Calcium Creatinine Clearance Ratio Research Articles

Abstract #1408170: Familial Hypocalciuric Hypercalcemia, Primary Hyperparathyroidism, or Both?

Primary hyperparathyroidism (PHPT) is the leading cause of hypercalcemia, and it is characterized by hypercalcemia and normal or inappropriately high levels of parathyroid hormone (PTH). Familial Hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant benign disease caused by inactivating genetic mutations in the calcium sensing receptor. Genetic analyses are expensive and not widely available, making the differential diagnosis challenging. A 77-year-old male with a past medical history of hypertension and chronic kidney disease was referred to the endocrinology clinic for evaluation of hypercalcemia. Routine tests showed total corrected calcium level of 10.5 mg/dL, hypophosphatemia 2.6 mg/dL and low 24h urinary calcium of 79 mg/24h with calcium creatinine clearance ratio (CCCR) of 0.008. 25 hydroxyvitamin D, 1,25 Dihydroxyvitamin D and magnesium were normal. PTH level was 33 pg/dL (normal 15-65 pg/dL). Patient had no hypercalcemic symptoms, history of nephrolithiasis, or bone fractures. No family history of hypercalcemia. Cancer screening and PTH related peptide were normal. He was not taking hydrochlorothiazide or lithium. Renal ultrasound showed no nephrolithiasis and DXA revealed no osteoporosis. Thyroid ultrasound showed a right 1.2cm thyroid nodule without visualization of parathyroid glands. Fine-needle aspiration biopsy (FNA) of the nodule with PTH washout was benign with PTH<10. The patient was diagnosed with FHH and was monitored semiannually. Four years after the initial evaluation, total corrected calcium level was elevated at 14 mg/dL with PTH of 378 despite 25 hydroxyvitamin D level >40, repeated urinary calcium 90 mg/24h, and CCCR 0.01. His renal function was unchanged. Parathyroid scintigraphy revealed increased uptake in the right upper thyroid lobe, and thyroid ultrasound revealed increased right thyroid nodule volume. Repeat FNA was benign, this time with a PTH washout >200. The patient opted against surgical consultation for parathyroidectomy. He was treated with cinacalcet 30 mg twice daily. The co-existence of FHH and PHPT is rare. The few reported cases include patients who maintained hypercalcemia after surgical treatment of PHPT. The best cost-effective test available is a CCCR < 0.02. Our patient had CCCR measured at different times with values < 0.01 and a PTH level that over time increased by 900%. The overlap of biochemical values in patients with FHH and PHPT contributes to the challenges in the differential diagnosis and highlights the importance of close follow up with a high degree of clinical suspicion.

ODP128 Unusually High Serum Calcium in a Patient with Familial Hypocalciuric Hypercalcemia

