bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mortality and Specific Causes of Death in Endogenous Cushing’s Syndrome: A Systematic Review, Meta-Analysis and Meta-Regression
Authors: Limumpornpetch Padiporn , Morgan Ann W , Tiganescu Ana , Pujades-Rodriguez Mar , Nyaga Victoria Nyawira , Baxter Paul D , Stewart Paul Michael 
Published: May 2021

Abstract
Background: Endogenous Cushing’s syndrome (CS) refers to an inappropriate hypercortisolism usually caused by either Cushing’s disease (CD) or adrenal CS (ACS). CS results in significant morbidity and excess mortality if untreated. Even in treated cases there is often a significant health burden. Due to the rarity of CS (incidence ~ 1/1M population), single cohort studies have insufficient power for reporting accurate mortality data. Only one previous systematic review and meta-analysis for CS has been reported that limited its scope to the inclusion of specific CD subgroup. Aims: To perform a meta-analysis and meta-regression analysis of all-cause and specific cause -mortality amongst patients with benign endogenous CS. Methods: The protocol was registered in PROSPERO (CRD42017067530). Searches were undertaken of PubMed, EMBASE, CINHAL, web of science and Cochrane Central from start until April 2019. The primary outcomes were proportion of mortality and SMR. The meta-analysis was done with STATA version 16.1 software. The I2 test, subgroup analysis and meta-regression statistics were used to assess heterogeneity among included studies. Results: A total of 11,527 articles, were retrieved. 87 articles with 100 study cohorts containing 17,276 CS patients reporting mortality were included. Fifty-three study cohorts reported Cushing’s disease (CD) patients, 27 study cohorts reported for adrenal CS patients and 20 studies cohorts reported on both types of CS. The overall SMR of all type CS was 2.91 (95% CI 2.41–3.68) with I2 =40.3%. The SMR for CD was 3.27 (95% CI 2.33–4.21) with I2 = 55.6%. The SMR in ACS was 1.62 (95% CI 0.08–3.16) with I2 =0.0%. The overall proportion of death in CS was 0.05 (95% CI 0.03–0.06) with I2 =51.86%; in CD was 0.04 (95% CI 0.03–0.06) with I2 = 62.7% and in ACS 0.06 (95% CI 0.04–0.11) with I2 = 40.3 %. The proportion of death during the 30-day operative period was highest before 1991 at 0.07 and decreased to 0.03 in 1991–2000 to 0.01 in 2001–2010 and zero after 2011. The causes of death reported across 64 studies were cardiac causes (24.7%), infection (14.4%), cerebrovascular diseases (9.4%), malignancy (9.0%), thromboembolism (4.2%), active disease (2.9%), and adrenal insufficiency (2.7%). Conclusion: CS is associated with increase in overall mortality. Advances in operative techniques and care have decreased peri-operative mortality over a 20 year period. The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thrombo-embolism, infection control and a normalised cortisol level.
