Markers of Mineral Homeostasis and Bone Turnover in Patients with Acute Hip Fractures

Markers of Mineral Homeostasis and Bone Turnover in Patients Presenting with Acute Hip Fractures. It is generally assumed that bone turnover increases soon after a fracture, particularly after a major fracture such as hip. However, very little data exists on bone turnover markers (BTM) immediately after a hip fracture. In addition, it is unclear if the BTMs are related to prevailing VDN and parathyroid function. As part of ongoing project we assessed these characteristics in a larger sample (162), and further evaluated the indices of mineral homeostasis (as assessed by serum PTH and 25-OHD levels), and bone turnover (as assessed by serum CTX and bone specific alkaline phosphatase (BSAP); commonly used markers of bone resorption and formation respectively, in clinical practice. 162 patients were admitted with proximal femur fractures over 5y (1/1/2011 to 12/31/2016). The electronic health records (EHR) of 162 patients were reviewed to determine the rate of BMD testing, VDN, parathyroid function and BTMs. There were 112 women (69%) and 72 (44%) Caucasians with a mean age 78.6 ± 12.4y (range 49-98y). Mean 25-OHD was 22.6 ±12.9 ng/ml, and PTH was 61.1 ± 37.9 pg/ml. Mean serum CTX was 481 ± 241 mmol/mol and BSAP was 20.2 ± 14.6. Prevalence of vitamin D deficiency (\u3c20ng/ml) was 44%, insufficiency (\u3c30ng/ml) was 36%, and only 20% had optimal VDN. Serum PTH \u3e70pg/ml in 25% (17/69), of whom 8 had 25-OD/ml. By contrast, 42% (22/52) patients with serum PTH/ml had a serum 25-OHD/ml; the difference in vitamin D insufficiency was similar between the two groups of patients with and without hyperparathyroidism. Serum CTX was/mol in 25% (21/80) patients, which we considered as low bone turnover, and the mean BSAP in these patients was 13.4 ± 4.9 µg/L. Sixteen patients (20%) had serum BSAP \u3e22 µg/L, all of whom had serum CTX \u3e300 mmol/mol, which we considered as high bone turnover. The remaining 55% had high serum CTX 300-600 mmol/mol and the mean BSAP in these patients was 16.2 ± 7.9 µg/L. In a sub-set of 51 patients with BMD, osteopenia was seen in 13% using spine and 12% using femoral neck T-Scores, and osteoporosis in 9% using spine and 14% using femoral neck T scores. Neither spine nor femoral neck BMD correlated with VDN, PTH, or BTMs. Conclusions: Despite acute major fracture 26% have low bone turnover as assessed by BTMs. Only 25% had PTH \u3e70 pg/ml that was not related to the prevailing VDN or renal function, but was related to age. High bone turnover was present in 74%, but was not related to PTH level or VDN. This is the first and most comprehensive study of mineral and skeletal homeostasis in a large sample of patients with hip fracture. Considering the large variation in BTMs, our findings may have therapeutic (antiresoprtive/anabolic) implications. Further studies are need to either confirm or refute our observations.https://scholarlycommons.henryford.com/merf2019clinres/1025/thumbnail.jp

Pneumocystis Carinii Pneumonia: A Rare Cause of Granulomatous Hypercalcemia

Pneumocystis Carinii pneumonia (PCP) is a well-known complication of immunosuppression. Scattered case reports have linked PCP and its ability to induce a granulomatous response to hypercalcemia. PCP related hypercalcemia appears to be resistant to standard therapy. We report a case of hypercalcemia that preceded PCP and continued to worsen during the course of infection. A 63y man with renal transplant for polycystic kidney disease one year prior, presented with a three week history of fatigue, cough and chills. Patient was hypoxic and CT of the thorax revealed diffuse ground glass opacities. He was started on empiric therapy for PCP with intravenous methylprednisolone, clindamycin, and primaquine. Laboratory studies revealed a serum calcium of 12 mg/dl (baseline 9.2mg/dl, reference range 8.6-10.4 mg/dl) and creatinine of 3.23 mg/dl, which rose from a baseline value of 1.6 mg /dl. The patient’s bronchoalveolar lavage confirmed PCP. Endocrinology was consulted for evaluation of hypercalcemia. Further investigations revealed a suppressed PTH of 15 pg/ml from a baseline of 97 pg/ml (reference range 15-65pg/ml) post-transplant, 25-hydroxyvitamin D level of 30 ng/ml (reference range \u3e20 ng/ml ), and 1,25-dihydroxyvitamin D(1,25D) level was elevated (\u3e156 pg/ml; reference range 20-79 pg/ml). A diagnosis of 1,25D mediated hypercalcemia was made, intravenous fluids started and high dose steroids continued. Serum calcium levels improved transiently but subsequently rose to a peak level of 13.5 mg/dl. Ketoconazole 200 mg every 8hrs was started to reduce 1,25D production. Serum calcium remained high despite a reduction in 1,25D level (33 pg/ml). Bisphosphonates therapy was considered unsafe because of decreased GFR. Therefore, denosumab 30mg was administered, which resulted in decrease in serum calcium level to 10.3 mg/dl by day 19. Improvement of hypercalcemia correlated with improvement of PCP and renal function. Patient was discharged home after completing the 21 day course of treatment for PCP. Five weeks later, serum calcium stayed normal with an elevated PTH of 153 pg/ml and 1,25D level of 20 pg/ml.Hypercalcemia heralding PCP infection has been reported in the literature. Elevated calcium of 10.6 mg/dl was present one month prior to our patient’s hospitalization around the time of onset of his symptoms. Of the 19 cases of hypercalcemia due to PCP infection, 5 had hypercalcemia that preceded PCP infection by few weeks. The gold standard for diagnosis of PCP involves identification of the organism in induced sputum or bronchoalveolar lavage specimen. Measurement of serum 1,3-β-d-Glucan, which has high sensitivity, may be used as a screening tool in the right clinical setting such as our patient with immunosuppression and hypercalcemia to diagnose PCP at an earlier stage. We believe that hypercalcemia in a patient with immunosuppression should alert the possibility of PCP infection.https://scholarlycommons.henryford.com/merf2019caserpt/1027/thumbnail.jp

