25-OH Vitamin Research Articles

Severe Osteomalacia and Fractures Secondary to Vitamin D Deficiency

Background: Vitamin D deficiency is a common entity among the elderly. Low vitamin D levels can lead to poor bone mineralization, in addition to elevations in PTH levels with resultant increases in bone turnover. However, severe Vitamin D deficiency causing osteomalacia has become uncommon in the United States due to increased screening and treatment. Vitamin D supplementation is a mainstay of therapy for osteoporosis, yet its effect on bone density is generally thought to be modest. We present here an extreme case of vitamin D deficiency leading to severe secondary hyperparathyroidism and bone demineralization, with excellent response to supplementation. Clinical Case: Patient was a 73-year-old woman with hypertension who presented to the ER with acute on chronic back and lower extremity pain. She had these pains for about a year, but they had worsened over the last 4 days. She had been homebound for the past 1–2 years due to severe pain while ambulating, reported a five-inch loss of height and 50 pounds weight loss, and maintained a vegan diet. She had not had medical care in 15 years. Imaging studies demonstrated a displaced left femoral neck fracture, a nondisplaced right femoral neck fracture, multilevel thoracolumbar compression fractures, and a nondisplaced right scapular fracture. Blood tests revealed normal renal function, calcium 8.6mg/dL (nl 8.5–10.5), phosphorus 2.6mg/dL (nl 2.5–4.5), and alkaline phosphatase 2,821U/L (nl 45–164). Secondary osteoporosis workup was negative for hypercalciuria or multiple myeloma, but was notable for a PTH level of 2,190 pg/mL (nl 10–65) and 25-OH Vitamin D level of <5ng/mL (nl >30). C-telopeptide was measured at 3,346 pg/mL (nl <1000) and osteocalcin >300ng/mL (nl 8–32). DEXA scan showed T-scores of -4.2 at the lumbar spine and -6.8 at the distal forearm. She was started on high-dose vitamin D supplementation, with serum Vitamin D level rising to 42.1ng/mL after 6 months of treatment. This corresponded to a decrease in PTH to 141.1pg/mL and alkaline phosphatase to 375U/L. Repeat DEXA two years later showed 52.8% increase in bone mineral density at the lumbar spine, and 27.1% increase at the forearm. The patient’s body pains have significantly improved and she is now ambulatory again. Conclusions: Vitamin D deficiency is an uncommon cause of severe bone demineralization in the United States. However, in certain high-risk populations, it can present with debilitating osteomalacia and numerous pathologic fractures. Even in cases of osteoporosis with severe PTH elevation, Vitamin D deficiency must be ruled out as a potential secondary etiology, as it can be easily treated with potentially dramatic response.

An Interesting Case of Isolated Bone Marrow Sarcoidosis

Introduction: About 30% cases of sarcoidosis have extrapulmonary manifestations but only 7% of patients present without any lung involvement. Among those 7%, most of the patients have manifestations on the skin but isolated bone marrow sarcoidosis has not been commonly reported. This case represents an unusual manifestation of isolated bone marrow sarcoidosis presenting with very high calcium levels. Case Presentation: A 58-year-old female presented to us with fatigue, poor appetite, and nausea. She did not report any weight changes. Her cancer screening was up to date. On examination, she appeared dehydrated. No neck swelling was appreciated. Cardiac, respiratory, abdominal, and neurological examinations were normal. Complete blood count showed hemoglobin of 10.6 mg/dL, white blood cell count of 3.8 k/dL, and platelet count of 87 x109/L. Metabolic panel revealed hypercalcemia with corrected calcium levels as high as 12.6 mg/dL. Ionized calcium was 8.1 mg/dL (normal 4.8 - 5.6). Her parathyroid hormone (PTH) level was elevated up to 64.6 mg/dL and then further increased to 134.3 mg/dL. A 24-hour urinary calcium level was normal. 1, 25-dihydroxy (1,25-OH) and 25-OH vitamin D levels were 97 mg/dL (normal 18–72) and 31.2 mg/dL, respectively. Serum protein electrophoresis and light chain analysis were normal. Hyperparathyroidism was suggested as a cause of hypercalcemia. Ultrasound of the neck and sestamibi scan showed a right lower pole parathyroid adenoma. Paraneoplastic hypercalcemia was also one of the differentials. Parathyroid hormone related peptide (PTHrP) was 9 pg/mL (normal 14 - 27). Colonoscopy was normal. Computerized tomography showed normal lungs, liver and spleen. No masses and lymphadenopathy was seen. A bone marrow biopsy was done for pancytopenia. Patient underwent parathyroid adenoma removal followed by a drop in serum calcium level (8.2 mg/dL). Patient was discharged on calcium carbonate and vitamin D tablets. Upon outpatient follow-up, calcium level started to rise again up to 9.8 mg/dL. Despite discontinuation of supplemental calcium and vitamin D, calcium continued to uptrend (11.5 mg/dL 4 weeks later). Angiotensin converting enzyme (ACE) level came back as high as 129 (normal level < 40 mcg/L). Meanwhile, the bone marrow biopsy results showed that 40% of bone marrow was occupied by non-caseating granulomas suggesting sarcoidosis. Patient was started on steroids for isolated bone marrow sarcoidosis, and eventually her serum calcium level normalized. Conclusion: An isolated bone marrow sarcoidosis is an extremely rare manifestation of extrapulmonary sarcoidosis. It can present with pancytopenia and should be sought in patients with persistent hypercalcemia. In addition, our case was challenging due to the presence of a concurrent hyperparathyroidism which was initially thought to be the only explanation of our patient’s hypercalcemia.

Prolonged Hypercalcemia After Recovery From Severe Rhabdomyolysis and Acute Renal Failure