Abstract Background Familial hypocalciuric hypercalcemia (FHH) causes hypercalcemia via inactivating genetic mutations in the calcium-sensing receptors of parathyroid cells. FHH generally presents as a chronic, mild, asymptomatic hypercalcemia (&amp;lt;12mg/dL) with normal to moderately-elevated serum PTH levels. Low renal calcium/creatinine clearance ratio (CCCR) is the primary biochemical method of distinguishing FHH from primary hyperparathyroidism (PHPT). Most patients do not require treatment. Surgery is generally inappropriate as hypercalcemia persists after subtotal parathyroidectomy. Clinical Cases A 19-year-old male was admitted to the psychiatry service due to suicidal ideation. He denied taking any medications or supplements. Initial labs noted a corrected calcium of 11.6 mg/dL (ref. 8.6-10.2 mg/dL) and repeat labs verified hypercalcemia. Intact PTH level was 118.8 pg/mL (ref. 15-65 pg/mL). He denied muscle weakness, fatigue, joint pain, constipation, kidney stones, or increased thirst. After IV-fluid repletion, his calcium remained elevated. Serum calcium was measured as high as 13.1mg/dL, corrected calcium was as high as 12.5 mg/dL, and ionized calcium was 6.9 mg/dL (ref. 4.5-5.6 mg/dL). 24-hour urine calcium was 93.6 mg/24-hr and CCCR was 0.29%. A presumptive diagnosis of FHH was made, based on the elevated calcium and PTH, with CCCR &amp;lt; 1%. His mood improved and he was discharged by psychiatry without starting any medications. Initiation of cinacalcet was discussed, but the patient preferred not to start medication. During outpatient follow-up, he did not endorse depression or suicidal ideation. He was referred for genetic analysis to confirm FHH. Due to his significant hypercalcemia, PHPT remained in consideration. Evaluation for MEN syndromes was also performed, since these are associated with early onset PHPT. He knew limited family history. His mother had hypercalcemia and hyperparathyroidism, requiring surgery. He was uncertain of her age at diagnosis or whether she had genetic testing. He also reported a maternal half-brother with hypercalcemia and renal disease, requiring dialysis in his 30s. Repeat labs a few months after his admission showed corrected calcium of 12. 0 mg/dL, ionized calcium of 6.8 mg/dL, and CCCR of 0.30%. Thyroid ultrasound and Tc-99m Sestamibi scan did not show evidence of parathyroid adenoma(s). Genetic analysis showed a known heterozygous pathogenic variant in the CASR gene, consistent with FHH, type 1. The patient continued to deny any symptoms, including psychiatric, and did not start cinacalcet. Conclusion FHH can occasionally present with corrected calcium &amp;gt; 12 mg/dL and PTH &amp;gt;100. CCCR is essential to distinguish FHH from PHPT. Genetic analysis should be pursued in patients with a questionable diagnosis. PHPT is primarily managed with surgery, while FHH is generally not managed with surgery, so correct diagnosis is essential. Rarely, FHH patients may present with pancreatitis, chondrocalcinosis, muscle cramps, poor memory and psychosis. Calcimimetic therapy may be considered in select, symptomatic patients. Presentation: No date and time listed

ODP271 Primary Aldosteronism and Primary Hyperparathyroidism: A Report of Dual Endocrine Hypertension

Abstract Background Primary aldosteronism (PA) is one of the common causes of secondary hypertension. Primary hyperparathyroidism (PHPT) is a less common etiology of secondary hypertension. The concomitance of both PA and PHPT is very rare, with a possible bilateral positive feedback loop between the adrenal cortex and the parathyroid gland[1]. Clinical case: A 64-year-old female was referred to the endocrine clinic for secondary hypertension assessment. She was diagnosed with hypertension 30 years earlier, poorly controlled on three antihypertensive medications, nifedipine 90 mg daily, lisinopril 40 mg daily, and atenolol 50 mg daily. She started experiencing muscle cramps two years prior to the referral and was found to be hypokalemic on multiple occasions, with potassium ranging between 2.5 to 3 mmol/L. She also had multiple admissions to the emergency department for hypertensive urgencies within the last year. Family history was positive for poorly controlled hypertension in the patient's mother. Physical examination showed class I obesity with a BMI of 31, but otherwise unremarkable. Workup showed elevated aldosterone concentration of 38 ng/dl and suppressed renin concentration (&amp;lt;1 pg/ml) with an aldosterone/renin ratio of 38. Overnight dexamethasone suppression test was normal (cortisol of 1.5 mcg/dl, suppressed ACTH of 5.5 pg/ml, and appropriately elevated dexamethasone of 324 ng/dl). 24-hour urine metanephrine and normetanephrine levels were normal. Imaging showed bilateral adrenal adenomas of about 13-14 mm in widest diameter, with an average density of 10 Hounsfield units. Adrenal venous sampling revealed hyperfunctioning left adrenal with normal right adrenal. The left adrenal gland was removed laparoscopically, and blood pressure normalized postoperatively on the single antihypertensive agent (lisinopril). Interestingly, during the initial workup, the patient also had elevated calcium of 11 mg/dl and low phosphate at 2.5 mg/dl. In addition, parathyroid hormone (PTH) was elevated at 103 and 95 pg/ml on two occasions, with normal 25-OH vitamin D levels. 24-hoururine calcium was 240mg/dl, and creatinine in urine was 76.4 mg/dl. The calcium creatinine clearance ratio was 2.5%. Diagnosis of primary hyperparathyroidism was made. She had no renal stone, chronic kidney disease, or fractures, with a normal DEXA scan. There was no current indication for parathyroidectomy, and the patient continued to be followed up in the clinic. Clinical lesson: Recent evidence shows cross-talk between the adrenal cortex and parathyroid gland. Our patient may represent such a case, with concomitance of two rare endocrinopathies resulting in difficult-to-control hypertension [1,2]. Thus it is essential to investigate multiple etiologies of secondary hypertension. Reference: Brown JM, Vaidya A. Interactions between adrenal-regulatory and calcium-regulatory hormones in human health. Curr Opin Endocrinol Diabetes Obes . 2014;21(3): 193-201. doi: 10.1097/MED. 0000000000000062 Maniero C, Fassina A, Guzzardo V, et al. Primary hyperparathyroidism with concurrent primary aldosteronism. Hypertension. 2011 Sep;58(3): 341-6. doi: 10.1161/HYPERTENSIONAHA.111.173948. Epub 2011 Aug 8. PMID: 21825220. Presentation: No date and time listed