Large parathyroid adenomas: Potential mechanisms to reconcile adenoma size and disease phenotype

Parathyroid adenomas weighing more than 3.5 g are reported variously as atypical , large or giant parathyroid adenomas. All such adenomas are rare variants accounting for no more than 1.5% of all parathyroid adenomas. Large parathyroid adenomas are often associated with more severe form of the disease, including osteitis fibrosa cystica (OFC) and share many biochemical, histological, and molecular features of both benign and malignant parathyroid neoplasms, and are considered a distinct clinical entity. However, the pathogenesis of oversized parathyroid adenomas and the often-associated skeletal phenotype remains unclear. We present 5 cases of primary hyperparathyroidism (PHPT) with OFC, an uncommon manifestation of contemporary PHPT, associated with larger parathyroid adenomas, seen in the Bone and Mineral Disorders Clinic of the Henry Ford Health in the last 30 years to illustrate the critical role of vitamin D nutrition in the pathogenesis of both the OFC and adenoma size. The estimated prevalence of OFC was very low 0.2%, 5 of the \u3e3000 surgically confirmed cases of PHPT seen during this time. The mean ± SD values were: age: 36.8 ± 22.1 years (4 of the 510 years of follow-up. Because OFC is a very rare in the West, but very common areas of endemic vitamin D deficiency, we also examined the relationship between vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D level, and parathyroid adenoma weight as well as prevalence of OFC in two large secularly diverse cohorts of patients with PHPT (Detroit, USA and Chandigarh, India). Based on this relationship and the relative prevalence of OFC in these two large cohorts, we propose that vitamin D nutrition (and perhaps calcium nutrition) best explains both the adenoma size and prevalence of OFC

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding: Novo Nordisk

Neuroblastoma Masquerading as Pheochromocytoma

Peripheral neuroblastic tumors (PNTs) are a group of tumors arising from sympathetic ganglion cells. It is a malignancy of childhood and rare in adults. The incidence in adulthood is only 0.12-0.2 cases per million per year. A 37 year old male presented with acute exacerbation of low back pain which started months prior to admission. MRI of the lumbar spine revealed a 3.6 x 3.4 cm lobulated heterogeneous mass-like lesion involving his right adrenal gland therefore, endocrinology evaluation was requested but not completed. He was a non-smoker without any significant past medical or surgical history and was not on any medications.On examination, He was normotensive and appeared to be in moderate distress. He had tenderness over the right sacroiliac joint. His renal and liver functions were normal. Serum metanephrines were normal however, normetanephrines were elevated to 501 pg/mL (\u3c or = 148 pg/mL). Urine normetanephrines were 3,192 ug/day (88-444 ug/d), Urine volume of 3 L, total metanephrines of 3,342 ug/d (140-785 ug/d). Chromogranin A was 1,379 ng/mL (0-95 ng/mL). DHEAS, 17- hydroxyprogesterone, androstendione, and ACTH were normal. CT of his abdomen and pelvis with contrast showed a lobular heterogeneous mass involving the right adrenal gland with an increased size of 4.9 x 4.3 cm measuring 55 Hounsfield Units (HU). Right iliac core needle biopsy was done to evaluate his diffuse osseous metastasis which showed crush artifact, with positive chromogranin and synaptophysin staining. Right posterior pelvic crest lesion excision biopsy showed primitive small round cell neoplasm with neuroendocrine features, favoring an adult type neuroblastoma confirmed by immunohistochemical staining. He received chemotherapy and radiation and prior to debulking surgery, we initiated doxazosin. Surgery revealed a 6 cm neuroblastoma with extraadrenal extension. Iodine 123-metaiodobenzylguanidine (I-123 MIBG) showed extensive diffuse osseous metastatic disease. His catecholamines declined after surgery. Bone marrow (BM) involvement was noted and he underwent bone marrow transplantation with clinical improvement six months post-transplant. Although pediatric neurblastoma has a 91% survival rate, rates progressively decline to 40% in adults aged 25-64 years. Metastatic dissemination occurs in up to 40% of adults, mainly in the bone and BM as seen in our case therefore, adults should have a BM assessment upon diagnosis. Main issue is differentiation between PNTs and pheochromocytoma, that might be challenging due to variable imaging characteristics of PNTs and secretion of catecholamines in up to 70% of PNTs. On the other hand, catecholamines can be used as tumor markers for monitoring. Majority of adult PNTs are high-risk tumors with poor prognosis. No guidelines for adult management exists due to the rarity of the disease.https://scholarlycommons.henryford.com/merf2019caserpt/1028/thumbnail.jp