Abstract Introduction: Rhabdomyolysis is characterized by elevated creatine kinase, electrolyte abnormalities and acute renal failure. After the initial hypocalcemic phase, serum calcium levels can normalize or become significantly elevated during the recovery phase. We report a case of persistent hypercalcemia during the recovery phase of rhabdomyolysis-induced acute renal failure. Case Description: A 26-year old woman with Cornelia de Lange syndrome initially presented with septic shock, complicated by severe rhabdomyolysis and acute renal failure requiring hemodialysis. On admission, creatine kinase level was &amp;gt;30,500 U/L [29–168], BUN 95 mg/dL [6–22], Creatinine 3.39 mg/dL [0.57–1.11], and Corrected Calcium 7.1 mg/dL [8.6–10.2]. Approximately 1 month after admission, the patient developed hypercalcemia with corrected calcium values ranging from 10.4 to 14.5 mg/dL with PTH 10.5 pg/mL [8.7–77.1] and 1,25-Dihydroxyvitamin D and 25-OH Vitamin D levels &amp;lt;8.0 pg/dL [18–78] and 21.20 ng/mL [30–80], respectively. Her renal function improved and dialysis was discontinued seven weeks after initial presentation, although her GFR remained impaired (22 mL/min/BSA). She remained hypercalcemic and was treated with intermittent doses of Calcitonin when the level rose above 12.0 mg/dL. Spot urinary calcium to creatinine ratio was low at 0.13. Improvement in her calcium was seen with a level of 10.8 mg/dL eleven weeks after she was initially noted to be hypercalcemic and she was able to be discharged. Two weeks after discharge, an outpatient calcium improved further to 10.4 mg/dL. Discussion: Rhabdomyolysis is a clinical syndrome that results from severe muscle damage with release of the breakdown products from injured muscle cells leading to acute renal failure and electrolyte abnormalities. The initial hypocalcemic phase is due to entry of calcium into damaged myocytes and deposition of calcium salts in damaged muscle. After recovery, most patients have normalization of calcium levels. However, in up to one-third of patients, a rebound hypercalcemia can ensue. The proposed mechanism is massive muscle calcium release during renal recovery. In the cases reported, the hypercalcemia phase resolves by an average of 8 days with the longest reported recovery being 3.5 months. We report a case of prolonged hypercalcemia in the setting of continued renal impairment. It appears that the patient’s low GFR impaired urinary calcium excretion resulting in persistent hypercalcemia which eventually resolved over time with some improvement in renal function. Other case reports have described treatment with IV fluids, Calcitonin, Pamidronate and hemodialysis, although the efficacy of these interventions is unclear. Rhabdomyolysis is an under-recognized cause of hypercalcemia. Our case highlights the potential for prolonged hypercalcemia after recovery from rhabdomyolysis in the setting of renal impairment.

Experience With Anti-Sclerostin Antibody for Osteoporosis Patient With End-Stage Renal Disease on Hemodialysis

Background: Romosozumab is a sclerostin inhibitor indicated for treatment of postmenopausal osteoporosis. Sclerostin inhibits Wnt/Beta-catenin signaling pathway. When sclerostin is inhibited, stimulation of this pathway leads to increased bone formation and production of osteoprotegerin, which also decreases bone resorption. Patients with chronic kidney disease (CKD) demonstrate increased levels of sclerostin that negatively correlates with the rate of bone formation; however, data is lacking for use of romosozumab in this patient population. The report herein details the experience of use of romosozumab in a patient with end-stage renal disease (ESRD) on hemodialysis (HD). Clinical Case: A 37-year-old old African American male was referred after multiple rib fractures and severe non-traumatic T8 compression fracture with nerve compression. His past medical history includes lupus nephritis and cerebritis, ESRD on HD since age 22 status post (s/p) failed renal transplant, and tertiary hyperparathyroidism complicated with fracture in iliac brown tumor and mediastinal parathyromatosis s/p three parathyroid surgeries. Bone mineral density by DXA (g/cm2, Z-score) were as follows: lumbar spine (0.700, -4.0) femoral neck (0.676, -3.8), total hip (0.628,-4.0), 1/3 radius(0.443,-6.2). No prior exposure to antiresorptive or osteoanabolic agents. Pertinent labs included serum calcium 8.5 mg/dL (nl 8.9–10.3 mg/dl), albumin 4.2 g/dL, alkaline phosphatase 319 U/L (nl 38–126), Phosphorus 3.1 mg/dL (2.4–4.7), Creatinine 5.62 mg/dl, 25-OH Vitamin D 31 ng/mL (nl 25 - 80), intact parathyroid hormone 17.9 pmol/L (nl 1.6–6.9). Patient was in excruciating pain and not a surgical candidate due to poor bone quality. Osteoanabolic therapy was recommended given the severity of osteoporosis; however, teriparatide and abaloparaitde were contraindicated given comorbidities. The patient was offered off-label use of Romosozumab with clear understanding that the drug is not approved for this indication and safety/efficacy data in ESRD is not known. The boxed warning regarding increased risk of stroke, myocardial infarction and death were discussed and patient was willing to proceed. Repeat DXA after eleven monthly doses of Romosozumab resulted in a remarkable improvement in bone mineral density at all sites: lumbar spine (+47%), femoral neck (+41%), total hip (+28%), 1/3 radius (+20%). Patient tolerated medication with no side effects or fractures. Serum calcium was monitored prior to initiation and before every dose. No doses were held due to abnormal laboratory values or side effects. Conclusion: This case report summarizes successful experience with the use of Romosozumab in one patient with ESRD on HD with favorable outcomes.

Extreme Secretion of PTHrP From a Pancreatic Neuroendocrine Tumor, A Shift From Severe Hypercalcemia to Hypocalcemia

Background: PTHrP-secreting pancreatic neuroendocrine tumors (PNET) are a recognized cause of malignancy associated hypercalcemia. Herein, we report a case of severe hypercalcemia due to an extreme elevation of PTHrP from a PNET, where after treatment of the hypercalcemia, symptomatic hypocalcemia occurred. Clinical Case: A 59 year-old-woman with a recurrent PNET with liver metastases undergoing an evaluation for multi-visceral transplant presented with acute confusion, nausea and vomiting. Diagnostic testing identified an extreme elevation of total calcium (Ca) [>20.1 mg/dL (8.5 - 10.2)] from two different samples [serum albumin 4.1 g/dL (3.9 - 4.9)]. The total Ca level one month earlier was 8.3 mg/dL with a serum albumin of 3.1 g/dL. Total Ca measurements were performed with the Ca Gen.2 assay on a cobas c702 chemistry analyzer (Roche Diagnostics). Results greater than the analytical measurement range (0.8 – 20.1 mg/dL) were diluted with saline and confirmed (22.6 mg/dL). A Radiometer ABL 800 Flex blood gas analyzer was used to determine the ionized Ca concentration [2.94 mmol/L (1.08 - 1.30)]. Upon presentation the serum creatinine (Cr) was 2.07 mg/dL (0.58 - 0.96); eGFR utilizing the MDRD equation 24 mL/min/1.73m2; baseline serum Cr 0.78 mg/dL. Her serum 25-OH vitamin D was 31 ng/mL (31.0 - 80.0), PTH 12 pg/mL (15 - 65), phosphate 4.3 mg/dL (2.7 - 4.8) and 1, 25-OH vitamin D 39.1 (15.0 - 60.0). PTHrP measurements were performed by ARUP Laboratories via liquid chromatography tandem mass spectrometry (LC-MS/MS) and resulted in a reported value of >2500 pmol/L (0.0 - 3.4). Her symptoms resolved and the corrected Ca gradually decreased to 8 mg/dL after treatment with IV fluids, calcitonin 200 units sc every 12 hours for 48 hours, 60 mg IV pamidronate, and five sessions of hemodialysis. Within thirteen days of receiving pamidronate, her corrected Ca slowly increased to 12mg/dL; thus, she received a single dose of 120 mg sc denosumab. Nine days later, the patient developed symptomatic hypocalcemia (7.3 mg/dL) manifested by paresthesia in the hands and feet and perioral numbness. She then received multiple doses of oral and intravenous Ca along with 50,000 units of oral ergocalciferol twice weekly. The corrected Ca normalized (8.1 mg/dL) and symptoms resolved. The patient was discharged with plans for future treatment of her underlying malignancy. Conclusion: This is the first report of a PNET producing an extreme elevation of PTHrP of higher than 2500 pmol/L, resulting in a concordant extreme elevation of total calcium within a month of documented normocalcemia. Treatment of hypercalcemia with denosumab may result in the development of hypocalcemia requiring treatment.