A Case of Acute Pancreatitis as a First Presentation of Primary Hyperparathyroidism
Authors: Elmaaz Ahmed , Akel Alberto Antonio Franco , Belokovskaya Regina 
Published: May 2021

Abstract
Introduction: Alcohol use and biliary stones cause the majority of cases of acute pancreatitis (AP). Hypercalcemia is considered a relatively uncommon sole reason for AP. The incidence of hypercalcemia induced AP is about 1.5%. AP as the first presentation of primary hyperparathyroidism (PHPT), in the absence of any other precipitating factors, is extremely rare. We present a case of AP combined with obstructive uropathy as the first clinical manifestations of occult PHPT. The clinical and biochemical recovery of the patient followed parathyroidectomy suggested the correlation between AP and PHPT. Case Presentation: A 63-year-old patient with a history of type 2 diabetes mellitus, hypertension, and coronary artery disease presented to the emergency room with progressive abdominal pain that started two days prior. The pain radiated to his back and was associated with nausea and vomiting. Additionally, he reported black urine and dysuria. He did not report any alcohol or illicit drug use. His surgical history was significant for cholecystectomy. Physical examination showed elevated blood pressure and severe epigastric tenderness. Laboratory findings were significant for calcium level 14.3 mg/dL (8.5–10.5 mg/dL), serum lipase level 679 U/L (13–60 U/L), serum amylase 327 U/L (28–100 U/L), serum PTH 239 pg/mL (15–65 pg/mL), and leukocytosis 11.9K (4-11K) with neutrophilia of 86.4 %, Hemoglobin 13.3 g/dL, and normal platelet count. Vitamin D 25 (OH) level was 12.5 ng/mL (30–80 ng/mL). Urine analysis had moderate hematuria. Lipid panel showed normal triglycerides and cholesterol concentrations. HbA1c was 6.1 % (4–5.6%). Normal levels of metanephrines were found. CT of the abdomen showed acute pancreatitis with peripancreatic edema and right ureteric stone. Thyroid ultrasound revealed a hypervascular mass posterior to the left thyroid lobe. Sestamibi scan further demonstrated abnormal retention of activity in the neck near the left thyroid lobe consistent with parathyroid adenoma. After hydration and a short course of calcitonin, Cinacalcet was started as a bridge to parathyroidectomy. The patient clinically improved with normalization of Calcium levels. The ureteric stone was removed and elective left parathyroidectomy was performed two weeks later. The histopathological exam confirmed a parathyroid adenoma. Postoperatively, intact PTH level was 26 pg/mL with Calcium level of 10.4 mg/dL. The patient was completely asymptomatic. Conclusion: Although AP is a rare presentation of a silent PHTP, it should warrant the measurement of serum calcium and PTH levels in absence of more common causes of AP, especially if combined with urinary stones. Furthermore, MEN type 2 should be considered in the setting of the thyroid mass with PHPT. Medical therapy could improve the clinical condition of the patient; however, the surgical resection of a parathyroid adenoma remains the curative treatment.
Bilateral Basal Ganglia Calcification; An Unusual Initial Presentation of Pseudohypoparathyroidism
Authors: Zare Ahmad , Choudhry Sara 
Published: May 2021

Abstract
Physiological intracranial calcification occurs in about 0.3–1.5% of cases. Hypoparathyroidism and pseudohypoparathyroidism are the most common causes of pathological basal ganglia calcification.
A 21-year-old female who was initially evaluated by neurology team for headache and diplopia, underwent MRI of brain which revealed Calcifications involving the bilateral basal ganglia, thalami, dentate nuclei as well as juxtacortical frontal lobes. She reported Fatigue and muscle pain, usually in her arms especially after playing sports which had been going on for many years. She had no history of fractures, seizures, psychiatric disorders, developmental delay or obvious cognitive impairments. She denied any family history of calcium disorders or autoimmune diseases. As she had been generally healthy in her whole life, she never had any lab testing done. On examination, Height 5’1”, Chvostek’s sign was positive. Fundoscopy was normal. she had no dysmorphic features or shortened 4th metacarpal. Investigations revealed serum calcium less than 5.0 mg (N 8.3 - 10.1 mg/dl), PTH 205.1 pg/ml (N 18.4 - 80.1 pg/ml), phosphate 7.1 mg (N 2.5 - 5 mg), Vitamin-D 36.2 ng/ml (N 30.0 - 100.0 pg/ml),magnesium 2.0 m (N 1.6 - 2.6 mg/dl) with normal albumin, alkaline phosphatase and renal function test. She was diagnosed with pseudohypoparathyroidism and started on calcium and active vitamin D supplement and was referred for genetic testing study. She reported significant improvement in myalgia after a few weeks of starting calcium and active vitamin D supplementations and repeat lab testing showed improved hypocalcemia and hyperphosphatemia. This case illustrates unusual presentation of PTH resistance with basal ganglia calcification as initial presentation prompting further workup. She likely has pseudohypoparathyroidism type 1b.