Successful management of patients with co-existent autoimmune hepatitis and graves\u27 disease.

Introduction Graves\u27 disease is an autoimmune disorder characterized by autoantibodies against the TSH receptor. Hyperthyroidism from Graves\u27 disease is a high turnover state which can result in elevated liver enzymes. Autoimmune hepatitis (AIH) is a chronic liver disease that presents with elevated liver enzymes, gammaglobulinemia, and unique histological features. Here, we report 4 cases of women diagnosed with AIH and Graves\u27 disease. Clinical cases Case 1 A 15 year old female was diagnosed with Graves\u27 disease after workup revealed low TSH, elevated thyroid hormones, and elevated TSI. At baseline, she had elevated liver enzymes attributed to hyperthyroidism. She underwent RAI ablation. Due to persistently elevated liver enzymes, liver biopsy was performed revealing portal fibrosis and interface hepatitis consistent with AIH. Steroid therapy was initiated and she responded well. Case 2 An 11 year old female was diagnosed with Graves\u27 disease after lab tests revealed low TSH with elevated T3 and T4. She failed anti-thyroid drug treatment and was eventually treated with RAI. Five years later, she developed AIH. This progressed despite treatment, and she underwent a successful liver transplant. Case 3 A 39 year old female presented to the hospital with malaise. She was diagnosed with Graves\u27 disease and AIH. She was started on prednisone and anti-thyroid drugs. Subsequently, she was treated with RAI and she went into remission with AIH as well. She had a recurrence of the latter and required a liver transplant. Case 4 A 47 year old female presented with jaundice. Workup revealed elevated liver enzymes with positive ANA and ASMA. Liver biopsy revealed hepatic necrosis and bridging fibrosis confirming AIH. Immunosuppression was initiated with good response. She was later diagnosed with Graves\u27 and was started on anti-thyroid drug therapy. She was maintained on long term methimazole and prednisone. Discussion As elevated liver enzymes are commonly seen in patients with Graves\u27 disease, a high index of suspicion is required to diagnose concomitant AIH since Graves\u27 disease is rarely associated with AIH. We described 4 patients with concomitant thyroid and liver disease. In some cases, the diagnosis of AIH was delayed as the initial liver enzyme abnormalities were attributed to hyperthyroidism. Physicians may be hesitant to use anti-thyroid drugs given their hepatic side effect profile. However, anti-thyroid drug therapy can be safely used even in the presence of advanced liver disease, and may prove beneficial. In 2 of our patients, liver enzymes improved after hyperthyroidism resolved. In patients with co-existent AIH and Graves\u27 disease, RAI ablation is the preferred modality for treatment. AIH treated with immunosuppression may also treat Graves\u27 disease with improvement of both liver and thyroid function

Successful management of patients with co-existent autoimmune hepatitis and graves\u27 disease.