Denosumab Induced Severe Prolonged Hypocalcemia in Metastatic Prostate Cancer

Background: Denosumab is a RANK-l inhibitor that, in addition to the treatment of osteoporosis, is used in patients with advanced cancer and metastatic bone disease to prevent skeletal-related events. Although denosumab is generally safe and effective, it can cause hypocalcemia which in some patients can be severe and life threatening. We present a case of severe prolonged hypocalcemia after a single dose of denosumab in a patient with metastatic prostate cancer. Case: A 78-year-old male with a past medical history of stage 4 prostate cancer on antiandrogen treatment with GnRH antagonist presented with severe hypocalcemia. Physical exam revealed a blood pressure 125/80 mm Hg, pulse 115 per min and weight 135 lb with negative Chvostek’s and Trousseau’s signs. The electrocardiogram showed supraventricular tachycardia with prolonged QTc interval of 503 ms (<430 ms). Labs showed serum calcium 4.9mg/dL (8.5–10.5), albumin 2.5g/dL (3.6–5.1), corrected calcium 5.7 mg/dL, ionized serum calcium 0.64mmol/L (1.05–1.3), creatinine 1.10mg/dL (0.7–1.2), eGFR >60, phosphorus 2.0mg/dL (2.5–4.5), magnesium 1.9 mg/dL (1.6–2.6), 25-OH vitamin D 29.7 ng/mL (30–100), 1,25 dihydroxy vitamin D 174 pg/mL (18–64), iPTH 244.0 pg/mL (11–68) and PSA 1860 ng/mL. Three weeks prior to presentation, the patient received 120 mg of subcutaneous denosumab. Pre-treatment serum calcium was 9.2 mg/dL (8.5–10.5), and Tc-99m bone scan showed multiple osteoblastic osseous metastatic lesions involving both axial and appendicular skeleton. The patient was diagnosed with denosumab-induced severe hypocalcemia and started on intravenous (IV) calcium gluconate infusion, oral phosphate 250 mg twice daily, and ergocalciferol 50,000 IU twice weekly. He required IV calcium gluconate up to 10 g per day in addition to oral calcium carbonate 2 g t.i.d. for 2 weeks to resolve hypocalcemia and normalize QTc interval. Patient was discharged to nursing home on calcium carbonate 2 g q.i.d. with IV calcium gluconate as needed to keep corrected calcium >8.0 mg/dL. After discharge he required up to 4 g of IV calcium and 8 g of oral calcium per day. Unfortunately, he presented again with severe hypocalcemia 5 weeks after discharge. In addition to current regimen of oral and IV calcium boluses, low dose calcitriol was started. We were only able to maintain his serum calcium>8.0 mg/dL by administering high daily dose of oral calcium carbonate 8 g /day and calcitriol 2 mcg daily. Due to poor prognosis, he was transitioned to hospice care and died 2 weeks later. Discussion: There are not many case reports on severe prolonged hypocalcemia secondary to denosumab in cancer patients but normal kidney function. Our patient remained on high dose of calcium even 101 days after denosumab administration. Reference: 1. Milat F et al. Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. Bone. 2013 Aug 1;55(2):305–8.

Increasing Pediatric Hospitalizations With Severe Vitamin D Deficiency: A Concerning Trend

Background: Deficiency of vitamin D can lead to multiple health issues in children. Though it can be asymptomatic in early stages, it can lead to symptomatic illnesses if severe/ prolonged including seizures and rickets. Deficiency can be prevented by adequate dietary vitamin D intake with/without supplementation in those at higher risk. However, there has been a recent reemergence and increase in the incidence of vitamin D deficiency in European nations, noted as early as 2008 and at least upto 2018. Hence, we performed a 10 year retrospective study of severe vitamin D deficiency in hospitalized patients at a Children’s Hospital in USA.Methods: Electronic medical record was searched to identify patients with the following inclusion criteria: admitted at our hospital between 1/1/2010 and 12/31/2019 and had a 25-OH vitamin D (25-OH D) level <13 ng/mL with/without hypocalcemia or had a diagnosis of rickets. The study was approved by our institutional review board and consent was waived. Patient demographics, medical history and data on laboratory results, treatment given were extracted. We then ran a summative analysis of most of the data collected, analyzed trends for the number of admissions per year and the response time of calcium levels.Results: Between 1/1/2010 and 12/31/2019, there were 109 hospital admissions with 25-OH D deficiency with or without hypocalcemia. Median 25-OH D level was 9.7 ng/mL. Admissions per year increased from 2010 to 2019 as follows: 2 in 2010, 5 in 2011, 4 in 2012, 6 in 2013, 6 in 2014, 7 in 2015, 12 in 2016, 13 in 2017, 23 in 2018, 25 in 2019. Median patient age was 27 months (range 0,228). Of those </=1 year (n=39), 13% were preterm, 38% were exclusively breastfed and 44% were formula fed. Ninety percent of these infants were not receiving vitamin D supplementation prior to hospitalization. Of the entire cohort of 109 patients, 63% were males and race distribution was as follows: 13% were White, 77% were Blacks and 10% were others. Seventy percent patients were on state sponsored insurance. About 33% had some diet restrictions/ peculiarities, 40% had a presenting complaint related to hypocalcemia including seizures, while 44% had hypocalcemia but it was not their primary reason for presentation. Seventy eight percent patients had hypocalcemia. Of the patients with initial calcium <7.5 mg/dL (n=64), it took a median of 72 hours (range 7,468) to improve to >/= 7.5 mg/dL.Conclusions: Our hospital has witnessed a significant increase in severe vitamin D deficiency in admitted patients between 2010 and 2019. A large proportion of these were Blacks, on state sponsored insurances and infants not on vitamin D supplementation. Greater than 3/4th of patients had hypocalcemia and over 50% patients had hypocalcemia that required a median of 3 days to correct. This is a concerning trend of an often easily preventable morbidity and another health issue that highlights disparities in our health system.