Since adequate treatment of hypoparathyroidism may lead to marked clinical improvement, determination of serum calcium, phosphorus, and parathyroid hormone is mandatory in all individuals with calcification of the basal ganglia to rule out hypoparathyroidism.
Diagnostic Dilemma of Elevated FGF23 in a Patient With Osteomalacia: A Case Report
Authors: Bulut Aysegul , Pena Samara 
Published: May 2021

Abstract
Introduction: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to FGF23 hypersecretion. It is mostly seen with benign mesenchymal tumors. Establishing the diagnosis could be challenging due to occult nature of the disease.
Case: A 54-year-old female presented with right thigh and upper back pain. On presentation, she had hypophosphatemia (1.8 mq/dl), low 25-hydroxyvitamin D (23 ng/ml), normal ionized calcium and normal iPTH (53 pg/mL). CT scan showed healing right 10th rib fracture and right proximal femoral fracture. DEXA scan was remarkable for osteoporosis. 99m-Technetium nuclear bone scan displayed hyperactivity on bilateral femurs and multiple ribs concerning for stress fractures. Patient was thought to have osteomalacia from vitamin D insufficiency and started on ergocalciferol. Two months later, patient was diagnosed with invasive ductal carcinoma. She had unilateral mastectomy and adjuvant chemotherapy. Surveillance studies were negative for recurrence. Patient lost to follow up for 2 years until she returned with right hip and upper back pain. Her labs showed hypophosphatemia (1.2 mg/dL), normocalcemia, elevated iPTH (131 pg/mL), low 25-hydroxyvitamin D (26 ng/ml), low normal 1,25-dihydroxyvitamin D (25 pg/ml, normal: 18 -72) and elevated FGF23 (285 RU/ml, normal level &lt;180). 24-hour urine studies showed phosphate of 330 mg and fractional phosphate excretion (FEPO4) of 12%. Nuclear bone scan reported subacute fractures in left 11th and right 6th ribs and right proximal femur. TIO was entertained as the unifying diagnosis. She was started on calcium, phosphate, ergocalciferol and calcitriol. Localizing studies with a PET scan showed FDG hyperactivity in the right vocal cord. Subsequent MRI showed asymmetric fat tissue between esophagus and left common carotid artery concerning for lipoma. She lost to follow up again during COVID-19 pandemic.
Discussion: We present a case of elevated FGF23 with renal phosphate wasting concerning for TIO. This case represents the diagnostic dilemma of elevated FGF23 as well as difficulty in discerning the source in TIO. Although exact tumor source remained unclear in our patient, adipose tissue in the thoracic inlet was a potential culprit. Elevated FGF23 leads to urinary phosphate wasting and inhibition of 1α- hydroxylase. Daily urine phosphate excretion &gt; 100 mg or FEPO4 &gt; 5 % strongly suggest renal phosphate wasting. TIO and iron-induced hypophosphatemia are two most common acquired causes of high FGF23. TIO is mostly caused by benign soft tissue and bone tumors. It can take years to establish the diagnosis due to small size and obscure location of the tumors. Advanced investigation with FDG-PET, 68Ga-DOTATATE scan, octreotide scan and venous sampling of FGF23 can aid in diagnosis. Tumor resection is usually curative. Burosumab (anti-FGF23 monoclonal antibody) can be considered when the tumor is not amenable to resect.
Hypophosphatasia Misdiagnosed as Osteoporosis in a Young Girl
Authors: Tsang Tiffany , Raghuwanshi Maya P 
Published: May 2021

Abstract
Introduction: Hypophosphatasia (HPP) is a rare inherited disease of mineral metabolism characterized by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNALP), which causes an inability to liberate inorganic phosphate for hydroxyapatite crystal propagation as well as toxic accumulation of inorganic pyrophosphate, pyridoxal-5’-phosphate and urinary phosphoethanolamine. It has a prevalence of 1/100,000 to 1/900,000, although milder forms have an estimated prevalence of 1/6,370. Variable mutations in TNALP cause clinical expressions ranging from a severe perinatal form, which is often fatal after birth from pulmonary complications, to an infantile form, which can cause vitamin B6-responsive seizures, to an asymptomatic adult form.