Introduction Graves\u27 disease is an autoimmune disorder characterized by autoantibodies against the TSH receptor. Hyperthyroidism from Graves\u27 disease is a high turnover state which can result in elevated liver enzymes. Autoimmune hepatitis (AIH) is a chronic liver disease that presents with elevated liver enzymes, gammaglobulinemia, and unique histological features. Here, we report 4 cases of women diagnosed with AIH and Graves\u27 disease. Clinical cases Case 1 A 15 year old female was diagnosed with Graves\u27 disease after workup revealed low TSH, elevated thyroid hormones, and elevated TSI. At baseline, she had elevated liver enzymes attributed to hyperthyroidism. She underwent RAI ablation. Due to persistently elevated liver enzymes, liver biopsy was performed revealing portal fibrosis and interface hepatitis consistent with AIH. Steroid therapy was initiated and she responded well. Case 2 An 11 year old female was diagnosed with Graves\u27 disease after lab tests revealed low TSH with elevated T3 and T4. She failed anti-thyroid drug treatment and was eventually treated with RAI. Five years later, she developed AIH. This progressed despite treatment, and she underwent a successful liver transplant. Case 3 A 39 year old female presented to the hospital with malaise. She was diagnosed with Graves\u27 disease and AIH. She was started on prednisone and anti-thyroid drugs. Subsequently, she was treated with RAI and she went into remission with AIH as well. She had a recurrence of the latter and required a liver transplant. Case 4 A 47 year old female presented with jaundice. Workup revealed elevated liver enzymes with positive ANA and ASMA. Liver biopsy revealed hepatic necrosis and bridging fibrosis confirming AIH. Immunosuppression was initiated with good response. She was later diagnosed with Graves\u27 and was started on anti-thyroid drug therapy. She was maintained on long term methimazole and prednisone. Discussion As elevated liver enzymes are commonly seen in patients with Graves\u27 disease, a high index of suspicion is required to diagnose concomitant AIH since Graves\u27 disease is rarely associated with AIH. We described 4 patients with concomitant thyroid and liver disease. In some cases, the diagnosis of AIH was delayed as the initial liver enzyme abnormalities were attributed to hyperthyroidism. Physicians may be hesitant to use anti-thyroid drugs given their hepatic side effect profile. However, anti-thyroid drug therapy can be safely used even in the presence of advanced liver disease, and may prove beneficial. In 2 of our patients, liver enzymes improved after hyperthyroidism resolved. In patients with co-existent AIH and Graves\u27 disease, RAI ablation is the preferred modality for treatment. AIH treated with immunosuppression may also treat Graves\u27 disease with improvement of both liver and thyroid function

Successful Management of Patients with Co-existent Graves\u27 Disease and Autoimmune Hepatitis

Graves\u27 disease may lead to hepatic dysfunction. This is due to the direct effect of increased circulation of thyroid hormones. Graves\u27 disease is associated with other autoimmune diseases, including autoimmune hepatitis. We report four cases of a rare occurrence of both Graves\u27 disease and autoimmune hepatitis. Two female patients underwent radioactive iodine ablation for Graves\u27 disease. Both patients were diagnosed with autoimmune hepatitis with liver biopsy after liver enzymes worsened despite stable thyroid function. Both patients received steroid immunosuppression therapy for autoimmune hepatitis. The first patient improved with return of thyroid function and liver enzymes to normal whereas the second patient\u27s liver disease progressed despite treatment and she eventually required liver transplant. A female patient with concomitantly diagnosed Graves\u27 disease and autoimmune hepatitis was initially treated with steroids and anti-thyroid medication. She then underwent radioactive iodine ablation but ultimately required liver transplant. Another female patient received treatment with immunosuppression and anti-thyroid therapy. She eventually underwent radioactive iodine ablation with normalization of thyroid function and liver profile. This case series illustrates the diagnostic challenge to determine the cause of elevated liver enzymes in patients presenting with both Graves\u27 disease and autoimmune hepatitis. A brief review of the literature on its clinical presentation and diagnosis is discussed

Successful Management of Patients with Co-existent Graves\u27 Disease and Autoimmune Hepatitis

Graves\u27 disease may lead to hepatic dysfunction. This is due to the direct effect of increased circulation of thyroid hormones. Graves\u27 disease is associated with other autoimmune diseases, including autoimmune hepatitis. We report four cases of a rare occurrence of both Graves\u27 disease and autoimmune hepatitis. Two female patients underwent radioactive iodine ablation for Graves\u27 disease. Both patients were diagnosed with autoimmune hepatitis with liver biopsy after liver enzymes worsened despite stable thyroid function. Both patients received steroid immunosuppression therapy for autoimmune hepatitis. The first patient improved with return of thyroid function and liver enzymes to normal whereas the second patient\u27s liver disease progressed despite treatment and she eventually required liver transplant. A female patient with concomitantly diagnosed Graves\u27 disease and autoimmune hepatitis was initially treated with steroids and anti-thyroid medication. She then underwent radioactive iodine ablation but ultimately required liver transplant. Another female patient received treatment with immunosuppression and anti-thyroid therapy. She eventually underwent radioactive iodine ablation with normalization of thyroid function and liver profile. This case series illustrates the diagnostic challenge to determine the cause of elevated liver enzymes in patients presenting with both Graves\u27 disease and autoimmune hepatitis. A brief review of the literature on its clinical presentation and diagnosis is discussed