Symptomatic Rebound Hypercalcemia After Denosumab Discontinuation in a Pediatric Patient With Cherubism

Background: Pediatric bone diseases due to osteoclast overactivity have limited therapeutic options. Denosumab, a human monoclonal antibody against RANK-ligand, has been used in the treatment of these conditions despite limited pediatric safety data. Rebound hypercalcemia after denosumab cessation is a rare and potentially serious complication in children with an unpredictable course (1). We present the first report of a child with cherubism who experienced acute symptomatic hypercalcemia five months after denosumab cessation. Clinical Case: An 11 year old male presented to our emergency department (ED) with 2 weeks of nausea, vomiting, abdominal pain, and bilateral leg pain. He was diagnosed with cherubism at age 3 years with progressive painless bilateral jaw swelling, teeth crowding, and proptosis. His bilateral maxilla and left mandible were debulked between ages 5-8 years due to tumors causing dyspnea. The resected tumors showed RANK-ligand expression. Thus, he started a 1-year course of denosumab 80 mg monthly subcutaneous injections for additional lesions not amenable to surgery with marked clinical and radiographic improvement. He had mild hypocalcemia during denosumab therapy, for which he received cholecalciferol 2000 IU and calcium citrate total 1500 mg per day. Calcium citrate was stopped with corrected serum calcium (Ca) 10.1 mg/dL (8.8-10.8 mg/dL) three months prior to ED visit. His presentation to ED five months after denosumab revealed marked hypercalcemia (corrected Ca 13.9 mg/dL), iPTH 5.4 pg/mL (7.5-53.5 pg/mL), 25-OH vitamin D 19 ng/mL (30-100 ng/mL), and hypercalciuria (urine Ca/creatinine ratio 0.58 mg/mg, normal <0.2 mg/mg) concerning for rebound hypercalcemia post-denosumab therapy. He received IV hyperhydration, furosemide, calcitonin, and IV pamidronate 0.5 mg/kg. At discharge, corrected Ca was 8.7 mg/dL. One week later he developed acute nausea and vomiting. Laboratory tests again showed hypercalcemia (Ca 13.3 mg/dL) and hypercalciuria. He received one dose of IV zoledronic acid at 0.025 mg/kg with resolution of hypercalcemia. He remains normocalcemic, normocalciuric, and asymptomatic two months after zoledronic acid treatment. Conclusion: This is the first case, to our knowledge, of a pediatric patient with cherubism with acute symptomatic hypercalcemia after denosumab treatment, reinforcing the need for frequent calcium monitoring months after cessation. Zoledronic acid is also shown to effectively treat rebound hypercalcemia after denosumab cessation. Larger studies are needed to further evaluate denosumab use and safety in pediatric bone diseases with osteoclast overactivity. Reference: (1)Upfill-Brown A, Bukata S, Bernthal NM, Felsenfeld AL, Nelson SD, Singh A, Wesseling-Perry K, Eilber FC, Federman NC. Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases. JBMR Plus. 2019 Aug 22;3(10):e10210

Atypical Parathyroid Adenoma in a Young Man

Patient is a 38-year-old man who developed sudden onset of pain in the upper left arm while carrying a case of water. The pain recurred periodically over the next few months. He presented to the emergency department where imaging showed a pathologic fracture in the proximal left humerus through a lytic lesion. Laboratory testing showed: calcium 13.8 mg/dL (8.5–10.1 mg/dL), 25-OH vitamin D 8 ng/mL (31–100 ng/mL), parathyroid hormone 1583.1 pg/mL (18.5–88 pg/mL). Neck ultrasound showed a complex nodule in the left neck measuring 4.2 x 1.7 x 2.5 cm. Subsequent biopsy of the left arm lesion showed a Brown tumor. The patient was referred to endocrinology. There was concern for parathyroid carcinoma given the elevated parathyroid hormone and large neck lesion. Technetium-99m sestamibi scan showed a 4.1 x 2.6 x 2.5 cm mass posterior to the left thyroid lobe. He subsequently underwent left hemithyroidectomy and parathyroidectomy. Pathology revealed a 3.1 cm parathyroid mass with scattered fibrous bands, foci of prominent nucleoli and foci of sheet-like trabecular and spindled architecture. It was without necrosis, lymphovascular invasion, perineural invasion, increased mitotic activity, atypical mitoses or invasion into adjacent structures. Thus, it was classified as an atypical parathyroid adenoma.Primary hyperparathyroidism is the third most common endocrine disorder, but fewer than 2% occur as a result of an atypical parathyroid adenoma. Patients with an atypical parathyroid adenoma tend to have a more dramatic clinical presentation compared to those with classic adenoma. We see higher calcium and parathyroid hormone levels. Atypical parathyroid adenomas are classified as such due to other features which place the lesion at a higher risk for malignant behavior including higher mitotic activity, adherence to adjacent structures, banding fibrosis and a growth pattern that is either solid or trabecular. In contrast to parathyroid carcinoma, atypical parathyroid adenomas do not show invasion into the surrounding tissues or lymphatic/vascular vessels, and there should be no evidence of metastatic disease. The exact definition of an atypical parathyroid adenoma varies among institutions, and recognition of the defining features (or lack thereof) necessitates an experienced endocrine pathologist.Due to their uncertain malignant potential, patients with an atypical parathyroid adenoma should undergo routine surveillance for recurrence. Routine follow-up of calcium, parathyroid hormone and imaging is indicated to detect for recurrence. A CDC73 germline mutation is associated with recurrence compared to CDC73-negative patients. Parafibromin expression is also thought to play a role although studies so far have had discrepant results.