PSAT214 Management of Hyperparathyroidism Associated with Severe Hypercalcemia Presenting During Labour

Abstract Background Hypercalcemia is a rare pathology in pregnancy, and primary hyperparathyroidism (PHPT) has been described as the most common cause. No guidelines exist concerning treatment of PHPT during pregnancy, although most authors favor surgery as the treatment of choice during the second trimester. Nonetheless, management during the third trimester of pregnancy is challenging due to lack of current guidelines. Clinical case This 29-year pregnant female presenting at 38-weeks gestation with spontaneous rupture of membranes and admitted for latent labor. She was incidentally found to have hypercalcemia. Endocrinology was consulted for asymptomatic hypercalcemia in the third trimester of pregnancy. A diagnosis of primary hyperparathyroidism (PHPT) was suspected based on elevated serum calcium adjusted for albumin (16 mg/dL, normal range 8.5-10.5 mg/dL) and elevated PTH levels (121 pg/mL, normal range 14-65 pg/mL). In addition, parathyroid hormone related peptide (PTHrP) was less than 2.0 pmol/L (normal range &amp;lt;2.0 pmol/L), 25-hydroxy vitamin D was 35.6 ng/mL (normal range 30-50 ng/mL) and urine calcium/creatinine clearance ratio (CCCR) level was 0.02 (&amp;lt;0.01 familial hypocalciuric hypercalcemia is likely, &amp;gt;0.02 PHPT is likely) further supporting the diagnosis of PHPT. No parathyroid imaging was performed as there was no plan for surgical intervention at that time. Conservative management was initiated with aggressive oral and intravenous fluid rehydration. The patient subsequently had an uneventful vaginal delivery with the arrival of a healthy newborn eight hours after treatment was initiated. With continued IV and oral hydration, corrected calcium fell by a total of 5 mg/dL. Given an uneventful postpartum course as well as improving calcium levels with hydration, the patient was discharged on day three of hospitalization with a plan for outpatient endocrinology follow up in preparation for future parathyroidectomy. Conclusion There is no previous case report describing severe hypercalcemia in the third trimester of pregnancy managed conservatively solely with hydration. Calcitonin has been attempted but use is limited secondary to tachyphylaxis. Additionally, some case reports suggest cinacalcet use but this drug crosses the placenta. In this unique and complicated case of severe hypercalcemia diagnosed in the third trimester of pregnancy, conservative management with intensive oral and intravenous fluid rehydration was safe and effective in lowering serum calcium levels and therefore conducive to a positive pregnancy outcome. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

A case of familial hypocalciuric hypercalcemia type 1 due to CASR p.Pro55Leu mutation

