt is surgery, with a long term cure a rate of 95-99% depending on criteria used (22-23). By contrast, for patients with FHH who often have a similar clinical and biochemical presentation, surgical cure is 0%. Therefore it is imperative to differentiate between these two disorders preoperatively. The purpose of this study was to evaluate the validity of a widely accepted diagnostic test, CCCR, for a modern population with surgically proven phpt. Our results show that CCCR is not a useful index to preoperatively differentiate phpt from FHH and its routine use should be abandoned. Almost two thirds (62.7%) of our patients had a CCCR<0.02 and therefore by current recommendations would have been recommended to have had preoperative genetic analysis for

8 CaSR mutations. Notwithstanding that this is neither a practical nor a cost effective strategy, it is also completely unnecessary. All of the patients in our population had abnormal parathyroid glands removed at operation and were biochemically cured post operatively. As the prevalence of FHH is extremely rare, reportedly between 1:10000 and 1: (11, 19), it is possible that our population did not include a patient with FHH based on probability. In addition, with increasing recognition of FHH, such patients may have been screened out by primary care providers and never referred to us. However, in our subgroup of patients with mild biochemical derangement, who by definition are more likely to overlap with patients with FHH, two thirds still had a CCCR <0.02. Despite this all of them were found to have parathyroid disease and improved after surgery, thereby eliminating the possibility of misdiagnosis. Historical case series have identified that almost one third of patients with mild phpt have CCCR<0.01 and an additional one third have CCCR<0.02 (25). Our subgroup analysis is complementary. 21.8% of patients with mild phpt in our population had CCCR<0.01 and a further 46.2% had CCCR between 0.01 and Glendenning et al rationalized that as the ratio is influenced by both the degree of urinary calcium excretion and the degree of elevation of serum calcium, CCCR is a sensitive but increasingly less specific for milder presentations (16). In our study, CCCR was non-discriminatory for all biochemical presentations, subtle and more severe. The distribution of pathology in our study was similar to other studies: 61.1 % single adenomas, 20% double adenomas and 18.9% four gland hyperplasia (22-24). We did not find a significant

9 difference in the distribution of CCCR for each histological subtype. For single adenomas, double adenomas and four gland hyperplasia alike, approximately one third of each cohort had a CCCR<0.01 and two thirds had a CCCR <0.02. To our knowledge, this has not previously been described. Genetic testing is presently viewed as the gold standard to diagnose FHH. Notwithstanding, false negatives are possible if there are novel CaSR mutations (26-27) and the vast number of possible mutations makes the diagnostic process even more complex (27-28). Long prior to the availability of genomic tests, Marx et al proposed the diagnosis of FHH depended on observation of characteristic features within a family (13). This remains true and should be upheld. Clinical red flags for FHH include: asymptomatic hypercalcemia beginning in early life, relative hypocalciuria and multiple affected family members in an autosomal dominant inheritance pattern. Fasting urinary calcium excretion (CaE) has also been advocated, in place of CCCR, to diagnose FHH (17, 30). It is advantageous for the ease of spot urinary testing without the need for acidification compared with 24 hour collection (16). CaE<30umol/L GFR indicates avid renal calcium conservation typical of FHH however overlap can occur with phpt in the setting of very high PTH, calcium poor diets and use of thiazide medication (30, 31). For these reasons we did not evaluate CaE. Kalderli et al reviewed factors influencing urinary calcium excretion in phpt (32). They reported that 1,25 (OH)2 D3 and Osteocalcin were the only factors to independently correlate

10 with CCCR. Riss et al also reviewed the impact of thiazides on biochemical parameters in phpt and concluded that withdrawal was necessary for accurate diagnosis prior to surgery (33). By contrast in our study, there was little difference in the distribution of CCCR between patients taking and not taking similar medications and therefore we conclude that it is not relevant. The major limitation of this study was that the timing in the acquisition of preoperative blood and urine tests was variable. This was related to surgical scheduling and high number of external referrals where repeating tests would be unnecessary. However we consistently selected laboratory results that were drawn together and as close as possible to the date of surgery. Secondly, we did not assess 24 hour urine volume (nor fasting status at the time of urine collection) which can theoretically affect urine flow rate and mineral concentration, however in a population with normal renal function this is not likely to be significant. Thirdly, we only included patients with complete sets of laboratory values required to calculate CCCR. Conclusion The role of CCCR to preoperatively differentiate between phpt and FHH is questionable. Its utility is not enhanced by any histological subtype, exclusion of confounding medications or even for mild biochemical presentations. CCCR is cumbersome to perform and interpretation has low yield. It should not be prioritized in the diagnostic algorithm for patients with phpt. References

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15 Table 1: Proportion of patients with phpt and their CCCR, stratified by histology Histology Number CCCR<0.01 % CCCR % CCCR>0.02 % of patients All patients Single Adenomas Double Adenomas Four Gland Hyperplasia

16

17

18 Serum Calcium (mg/dl) 15 Regression Analysis of Serum Calcium and CCCR for the Total Population Suspect for FHH Marginal for FHHUnlikely FHH R² = Calcium Creatinine Clearance Ratio (CCCR)

19 Serum Calcium (mg/dl) 16 Regression Analysis of Serum Calcium and CCCR for Patients with Four Gland Hyperplasia Suspect for FHHMarginal for FHHUnlikely FHH R² = Calcium Creatinine Clearance Ratio (CCCR)