Paget’s Disease of Bone Affecting Site With Orthopedic Hardware

Introduction: Paget’s disease of bone is a focal disorder of accelerated bone remodeling which leads to bone hypertrophy, cortical expansion and abnormal bone architecture. Either a single bone (monostotic) or multiple bones (polyostotic) can be affected. Although it has been suggested to be caused by a chronic slow viral infection of the bone, a cause and effect relationship has not been clearly established. Therefore, the etiology of Paget’s disease remains an uncertain and controversial topic of discussion. Case Description: A 62-year-old African American male with a past medical history of a left tibial fracture presented with worsening left leg pain for the past 6 months. He denied any recent traumatic events, falls or strenuous physical activity. Since the pain started, his ambulation had been significantly affected requiring the use of a cane for gait stability. His left tibial fracture occurred over 20 years ago after landing on another person’s foot while playing basketball. It was surgically treated with intramedullary nailing and metal rod insertion into the canal of the tibia. Since then, he remained an active person with no physical limitations or ailments until the recent developments that brought him to clinic. A left leg CT-Scan ordered for evaluation of the tibial hardware revealed cortical thickening, marrow expansion and coarse trabeculae throughout the majority of the tibia consistent with Paget’s disease. The hardware was intact with no peri-hardware lucency to suggest loosening or infection. His laboratory workup showed a normal alkaline phosphatase level (94 U/L; normal range 40 - 115 U/L) and low 25-OH Vitamin D level of 14. A Radionuclide Bone Scan done for evaluation of location and extent of bone disease resulted in diffusely abnormal uptake present in the left tibia with no other locations of suspicious uptake. After his 25-OH Vitamin D levels were replenished, a dose of Zoledronic acid IV infusion was given with significant improvement of pain several months after. Discussion: Paget’s disease of bone is the second most common bone disease after osteoporosis. Affected skeletal sites develop a disorganized mosaic of woven and lamellar bone more susceptible to deformities and fractures than normal bone. It is often asymptomatic, but classical features include bone pain experienced either at rest or with motion, cutaneous erythema and warmth. The goal of medical therapy is to relieve symptoms and to prevent future complications with high potency bisphosphonates. Although it is well known that Paget’s disease increase the risk of fractures, this case brings up an interesting take about the possibility of fractures managed with hardware placement increasing the risk of Paget’s disease in the involved site.

Hypercalcemia in an Infant With Pseudohypoaldosteronism Type 1

Background: Pseudohypoaldosteronism type 1 (PHA1) is an aldosterone resistance syndrome due to insensitivity of target tissues to aldosterone action, with supraphysiologic aldosterone and renin levels. PHA1 presents usually in infancy and is divided into autosomal dominant (AD) and autosomal recessive (AR) form. A secondary form of PHA1 associated with UTI and/or renal malformations was described. In AD PHA1, salt loss is due to renal mineralocorticoid resistance while hyponatremia in AR PHA1 is caused by multi-organ salt loss. PHA1 has variable signs/symptoms associated with hyponatremia and hyperkalemia; thus, this clinical picture can be attributed to more common conditions such as dehydration, poor feeding, congenital adrenal hyperplasia. Clinical Case: A 5-month old male was admitted for airway evaluation. He was a 23-week gestation preemie, with chronic lung disease, failure to thrive. Patient was found to have hyponatremia, hyperkalemia, high FeNa of 1.3% (intrinsic renal disease) and elevated BUN/Cr (92/1.15). Renal US found echogenic kidneys with poor cortical medullary differentiation suggesting renal disease. Further evaluation noted high aldosterone (1700 ng/dL) and renin (400 ng/mL/hr) levels. He was placed on low protein formula to help optimize BUN level. Baby was diagnosed with secondary PHA1 due to renal disease and started on NaCl supplementation. This led to normalization of BUN, creatinine and improvement in electrolytes. Patient also had high serum calcium ranging from 11.1 to 12.0 mg/dL. Hyponatremia, hyperkalemia, hypercalcemia could be attributed to possible CAH, however state screen and ACTH stimulation test were normal. Further workup showed high 25-OH-vitamin D > 99 ng/mL, PTH 46.9 pg/mL, phosphorous 5.4 mg/dL and 1,25-OH-vitamin D 63.1 pg/mL. Urine Ca/cr ratio was 0.522. Vitamin D supplementation was stopped and daily total fluids increased. Subsequently, there was improvement in serum Ca at 10.9 mg/dL and 25-OH Vitamin D of 74 pg/mL. Next Generation Sequencing (NGS) was carried out, with a focus on the etiology of persisting hypercalcemia, including familial forms of hypercalcemia and Williams Syndrome. NGS revealed a likely pathogenic variant, c.2365 + 2T>C (p.?), in NR3C2, consistent with a diagnosis of AD PHA 1. Conclusion: This is a case of AD PHA1, marked by renal mineralocorticoid receptor resistance associated with persisting hypercalcemia. Initial hypercalcemia could be explained by hypervitaminosis D. It is important to note that electrolyte abnormalities, including persistent hypercalcemia, could be also secondary to the kidney disease found on renal US. There are only few reports of hypercalcemia in patients with PHA1 in the literature. In children with electrolyte abnormalities and failure to thrive, monitoring of serum and urine electrolytes would facilitate early accurate diagnosis and timely treatment.

Single Dose of Denosumab Effective for Management of Bisphosphonate-Refractory Hypercalcemia of Malignancy Related to Non-Small Cell Lung Cancer

Background: First line therapy for hypercalcemia of malignancy (HCM) includes cancer directed treatment and bisphosphonate therapy. Denosumab is effective in bisphosphonate-refractory HCM (BR-HCM), approved for treatment with dosing schedule at 1, 8, 15, and 29 days and then monthly.Clinical Case: We present the case of a 64 year-old man with Stage IIIA squamous cell lung carcinoma diagnosed 5/2019 with corrected serum calcium (CSC) of 11.2 mg/dL (8.4–10.2) at presentation. Prior to treatment, he developed symptomatic CSC 14.0 mg/dL, treated with IV pamidronate 90mg and IV fluids (IVF) 6/28/2019 with improvement to CSC 9.7 mg/dL. Hypercalcemia recurred 8/2019 while undergoing radiation therapy with CSC 14.7 mg/dL, phosphorus 2.5 mg/dL (2.7–4.5), PTH 7 pg/mL (15–65), PTHrP 2.2 pmol/L (<2.0), 25-OH vitamin D 30.16 ng/mL (30–100), and 1,25-OH2 vitamin D 98.7 pg/mL (19.9–79.3). He was treated with IVF and 4mg zoledronic acid (ZA) on 8/20 and 8/29/2019. CSC normalized 9/30/2019 and he subsequently received three cycles of pembrolizumab 11/25/2019 to 1/6/2020, discontinued for associated pneumonitis He again developed HCM 6/5/2020 with CSC 12.6 mg/dL. He was treated with ZA 4mg on 6/16 and 6/29/2020 with persistent, symptomatic hypercalcemia to 13.7 mg/dL 7/9/2020 with ongoing confusion, constipation, and lethargy. Endocrinology was consulted 7/9/2020 and initiated IVF, calcitonin SQ 4U/kg q12h for 48 hours, and prednisone 30mg daily for 5 days. Chemotherapy was initiated 7/14/2020. CSC remained stable <11.5 mg/dL until 8/3/2020 with recurrent calcium to 13.0 mg/dL despite cancer-directed therapy. He was then given 120mg SQ denosumab on 8/7/2020. CSC improved to 10.6 mg/dL on 8/11/2020 and has remained <11 mg/dL at 70 days after a single dose of denosumab.Conclusion: Denosumab was approved for BR-HCM with a complex treatment schedule based on a single-arm study of 33 patients, of whom 39% had treatment-related adverse events.1 We present a case of successful management of BR-HCM with a single dose of 120mg denosumab with CSC <11.5 mg/dL at day 4 after treatment and persistent control of calcium at day 70 without further treatment. Further investigation is warranted to determine the most effective treatment schedule of denosumab for BR-HCM to reduce adverse events including hypocalcemia and overtreatment.