BackgroundFamilial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disease, which requires differential diagnosis from relatively common primary hyperparathyroidism (PHPT) in order to avoid unnecessary surgery.Case presentationA 16-year-old female had been followed by the department of psychosomatic medicine at our institution. Throughout the follow-up period, her plasma calcium levels were high, plasma Pi levels were relatively low, and plasma intact PTH was relatively high. She was referred to our department to determine the cause of her hypercalcemia. Her 24 h urinary calcium excretion was as low as 100 mg/day, and calcium creatinine clearance ratio was below 0.01. Moreover, she had a family history of hypercalcemia (proband, her brother, and her father). The genetic testing for her family revealed that she, her brother, and her father were definitively diagnosed with FHH type 1 due to the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu).ConclusionWe experienced a 16-year-old female with FHH, in whom genetic testing identified the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu) as pathogenic, permitting a definitive diagnosis of FHH type 1. The genetic testing for calcium sensing receptor is beneficial to distinguish asymptomatic primary hyperparathyroidism from FHH.

Persistent hypercalcemia with similar familial Hypocalciuric hypercalcemia features: a case report and literature review

BackgroundPrimary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcemia (FHH) are the most important differential diagnosis of parathyroid hormone (PTH)-dependent hypercalcemia. The clinical features of FHH and PHPT can overlap in some cases. Therefore, these two diseases must be differentiated to prevent unnecessary parathyroidectomy. Here, we present a case that was not entirely matched with any of the known differential diagnoses of hypercalcemia.Case presentationA 19-year-old girl with no history of any disease presented with persistent hypercalcemia without any specific musculoskeletal complaint. We found persistent hypercalcemia in her routine laboratory data from 3 years ago; while no data was available during the childhood period. Her dietary calcium intake was normal. She did not mention any history of renal stone, bone fracture as well as family history of hypercalcemia. Biochemical features showed normal values of serum creatinine, high normal serum calcium (range, 10.3–11.3 mg/dL; (normal range: 8.8–10.4)), and non-suppressed PTH levels (range, 37.2–58.1 pg/mL; (normal range: 10–65)). Serum 25 OH vitamin D level at the first visit was 16.1 ng/mL that treated by vitamin D supplementation. Since then, all 25 OH vitamin D levels were in the acceptable range. After correction of vitamin D deficiency during the follow-up period the calcium creatinine clearance ratio(s) (CCCR) were calculated in the range of 0.009 to 0.014 (means below 1%). The clinical and laboratory data indicate more FHH rather than PHPT. Genetic studies were negative for the common genes associated with FHH (CASR, GNA11, and AP2S1 genes) and multiple endocrine neoplasia type1 (MEN1). On the other hand, no evidence of autoimmunity was found in her to support an autoimmune FHH-like syndrome. Hence, the case did not match completely to any diagnosis of FHH and PHPT, so we decided to follow her.ConclusionWe presented a patient with FHH phenotype whose common genetic tests were negative. Further research is needed to ascertain other causes leading to similar manifestations.

A novel CASR variant in a family with familial hypocalciuric hypercalcaemia and primary hyperparathyroidism.

SummaryFamilial hypocalciuric hypercalcaemia (FHH) is a dominantly inherited, lifelong benign disorder characterised by asymptomatic hypercalcaemia, relative hypocalciuria and variable parathyroid hormone levels. It is caused by loss-of-function pathogenic variants in the calcium-sensing receptor (CASR) gene. Primary hyperparathyroidism (PHPT) is characterised by variable hypercalcaemia in the context of non-suppressed parathyroid hormone levels. Unlike patients with FHH, patients with severe hypercalcaemia due to PHPT are usually symptomatic and are at risk of end-organ damage affecting the kidneys, bone, heart, gastrointestinal system and CNS. Surgical resection of the offending parathyroid gland(s) is the treatment of choice for PHPT, while dietary adjustment and reassurance is the mainstay of management for patients with FHH. The occurrence of both FHH and primary hyperparathyroidism (PHPT) in the same patient has been described. We report an interesting case of FHH due to a novel CASR variant confirmed in a mother and her two daughters and the possible coexistence of FHH and PHPT in the mother, highlighting the challenges involved in diagnosis and management.Learning points:Familial hypocalciuric hypercalcaemia (FHH) and primary hyperparathyroidism (PHPT) can coexist in the same patient.Urinary calcium creatinine clearance ratio can play a role in distinguishing between PHPT and FHH.Genetic testing should be considered in managing patients with PHPT and FHH where the benefit may extend to the wider family.Family segregation studies can play an important role in the reclassification of variants of uncertain significance.Parathyroidectomy has no benefit in patients with FHH and therefore, it is important to exclude FHH prior to considering surgery.For patients with coexisting FHH and PHPT, parathyroidectomy will reduce the risk of complications from the severe hypercalcaemia associated with PHPT.