Case: A 27-year-old, ventilator-dependent female with osteoporosis, hypothyroidism, cerebral palsy with previous spinal fusion, seizure disorder and nephrocalcinosis presented with surgical site infection from a right femur ORIF she underwent a month ago. She had a history of microfractures and low-impact fractures of both femurs requiring several surgeries. Osteoporosis was diagnosed at age 5 and she had been on Fosamax ever since. She did not meet any developmental milestones as a baby and never reached menarche. Various diagnoses by multiple specialists did not fully explain her clinical presentation. Her medications included alendronate 5 mg, calcium carbonate 600 mg, ergocalciferol 400 U and levothyroxine 50 mcg. Physical exam showed poor dentition, a misshapen skull and bowed legs with contractures of her extremities. Her labs revealed Ca 9.1 mg/dL (8.4–10.2 mg/dL), albumin 3.2 gm/dL (3.5–5.2 gm/dL), phosphorus 5.1 mg/dL (2.5–4.5 mg/dL), alkaline phosphatase 32 U/L (35–105 U/L), PTH 28 pg/mL (15–65 pg/mL), vitamin D 33.5 ng/mL (30–100 ng/mL), C-telopeptide 509 pg/mL (34–635 pg/mL). A right knee X-Ray reported diffusely gracile and demineralized bones with muscular atrophy. She recently transitioned care from a pediatric endocrinologist to an adult endocrinologist, who tested her positive for heterozygous ALPL pathogenic variant hypophosphatasia and was considering her for asfotase alfa enzyme replacement therapy.
Discussion: Our patient had infantile HPP, but due to misdiagnosis as osteoporosis, she was inappropriately treated with a bisphosphate for over 20 years. Treatment of HPP had been supportive until the approval of asfotase alfa (Strensiq) in October 2015. It is a bone-targeted human recombinant enzyme replacement therapy approved for infantile- and juvenile-onset HPP and has been shown to decrease mortality from 73% to 16% at age 5. With improvement in life-sustaining technology, more HPP patients are able to survive into adulthood. Awareness of the complex and polymorphic presentation of HPP by adult endocrinologists is paramount for accurate diagnosis, thus avoiding inappropriate treatments.
Paraneoplastic Hypercalcemia as the Initial Presenting Sign of Metastatic Renal Cell Carcinoma
Authors: Gaballa Salem , Malkhasian Armen 
Published: May 2021

Abstract
Introduction: Malignant hypercalcemia can occur in patients with renal cell carcinoma as part of a paraneoplastic syndrome. The suggested mechanisms of malignant hypercalcemia include overproduction of parathyroid hormone-related peptide (PTHrP), interleukin-6 (IL-6), prostaglandins, and tumor necrosis factor-alpha (TNF-α). This report describes an unusual case of paraneoplastic hypercalcemia as the initial manifestation of metastatic renal cell carcinoma (RCC). Case presentation: A 44-year-old Caucasian male with no past medical history who presented to his PCP complaining of unintentional weight loss of 25 lbs, increasing fatigue, occasional right flank pain, and nausea. His family history is significant for multiple myeloma of his mother. The physical exam was unremarkable. Labs were remarkable for serum calcium of 11.5 mg/dL, Albumin of 4.5 g/dL, intact parathyroid hormone (PTH) of 9 pg/mL, undetectable PTHrP, 25 hydroxy VitD of 26.4 ng/mL, and 1, 25 hydroxy VitD of 18 pg/mL. Serum and urine protein electrophoresis and PSA were unremarkable. CXR revealed the right lower lobe noncalcified nodule of 15×11×7 mm. CT abdomen/Pelvis revealed a right renal mass of 13×14×12 cm without lymphadenopathy or local metastasis. The patient was referred to a medical