Hypercalcemia With Non Suppressed Parathyroid Hormone in a Young Female- A Rare Case of Calcium Sensing Receptor Gene Related Familial Hypocalciuric Hypercalcemia-1

Abstract Background: Familial Hypocalciuric Hypercalcemia (FHH) is a rare disorder, associated with hypercalcemia and hypocalciuria and inherited in an autosomal dominant manner. Its true prevalence is unknown, and is estimated to be around 1 in 78,000 as compared to primary hyperparathyroidism (PHPT) which is around 1 in 1000. There are 3 mutations known to cause FHH. FHH-1 is caused by inactivating mutation in the calcium sensing receptor (CaSR) gene. Mutations associated with FHH-2 and FHH-3 are GNA11 and AP2S1 respectively. Case Presentation: 38-year-old female presented to endocrinology, for evaluation of hypercalcemia (10.8 mg/dL, with normal albumin). She was not on any calcium supplements or any other medications which can cause hypercalcemia. She did not have any prior fracture or nephrolithiasis or renal insufficiency. Her father reported to have hypercalcemia; no further evaluations of her father were available. Examination revealed an obese female with no skeletal or dental or other physical abnormalities. Laboratory evaluations: PTH= 37 pg/ml (15–65), 25 OH vitamin=D-30 pg/ml, Mg=2 mg/dL (1.5–2.6), phosphorus=3.1 mg/dl (2.5–4.8), 24 hour urine calcium=0.151 g/24 hours-with 24 hour urine calcium clearance of 0.008. Therefore, evaluations were highly suggestive of FHH. Subsequently, she had genetic evaluation which confirmed heterozygous CaSR mutation, confirming FHH-1. Her mother had genetic testing and was not found to have the mutation. So, it was concluded that the patient likely inherited the gene from her father, who also had hypercalcemia. She is being monitored clinically and with serial laboratory evaluations to monitor her calcium levels. Discussion: CaSR is expressed in parathyroid glands and kidneys which plays a key role in calcium regulation. CaSR inactivating mutation (seen in FHH-1) leads to hypocalciuria and hypercalcemia. 24 hour urine calcium clearance (urine Ca x serum Cr/ serum Ca x urine Cr) of &amp;lt;0.01 is highly suggestive of FHH. Furthermore, higher concentration of calcium is required to suppress PTH release leading to high or nonsuppressed PTH. This finding can mislead towards the diagnosis of PHPT and unnecessary parathyroid surgery, if the diagnosis of FHH is missed. FHH is usually a benign disorder; subtotal parathyroidectomy does not cure the disease. FHH, rarely can cause atypical complications such as pancreatitis and total parathyroidectomy may be indicated to prevent further episodes of pancreatitis. Conclusions: This is a rare case presentation of hypercalcemia due to CaSR inactivating mutation related FHH. FHH and PHPT are competing diagnoses, when a patient presents with hypercalcemia and has nonsuppressed PTH. FHH is rare, however needs to be suspected in a young patient with family history of hypercalcemia, to avoid misdiagnosis of PHPT and unnecessary surgical intervention.

Hypomagnesemia-Induced Hypocalcemia Successfully Treated With Sodium-Glucose Cotransport Inhibitor (SGLT-2i), a Case Report

Background: Severe hypomagnesemia can result in hypocalcemia as magnesium is a co-factor necessary for PTH production in the parathyroid glands. Calcium replacement alone can prove difficult in the setting of hypomagnesemia, therefore optimal treatment should also include repletion and normalization of magnesium levels. Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are a class of oral medications used in the treatment of type 2 diabetes and recently in heart failure which inhibit the sodium-glucose transporter in the proximal tubule of the kidney. A lesser known effect of SGLT-2i is renal tubular resorption of magnesium leading to increased serum magnesium levels. We report a case of refractory diuretic-induced hypomagnesemia and subsequent hypocalcemia which was successfully treated with SGLT-2i. Clinical Case: A 74-year-old male with uncontrolled type 2 DM, vitamin D deficiency, NASH cirrhosis, chronic lower extremity edema on furosemide therapy, and CKD stage III presented with unexplained hypocalcemia at 7.4–8.4 mg/dL (n: 8.8 – 10.4 mg/dL) and hypomagnesemia at 1.0–1.3 mg/dL (n: 1.5 – 2.5 mg/dL) for the past two years. He had been followed by his PCP who performed a workup revealing 25-OH vitamin D level 22.6 ng/mL, PTH 43 pg/mL (n: 10–55 pg/mL) with corresponding calcium 8.1 mg/dL. He was started on ergocalciferol 50,000IU, magnesium oxide 400mg daily, titrated up to 400mg BID, and calcium carbonate 400mg BID with no improvement in magnesium or calcium level. Later, he was admitted to the hospital with volume overload. During admission, magnesium was repleted with IV magnesium sulfate to a level of 2.1 mg/dL and serum calcium level normalized to 8.8 mg/dL without supplementation once magnesium level was replete. He was discharged with resumption of oral magnesium sulfate 400mg BID, but within 10 days his serum magnesium level dropped to 1.0 mg/dL. Endocrinology was consulted, and due to the severe hypomagnesemia, empagliflozin 10mg daily was started for the purpose of increasing the serum magnesium level and secondarily for improvement in glucose and edema control. After one week of treatment, the magnesium level increased to 1.4mg/dL and calcium level to 8.7mg/dL. Six months later, magnesium and calcium levels remained stable at 1.7 mg/dL and 9.1 mg/dL, respectively. The patient continues to now remain normocalcemic and normomagnesemic on empagliflozin 12.5mg daily. Conclusion: SGLT-2i represent a potent class of anti-hyperglycemic agents with the secondary effect of renal tubular absorption of magnesium which may help achieve appropriate PTH secretion in cases of treatment refractory hypocalcemia. This is one of the first cases to report the off-label use of SGLT-2i for refractory hypocalcemia due to hypomagnesemia. SGLT-2i should be considered in these cases especially in the setting of suboptimally controlled type 2 DM when other interventions have been unsuccessful.