Think twice: a rare calcium sensing receptor mutation and a new diagnosis of familial hypocalciuric hypercalcaemia.

SummaryDistinguishing primary hyperparathyroidism (PHPT) from familial hypocalciuric hypercalcaemia (FHH) can be challenging. Currently, 24-h urinary calcium is used to differentiate between the two conditions in vitamin D replete patients, with urinary calcium creatinine clearance ratio (UCCR) <0.01 suggestive of FHH and >0.02 supportive of PHPT. A 26-year-old Caucasian gentleman presented with recurrent mild hypercalcaemia and inappropriately normal parathyroid hormone (PTH) following previous parathyroidectomy 3 years prior. He had symptoms of fatigue and light-headedness. He did not have any other symptoms of hypercalcaemia. His previous evaluation appeared to be consistent with PHPT as evidenced by hypercalcaemia with inappropriately normal PTH and UCCR of 0.0118 (borderline low using guidelines of >0.01 consistent with PHPT). He underwent parathyroidectomy and three parathyroid glands were removed. His calcium briefly normalised after surgery, but rose again to pre-surgery levels within 3 months. Subsequently, he presented to our centre and repeated investigations showed 24-h urinary calcium of 4.6 mmol/day and UCCR of 0.0081 which prompted assessment for FHH. His calcium-sensing receptor (CASR) gene was sequenced and a rare inactivating variant was detected. This variant was described once previously in the literature. His mother was also confirmed to have mild hypercalcaemia with hypocalciuria and, on further enquiry, had the same CASR variant. The CASR variant was classified as likely pathogenic and is consistent with the diagnosis of FHH. This case highlights the challenges in differentiating FHH from PHPT. Accurate diagnosis is vital to prevent unnecessary surgical intervention in the FHH population and is not always straightforward.Learning points:Distinguishing FHH from PHPT with co-existing vitamin D deficiency is difficult as this can mimic FHH. Therefore, ensure patients are vitamin D replete prior to performing 24-h urinary calcium collection.Individuals with borderline UCCR could have either FHH or PHPT. Consider performing CASR gene sequencing for UCCR between 0.01 and 0.02.Parathyroid imaging is not required for making the diagnosis of PHPT. It is performed when surgery is considered after confirming the diagnosis of PHPT.

Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort.

Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism-jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost-effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR>0.02 presenting (i) <35years of age, or (ii) <45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR<0.02. A retrospective review of patients referred for genetic testing over a 4year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next-generation sequencing of the following genes; MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1 in NHS-accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort. A total of 121 patients were included in this study (92 female) with a mean age of 41years (SD 17). A pathogenic germline variant was identified in 16% (n=19). A pathogenic variant was identified in the PHPTH genes CDC73 in a single patient and MEN1 in six patients (6% of total), in the FHH genes, CASR in 11 patients and AP2S1 in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re-classification of four of the variants, with two VUS's in the CASR gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (P=.0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified CASR pathogenic variant versus those without (P=.0001) was demonstrated in this study. Thirty-three patients were aged over 50years and the diagnostic rate of a pathogenic variant was 15.1% in those patients >50years of age compared to 15.9% in those <50years. Five patients >50years and with a CCCR of <0.01, were diagnosed with a pathogenic variant in CASR. Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re-evaluating VUS's in order to inform patient management and enable appropriate genetic counselling. Finally, this study has demonstrated the need to consider genetic testing for PHPTH in patients of any age, particularly those with additional risk factors.

P1833HOW DO WE DEFINE HYPERCALCIURIA IN 24 HR URINE?