oncologist and further workup including PET/CT scan that demonstrated increased uptake in right lung nodule of SUV 6, right renal mass uptake of SUV 72, and MRI brain without metastasis. The patient treated with right total nephrectomy that revealed a sarcomatoid renal cell carcinoma. Right lung nodule biopsy revealed a clear cell renal carcinoma. The patient further treated with two cycles of Gemcitabine/oxaliplatin and four cycles of nivolumab/ipilimumab. A repeated PET/CT scan showed a complete resolution of a right lung nodule. Repeated labs were unremarkable, including serum calcium of 8.7 mg/dL. Discussion: Hypercalcemia is a frequent occurrence in patients with RCC, but it is an unusual presenting symptom. The initial evaluation should focus on whether the hypercalcemia is parathyroid-dependent or medication-related. Basic laboratory investigations for hypercalcemia include PTH, PTHrP, and 1, 25(OH)2D. Bone-resorbing cytokines may be present in those patients in which the cause of the hypercalcemia is unclear. In our case, we could not determine the specific cytokine that caused hypercalcemia, as IL-6 and TNF-α were unavailable. If laboratory tests are unavailable, bone scan, CT scan, or PET-CT should be considered to evaluate for lytic bone lesions or underlying malignancy. Evaluation for carcinoma should be persistently pursued in a patient who has symptoms suggestive of paraneoplastic hypercalcemia. Finally, symptomatic malignant hypercalcemia can be treated with IV fluids and bisphosphonates. Approximately 50% of patients who undergo nephrectomy and/or tumor debulking will revert to normocalcemia.
Profound Hypocalcemia Following Thyroidectomy for Graves’ Disease
Authors: New Ru H , Hare Matthew J L , MacKay Diana , Kasireddy Vidya , Ellis Elna , Thomas Mahiban E , Chitturi Sridhar 
Published: May 2021

Abstract
Introduction: While transient parathyroid insufficiency is not an uncommon complication of thyroidectomy, severe and prolonged hypocalcemia attributed to a combination of post-surgical hypoparathyroidism, hungry bone syndrome (HBS) and hypovitaminosis D is unusual.
Clinical Case: A 17-year-old female from a remote community in Australia with Graves’ disease, complicated by exophthalmos and atrial flutter, underwent total thyroidectomy due to challenges with medication adherence leading to persistent thyrotoxicosis. FT4 was &gt;150 pmol/L (normal 10–20 pmol/L) almost two years after diagnosis. Pre-operatively, she received Lugol’s iodine, carbimazole and beta-blockade. The operation was uncomplicated and three parathyroid glands were preserved. Within six hours of thyroidectomy, she developed symptomatic hypocalcemia with corrected calcium 1.9 mmol/L (7.6 mg/dL) (normal 2.2–2.65 mmol/L). PTH level was 0.8 pmol/L (normal 1.4–9.0 pmol/L). Magnesium and phosphate levels were initially normal but hyperphosphatemia developed the following day. 25-OH vitamin D was low (29 nmol/L, normal 50–150 nmol/L) and was corrected with high dose cholecalciferol.
Despite use of continuous intravenous calcium gluconate in addition to oral calcium carbonate, as well as both intravenous and oral calcitriol and magnesium, urinary calcium excretion remained undetectable. Teriparatide 20 mcg BD was commenced on post-operative day 14 with no demonstrable improvement in serum calcium. Less than 48 hours after cessation of parenteral calcium on day 18 post-operation, corrected calcium and ionised calcium declined to 1.47 mmol/L (5.9 mg/dL) and 0.46 mmol/L (normal 1.15–1.33 mmol/L) respectively, prompting recommencement of calcium infusion.