Intravenous Iron Induced Severe Hypophosphatemia

Introduction: Hypophosphatemia is a recently recognized adverse effect of certain intravenous iron formulations. It was previously thought to be asymptomatic and transient, however it can cause severe hypophosphatemia associated with renal phosphate wasting. We present a case of severe hypophosphatemia following intravenous ferric carboxymaltose administration. Clinical Case: A 40-year-old female with history of iron deficiency anemia, Hashimoto’s hypothyroidism and multinodular goiter status post thyroidectomy and obesity status post gastric sleeve presents to the hospital due to dizziness, generalized weakness, bone pain and severe myalgia right after 2nd dose of 750 mg of ferric carboxymaltose administration. She received 1st dose of 750 mg of ferric carboxymaltose a week ago prior to the presentation. She was found to have severe hypophosphatemia with a phosphorus level 1.0 mg/dl (2.4 - 4.8 mg/dl), hypocalcemia with calcium level at 8.7 mg/dl, normal PTH at 40 pg/ml and normal 25-OH Vitamin D level at 59.1 ng/ml. The fractional excretion of filtered phosphate (FEPO4) was 19.5%, supporting renal phosphate wasting. She was hospitalized for 5 days and received intravenous phosphate 45 mmol on hospitalization day 1, 15 mmol on day 2 and 30 mmol on day 3. She was discharged on K-phos Neutral 250 mg TID, Calcium carbonate/Vitamin D3 600 mg/500 IU 2 tablets TID and Calcitriol 0.5 mcg daily. While she was taking K-phos Neutral, Calcitriol and Calcium carbonate/Vitamin D3, her phosphorous level was down to 1.3 mg/dl, which was 4 weeks after 1st dose of ferric carboxymatose administration. She presented to the ED and received intravenous phosphate 15 mmol. She is currently taking K-phos Neutral 250 mg QID, Calcitriol 0.5 mcg daily and Calcium carbonate/Vitamin D3 600 mg/500 IU 2 tablets TID. Her phosphorous levels ranged at 2.5 - 3.0 mg/dl. Her bone pain and myalgia have gradually improved. Conclusion: Clinician should be aware of the side effect of hypophosphatemia following ferric carboxymaltose administration. Recent studies showed that incidence of hypophosphatemia associated with intravenous iron administration was significantly higher in ferric carboxymatose group compared with either iron isomaltoside group or ferumoxytol group. The impact of severe hypophosphatemia should be considered when choosing an intravenous iron medication.

Hypercalcemia: A Metabolic Complication of an AIDS-Defining Illness

Abstract Background: Hypercalcemia may result from the activation of macrophages in granulomatous diseases with increased production of 1,25 dihydroxyvitamin D/calcitriol. Its occurrence in patients with human immunodeficiency virus-1 (HIV-1) infection may be atypical and signal major changes in immune status. We report on a patient with acquired immunodeficiency syndrome (AIDS) presenting with new-onset hypercalcemia after months of treatment for mycobacterium avium complex (MAC) infection and normal calcitriol levels. Clinical Case: A 37-year-old man on treatment for HIV-1 and disseminated MAC infection presented to the hospital 6 months after initial diagnosis with worsening headache, cough, and abdominal pain. On arrival he was afebrile and without palpable lymphadenopathy. He was found to have a high serum calcium (13.4 mg/dL, n 8.6–10.6 mg/dL) and acute kidney injury (AKI) (creatinine 4 mg/dL, n 0.6–1.25 mg/dL). His CD4 count had increased from 24 at time of diagnosis to 162 cells/μL (n 410–1,590 cells/μL); his HIV viral load was undetectable. Workup for hypercalcemia revealed an elevated phosphorus (5.2 mg/dL, n 2.5–5.0 mg/dL), low 25-OH vitamin D level (&amp;lt;13 ng/mL, n 25–80 ng/dL), low PTH (4.8 pg/mL, n 12–88 pg/mL), and calcitriol level of 31.4 pg/mL, n 19.9–73.3 pg/mL). Additional tests, including serum electrophoresis, thyroid stimulating hormone, and parathyroid hormone-related peptide levels, were unremarkable. The patient was diagnosed with hypercalcemia secondary to dysregulated calcitriol production in the setting of disseminated MAC and possible immune reconstitution. Hypercalcemia resolved with hydration and prednisone 20 mg daily. Patient was discharged with an 8-day prednisone taper, but readmitted to the hospital 3 weeks later with recurrent hypercalcemia (13.8 mg/dL) and AKI. Urine calcium was found to be elevated (484 mg/24 hours, n100-300 mg/24 hours) and repeat calcitriol was 53.6 pg/ml. Patient was restarted on prednisone 40 mg daily with normalization of calcium within 5 days (calcium 10.3 mg/dL). Conclusion: Hypercalcemia due to increased calcitriol production in the setting of MAC infection, an AIDS-defining illness, may occur months after initiation of effective antibiotic and antiviral therapy and could represent a manifestation of immune reconstitution. The deleterious effects of excess calcitriol may be present even in patients with chronic vitamin D deficiency and a calcitriol level that inappropriately remains within the normal range.

Type 1 Familial Hypocalciuric Hypercalcemia Caused by p.M74L Variant in the Calcium Sensing Receptor (CASR) Gene

Background: Familial hypocalciuric hypercalcemia (FHH) is a rare cause of hypercalcemia caused by inactivating mutations in specific regions of chromosome 3 and 19. Most cases are due to inactivating mutations in the Calcium sensing receptor (CASR) which is encoded by the gene located on the long arm of chromosome 3 (3q 21.1). FHH is characterized by hypercalcemia, an inappropriately normal to elevated serum PTH level, hypocalciuria, and a family history of hypercalcemia. Several mutations in the CASR gene have been described in literature. However, the p.M74L variant in the CASR gene has an extremely low frequency of occurrence in population databases such as the genome aggregation database (gnomAD)1. Clinical Case: A 67 years old woman with a past medical history of hypertension, dyslipidemia, type 2 diabetes mellitus, and chronic kidney disease presented for an evaluation of a long standing history of hypercalcemia. Patient reported non-specific symptoms including chronic fatigue and arthralgias. She denied a history of renal stone or chronic use of lithium. She distinctly recalled that her mother and maternal grandmother had high blood calcium levels. Review of old records showed an elevated corrected calcium level of 11.3 mg/dl, which was elevated since at least October 2013 (no medical records prior to October 2013 were available) which persisted to-date. Patient underwent work-up which revealed a high corrected serum calcium of 10.4 (8.6–10.0mg/dl), high serum PTH of 101 (15–65 pg/ml), an extremely low 24hr urine calcium of <9.2 (100–300 mg/24hr) with corresponding urine volume of 1150 cc and urine creatinine of 1392 (740–1570 mg/24hr), low 25-OH vitamin D of 20.6 (30–100 ng/ml), and a low eGFR of 47 ml/m/1.73. SPECT parathyroid gland was negative. FHH was suspected and subsequent CASR gene analysis panel showed a heterogenous DNA sequence change at nucleotide position c.220 in exon 3 of the CASR gene (c.220A>C). This nucleotide change results in an amino acid change from methionine (M) to leucine (L) at position 74 in the CASR protein (p.M74L). Conclusion: We report a case of a p.M74L variant in the CASR gene which is an extremely uncommon mutation in the CASR gene1. Our case supports the current limited evidence that p.M74L variant in the CASR gene can cause FHH.