Abstract Background and Aims Hypercalciuria can clinically present itself as gross hematuria, microscopic hematuria, dysuria or abdominal pain without urinary lithiasis. It is also one of main metabolic causes of urinary lithiasis in children. In Nelson pediatrics, hypercalciuria is defined by a 24 -hour urine for calcium excretion&amp;gt;4mg/kg/day. A spot urine calcium creatinine ratio of &amp;gt;0.2, is considered abnormal in older children and adolescents. Both of them are not a standardized detect in children. Fasting and postprandial spot urinary calcium creatinine ratios may not detect hypercalciuria so accurately, that a 24-hour urine is preferred. In addition, 24hr urine collection is frequently under- or over-collected, which leads to an inadequate sampling hard to pick up which one the more accurate calculating methodology for the hypercalciuria detection with 24hr urine is. In this study, we evaluated the comparisons of 24 hr urine calcium creatinine ratio(Ca/Cr), 24hr urine calcium excretion(mg/kg)(Ca/Kg) and CCCR in school aged children. 24-hour urine for calcium excretion&amp;gt;4mg/kg/day 24-hour urine calcium creatinine ratio of &amp;gt;0.2 Calcium creatinine clearance ratio(CCCR); (24-hour U-calcium/P-total calcium) / (24-hour U-creatinine/P-creatinine), as known as fractional excretion of calcium(FeCa) Method We enrolled 250 normal kidney function patients who’s age is 7 to 18 year, was able to collect 24 hr urine in a single hospital unit. We conducted 24 hr urine collection, serum calcium creatinine levels on the same day from January 2007 to December 2019. We analyze of each values. We used SPSS. 25.0 Results

A tale of two siblings; the importance of urine calcium creatinine clearance ratio

A tale of two siblings; the importance of urine calcium creatinine clearance ratio

Expanding the spectrum of genetic variants in the calcium-sensing receptor (CASR) gene in hypercalcemic individuals.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominantly inherited disorder with overlapping biochemistry profile with primary hyperparathyroidism (PHPT), making the correct diagnosis a challenge. The objective of the study was to evaluate the results of the clinical work-up of a large group of hypercalcemic individuals. Cross-sectional study. Patients undergoing clinical work-up of hypercalcemia. Molecular genetic analysis of the CASR gene and exon 2 of the AP2S1 gene. Plasma levels of ionized calcium and PTH as well as calcium creatinine clearance ratio (CCCR). A rare CASR variant was identified in 38 of 624 index patients (6.1%). A total of 18 CASR variants identified in this study were novel. No variants were identified in exon 2 of the AP2S1 gene. The majority of the variants (N=16) were classified as likely pathogenic. The level of plasma calcium, plasma PTH and the CCCR was not affected by the type of variant (ie nonsense vs missense) (all P-values >.05). The CCCR was found to be significantly lower for variants in the transmembrane domain compared with variants located in the extracellular domain (P<.05). Plasma levels of calcium and PTH were not associated with the location of the variant (P>.05). We expanded the spectrum of CASR variants in hypercalcemia with 18 novel variants, and suggest that the location of the CASR variant may affect calcium excretion as determined by the CCCR.

Calcium-Creatinine Clearance Ratio is not Helpful in Differentiating Primary Hyperparathyroidism from Familial Hypercalcemic Hypocalciuria: A Study of 1,000 Patients

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 (0.01-0.02). The aim of this study is to assess the relevance of CCCR in a modern series of patients with surgically managed pHPT. 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. 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 0.01-0.02 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). 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.

Familial Hypocalciuric Hypercalcaemia (FHH): A Case Report

Familial hypocalciuric hypercalcaemia (FHH) is a rare genetic autosomal dominant disorder, with 3 variants described. An inactivating mutation in the calcium sensor receptor (CASR) gene causes the subtype 1, which represents 65% of the cases. Inactivation of Ca-sensing receptors (CaSR) can also lead to hypercalcemia associated with increased parathyroid hormone (PTH) secretion.[1]&#x0D; It is characterised by causes mild asymptomatic hypercalcemia[2] and hypocalciuria with normal or elevated PTH. FHH is generally asymptomatic and treatment is not needed. Differential diagnosis with primary hyperparathyroidism (PHPT) is crucial and based on calcium-creatinine clearance ratio (CCCR), which, when under 0.02 points to the diagnosis of FHH.[3] Genetic test is necessary for confirmation.[4]

Presentation, diagnostic assessment and surgical outcomes in primary hyperparathyroidism: a single centre's experience.