Her remarkably high requirement for calcium replacement with negligible urinary calcium excretion for at least one month in spite of parenteral calcium infusion for a total of three weeks’ duration is highly suggestive of HBS which became evident due to post-surgical hypoparathyroidism. She had elevated ALP (618 U/L, normal 35–140 U/L) and increased bone resorption marker (N-telopeptide/creatinine 262 nmol BCE/mmol, normal &lt;100 nmol BCE/mmol), with osteopenia at lumbar spine (Z-score -1.7) and femur (Z-score -1.3). Additionally, vitamin D deficiency is likely to have contributed to the severity of hypocalcemia.
60 days after surgery, she was still requiring calcium carbonate 2500 mg QID (4 g/day elemental calcium) and calcitriol 1 mcg TDS. Her phosphate level had normalised and ALP gradually declined to 241 U/L.
Clinical Lesson: This case highlights the importance of attaining euthyroid status as early as possible pre-operatively to allow near-complete reversal of thyrotoxicosis-induced osteodystrophy, as indicated by normalisation of serum ALP, and ensuring vitamin D levels are replete prior to thyroidectomy for Graves’ disease.
Radiotherapy-Associated Pelvic Insufficiency Fracture Treated by Romosozumab: Course of L1 and L5 Vertebral Body CT Attenuation
Authors: Adly Hussein , Ing Steven 
Published: May 2021

Abstract
Background: Radiotherapy is a risk factor for osteoporosis and insufficiency fractures via osteoblast apoptosis and vascular injury. PTH analogs teriparatide and abaloparatide are contraindicated in patients with prior exposure to radiotherapy crossing bone due to the increased risk of osteosarcoma. Patients with radiotherapy-associated fractures or osteoporosis were eligible only for antiresorptive agents until romosozumab was recently FDA-approved. Current International Society for Clinical Densitometry (ISCD) guidelines include assessment of “opportunistic CT” as a surrogate for DXA scan using L1 vertebral body attenuation: &gt;150 Hounsfield units (HU) is normal and &lt;100 HU signifies osteoporosis.
Clinical Case: A 60 year old female patient with history of endometrial cancer diagnosed at age of 57 and treated with hysterectomy and bilateral salpingo-oophorectomy, chemotherapy, then pelvic radiotherapy, was referred to endocrinology for pelvic insufficiency fractures evaluation. Two years after completing chemoradiotherapy, she complained of right groin and low back pain with difficulty walking. MRI pelvis showed bilateral sacral ala and right pubic ramus insufficiency fractures. She had normal serum mineral concentration, 25-OH vitamin D sufficiency, normal PTH, eGFR, liver function tests and 24-hour urine calcium excretion. Screening for celiac disease and multiple myeloma was negative. DXA scan BMD T-score showed osteoporosis, -3.0 at the right femoral neck. L1-L4 T-score was +0.4 but unreliable due to presence of degenerative changes. Four months after onset of pain, patient started romosozumab 210mg SQ monthly for a total of 12 doses, after which she started oral alendronate. Pain essentially resolved within 6 months of romosozumab therapy. C-telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were obtained at baseline, 3 and 12 months after romosozumab initiation. CTX was 362, 247 and 258 pg/mL (reference range, &gt;49 years: not established), and P1NP was 82, 178 and 62 mcg/L (reference range, 20 - 108), respectively. Attenuation of L1 and L5 vertebral body was measured using CT abdomen and pelvis scans before and 5 months after radiotherapy, and before and after completion of romosozumab therapy. L1 attenuation measured 161, 132, 127 and 179 HU, and L5 measured 150, 46, 50 and 86 HU, respectively.
Conclusion: Pelvic radiotherapy was associated with a decline in L1 CT attenuation and even greater magnitude of decrease at L5. Romosozumab was associated with clinical improvement, restoration of L1 CT attenuation and diminishment of regain at L5. Although L5 attenuation has not been previously assessed for osteoporosis, this site may be of predictive value in patients who receive pelvic radiotherapy.