Ectopic Intact PTH Secretion Causing Humoral Hypercalcemia of Malignancy

Background: Tumor-generated ectopic intact PTH is difficult to diagnose and should be suspected in patients with apparent primary hyperparathyroidism but with normal parathyroid glands.Clinical Case: A 72-year-old man presented with symptoms of hypercalcemia including generalized weakness, polyuria, and polydipsia. Initial labs were consistent with primary hyperparathyroidism: calcium 12.1 mg/dL (n 8.6–10.3 mg/dL, albumin-corrected 12.5 mg/dL), intact PTH (iPTH) 115.6 pg/mL (n 10–65 pg/mL), low normal 25-OH vitamin D (25 ng/mL, n 25–100 ng/mL), and relatively high normal 1,25 dihydroxyvitamin D (52 pg/mL, n 18–78 pg/mL). 24-hour urine calcium was 381 mg/day (n 100–300 mg/day) and PTHrP was 1.6 pmol/L (n <4.2 pmol/L). Neck ultrasound demonstrated a 0.5 x 1 cm hypoechoic mass near right thyroid inferior pole, though sestamibi SPECT/CT scan did not reveal scintographic evidence of a parathyroid adenoma. He underwent subtotal parathyroidectomy with largest excised gland weighing 0.262 grams. The left inferior parathyroid gland appeared normal intraoperatively, thus was clipped and left in place. PTH decreased from 194 pg/mL to 98 pg/mL postoperatively. Pathological examination revealed three normocellular parathyroid glands with enlargement of only the right superior gland. Venous sampling of the parathyroid vasculature failed to identify the source of autonomous iPTH post operatively. Due to refractory hypercalcemia, cinacalcet was initiated. However, hypercalcemia as high as 12.6 mg/dl and hyperparathyroidism to 672 pg/mL persisted despite dose escalation. He eventually received pamidronate with subsequent transition to denosumab due to declining renal function. A 68Ga DOTATATE scan was performed to locate occult ectopic parathyroid, which reported multiple foci of presumed somatostatin receptor expression involving the liver and intra-abdominal lymph nodes without significant uptake in the neck concerning for metastatic disease. Liver lesion biopsy was consistent with pancreato-biliary adenocarcinoma. Surprisingly, the biopsy was negative for iPTH and neuroendocrine tumor markers on staining/immunohistochemistry. Given his poor prognosis and multiple comorbidities, the patient opted not to pursue any further workup or therapy for his malignancy.Conclusion: Occult malignancy should be suspected for a patient with persistent hyperparathyroidism after parathyroidectomy. Treatment of the malignancy may lead to an improvement in hypercalcemia and iPTH levels. Employment of iPTH mRNA testing or intra-abdominal venous sampling to prove ectopic iPTH secretion would be ideal, as iPTH staining could be falsely negative. Further testing was not completed as the patient declined further evaluation.

Relationship of Vitamin D Deficiency and Fatty Liver in Children as Defined by Multiple Imaging and Histologic Endpoints.

The relationship between vitamin D deficiency (VDD) and pediatric nonalcoholic fatty liver disease (NAFLD) remains uncertain due to conflicting results and few studies with histologic endpoints. We therefore used multiple imaging and histologic NAFLD endpoints to more comprehensively assess the association between VDD and NAFLD in a large pediatric population. Data were obtained from an ongoing pediatric NAFLD study in Bronx, NY. Briefly, overweight and obese children aged 2-18 years with alanine aminotransferase (ALT) levels ≥ 35 U/L were serially enrolled. Liver biopsy was obtained in accordance with clinical guidelines. All participants had liver imaging, namely, controlled attenuation parameter (CAP; Echosens, France) to assess steatosis and, to assess fibrosis, vibration controlled transient elastography (VCTE; FibroScan™, Echosens, France) and acoustic radiation force impulse (ARFI; Philips, Netherlands) imaging. Levels of 25-hydroxyvitamin D were measured serologically. N=276 (88%) of 315 participants had 25-OH vitamin D results, of whom 241 (87%) were Hispanic, 199 (72%) were male, and 92 (33%) underwent liver biopsy. VDD was univariately associated with high waist circumference (p=0.004), high-density lipoprotein level (p=0.01), season (p=0.009), and CAP score (p=0.01). In multivariate analysis, only waist circumference (p=0.0002) and biopsy inflammation grade (p=0.03) were associated with VDD, though the latter had not approximated statistical significance in univariate analysis (p=0.56). There was no association between VDD and hepatic steatosis, ballooning, NAFLD Activity Score, ARFI or VCTE elasticity scores. VDD was not associated with NAFLD defined by imaging and histologic endpoints, except for a possible relation with histologic inflammation grade.

A prospective case\u2013control pilot study to evaluate bone microarchitecture in children and teenagers on long-term parenteral nutrition using HR-pQCT

Long-term parenteral nutrition (PN) may induce bone complications. Tridimensional bone imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT) allow the assessment of both compartmental volumetric densities and microarchitecture. Our aim was to evaluate these parameters in children and teenagers receiving long-term PN. This cross-sectional, case–control study included children older than 9 years undergoing PN for at least 2 years. They were age-, gender- and puberty-matched with healthy controls (1:2). Evaluation included biological assessment of bone metabolism (serum calcium, phosphate, and albumin; urinary calcium and creatinine; 25-OH vitamin D, osteocalcin and PTH), dual X-ray absorptiometry (DXA) and HR-pQCT at the ultradistal tibia and radius. Results are presented as median [range]. Eleven patients (3 girls) with a median age of 16 [9–19] years were included. Bone parameters assessed by HR-pQCT at the ultradistal radius and tibia were similar in patients and controls. Parathyroid hormone (PTH) levels were higher (14 [7–115] vs 16 [12–27]) and osteocalcin levels were lower (44 [15–65] vs 65 [38–142]) in patients than in controls, although within the normal range. Conclusions: there were no differences for compartmental bone densities and microarchitecture in patients undergoing chronic PN. Further longitudinal studies are required to confirm these quite reassuring preliminary results.