ObjectivePrimary hyperparathyroidism (PHPT) is a common reason for referral to endocrinology but the evidence base guiding assessment is limited. We evaluated the clinical presentation, assessment and subsequent management in PHPT.DesignRetrospective cohort study.PatientsPHPT assessed between 2006 and 2014 (n = 611) in a university hospital.MeasurementsSymptoms, clinical features, biochemistry, neck radiology and surgical outcomes.ResultsFatigue (23.8%), polyuria (15.6%) and polydipsia (14.9%) were associated with PHPT biochemistry. Bone fracture was present in 16.4% but was not associated with biochemistry. A history of nephrolithiasis (10.0%) was associated only with younger age (P = 0.006) and male gender (P = 0.037). Thiazide diuretic discontinuation was not associated with any subsequent change in calcium (P = 0.514). Urine calcium creatinine clearance ratio (CCCR) was <0.01 in 18.2% of patients with confirmed PHPT. Older age (P < 0.001) and lower PTH (P = 0.043) were associated with failure to locate an adenoma on ultrasound (44.0% of scans). When an adenoma was identified on ultrasound the lateralisation was correct in 94.5%. Non-curative surgery occurred in 8.2% and was greater in those requiring more than one neck imaging modality (OR 2.42, P = 0.035).ConclusionsClinical features associated with PHPT are not strongly related to biochemistry. Thiazide cessation does not appear to attenuate hypercalcaemia. PHPT remains the likeliest diagnosis in the presence of low CCCR. Ultrasound is highly discriminant when an adenoma is identified but surgical failure is more likely when more than one imaging modality is required.

Familial Hypocalciuric Hypocalcemia: Pitfalls and Implications for the Parathyroid Surgeon

Objectives: Modifications to the Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism (2008) eliminated the recommendation for routine 24-hour urine calcium collection. Surgeons are now seeing an increasing number of referrals for surgical evaluation of hyperparathyroidism without this test that can help differentiate between primary hyperparathyroidism (PHPT), a surgical disease and familial hypocalciuric hypercalcemia (FHH), a medical disease. We will review the characteristics of our cohort of FHH patients and describe findings that should raise suspicion for this diagnosis. Methods: Subjects were evaluated at Oregon Health and Science University from 2011 to 2013. Retrospective chart review was performed of a cohort of 11 patients with FHH confirmed by calcium-creatinine clearance ratio (CCCR) and/or CASR gene mutation. Results: All patients had CCCR of &lt;0.015, In 8 patients imaging studies could not localize an adenoma, and 6 patients reported a family history of hypercalcemia. Conclusions: FHH is a benign, autosomal dominantly inherited disorder from heterozygous mutations in the calcium sensing receptor gene, resulting in lifelong hypercalcemia and relative hypocalciuria. Suspicion for FHH is raised with the presence of long-term hypercalcemia, a positive family history of hypercalcemia, and inability to localize an adenoma on imaging studies. Further evaluation is indicated including a 24-hour urine calculation of the calcium creatinine clearance ratio (CCCR). Significant clinical overlap with PHPT presents certain diagnostic challenges. Additionally, we report novel CASR mutations clinically associated with FHH, highlighting the broad spectrum of this disorder. Heightened awareness of the diagnostic criteria for FHH should decrease the incidence of unnecessary surgeries performed.

Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric patients as differential diagnosis from primary hyperparathyroidism: detection of two novel inactivating mutations in an Italian population.

Inactivating mutations of the calcium-sensing receptor (CaSR), of the G-protein subunit α11 (GNA11) and of the adaptor-related protein complex 2, sigma 1 subunit (AP2S1) genes are responsible for familial hypocalciuric hypercalcaemia (FHH). The aim of this study was to analyse prevalence and pathogenicity of CaSR, GNA11 and AP2S1 mutations in patients with an FHH phenotype and to compare them with a sample of patients with primary hyperparathyroidism (PHPT) in order to identify the most useful laboratory parameter for a differential diagnosis. Patients with an FHH phenotype were studied with polymerase chain reaction amplification and direct sequencing of the entire CaSR, GNA11 and AP2S1 coding sequences. Novel mutations were introduced in a Myc-tagged human wild-type (WT) CaSR cDNA-expressing vector, and functional assay was performed on human embryonic kidney cells evaluating expression and function of mutated proteins. Among 16 FHH patients, none had an inactivating GNA11 or AP2S1 mutation while 3 (18.8%) carried a CaSR mutation and 10 (62.5%) at least one CaSR polymorphism. Within the latter group, 7 of 10 patients had more than one polymorphism (4.1 ± 2.1 per patient). Two novel CaSR mutations [c.2120A>T (E707V) and c.2320G>A (G774S)] were identified: the E707V mutation prevented CaSR expression (western blot), whereas the G774S mutation determined a reduced receptor sensitivity to calcium (IP3 assay). PHPT patients showed significantly (P < 0.001) higher serum calcium, parathyroid hormone, urinary calcium and calcium-creatinine clearance ratio (CCCR) and significantly lower serum phosphate than FHH ones. FHH should be clearly differentiated by PHPT to avoid unnecessary surgery: CCCR could be a useful screening tool while genetic analysis should include the two novel CaSR mutations herein described. The role of multiple polymorphisms deserves further investigation in patients with an FHH phenotype.

Lithium-induced parathyroid dysfunction: A new case

Lithium salts are widely used in psychiatric practice and are known to induce thyroid dysfunction. Lithium-induced parathyroid dysfunction is rare. We are reporting a case of hyperparathyroidism in a 28-year-old female patient who was on lithium carbonate for 2 years, when she developed osteopenia and girdle girdle-type muscle weakness. Biochemical parameters showed hyperparathyroidism with shift of calcium creatinine clearance ratio to 0.013, indicating an error in threshold of calcium sensing receptor. The patient eventually required parathyroidectomy and the histology of the gland showed atypical features.

Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow‐up study on methods

Familial hypocalciuric hypercalcaemia (FHH) must be differentiated from primary hyperparathyroidism (PHPT) because prognosis and treatment differ. In daily practice this discrimination is often based on the renal calcium excretion or the calcium/creatinine clearance ratio (CCCR). However, the diagnostic performance of these variables is poorly documented. To appraise the power of various simple biochemical variables to differentiate between FHH and PHPT using calcium sensing receptor (CASR) gene analysis and histopathological findings as gold standards. Follow-up approach (direct design). We included 54 FHH patients (17 males and 37 females, aged 18-75 years) with clinically significant mutations in the CASR gene and 97 hypercalcaemic patients with histologically verified PHPT (17 males and 80 females, aged 19-86 years). All PHPT patients became normocalcaemic following successful neck exploration. Based on receiver operating characteristic (ROC) curve analysis, the CCCR was only marginally better, as judged by the area under curve (AUC = 0.923 +/- 0.021 (SE)), than the 24-h calcium/creatinine excretion ratio (AUC = 0.903 +/- 0.027) and the 24-h calcium excretion (AUC = 0.876 +/- 0.029). However, overlap performance analysis disclosed that the CCCR included fewer patients with PHPT together with the FHH patients than the other two variables at different cut-off points. Based on the ROC curve, the optimal cut-off point for diagnosing FHH using CCCR was < 0.0115, which yielded a diagnostic specificity of 0.88 and a sensitivity of 0.80. Overlap analysis revealed that a cut-off point for CCCR at < 0.020 would sample 98% (53/54) of all patients with FHH and include 35% (34/97) of the PHPT patients. Our results support the use of the CCCR as an initial screening test for FHH. We suggest a two-step diagnostic procedure, where the first step is based on the CCCR with a cut-off at < 0.020, and the second step is CASR gene analysis in patients with FHH or PHPT.