Jad G. Sfeir

Use of recombinant human parathyroid hormone in hypocalcemic cardiomyopathy

Hypocalcemia secondary to hypoparathyroidism is a rare cause of congestive heart failure. However, its early recognition and treatment lead to significant improvement in cardiac function. We report a middle-aged woman presenting with symptoms of heart failure with a serum calcium level of 3.7 mg/dl and a serum inorganic phosphate level of 17.6 mg/dl 22 years after subtotal thyroidectomy. Besides calcium and calcitriol supplementation, she was the first patient with severe hypocalcemic cardiomyopathy to be given off-label recombinant human parathyroid hormone (PTH) because of an elevated serum calcium-phosphate product. We discuss the management and outcome of the patient and then present a brief review of similar previously reported cases. We also describe the pivotal role of calcium ion and the potential role of PTH in maintaining myocardial contractility, effective natriuresis, and possible pathogenic mechanisms contributing to heart failure secondary to hypocalcemia and hypoparathyroidism.

Validation of a vitamin D replacement strategy in vitamin D-insufficient patients with lymphoma or chronic lymphocytic leukemia

Validation of a vitamin D replacement strategy in vitamin D-insufficient patients with lymphoma or chronic lymphocytic leukemia

GH Therapy in Childhood Cancer Survivors: A Systematic Review and Meta-Analysis

Background GH deficiency (GHD) is common among childhood cancer survivors (CCSs) with history of tumors, surgery, and/or radiotherapy involving the hypothalamus-pituitary region. We aimed to evaluate the effects of GH therapy (GHT) in CCSs on adult height, risk of diabetes mellitus, abnormal lipids, metabolic syndrome, quality of life, secondary tumors, and disease recurrence. Methods We searched multiple databases for randomized and observational studies. Pairs of reviewers independently selected studies and collected data. Random effects meta-analysis was used to pool outcomes across the studies. Results We included 29 observational studies at moderate to high risk of bias. Sixteen studies compared CCSs on GHT with those not on GHT (512 patients, GH dose: 0.3 to 0.9 IU/kg/week). GHT was significantly associated with height gain [standard deviation score, 0.61; 95% CI, 0.08 to 1.13] and was not significantly associated with the occurrence of secondary tumors [odds ratio (OR), 1.10; 95% CI, 0.72 to 1.67] or tumor recurrence (OR, 0.57; 95% CI, 0.31 to 1.02). Thirteen studies compared CCSs on GHT with normal age- or sex-matched controls or controls with idiopathic GHD or short stature. GHT was associated with either improved or unchanged risk of diabetes, lipid profiles, and metabolic syndrome. GHT was associated with improvements in quality of life. Conclusion CCSs treated with GHT gain height compared with the untreated controls. GHT may improve lipid profiles and quality of life and does not appear to increase the risk of diabetes or the development of secondary tumors, although close monitoring for such complications remains warranted due to uncertainty in the current evidence.

Multi-drug resistant Acinetobacter species: a seven-year experience from a tertiary care center in Lebanon

BackgroundAcinetobacter species have become increasingly common in the intensive care units (ICU) over the past two decades, causing serious infections. At the American University of Beirut Medical Center, the incidence of multi-drug resistant Acinetobacter baumannii (MDR-Ab) infections in the ICU increased sharply in 2007 by around 120%, and these infections have continued to cause a serious problem to this day.MethodsWe conducted a seven-year prospective cohort study between 2007 and 2014 in the ICU. Early in the epidemic, a case-control study was performed that included MDR-Ab cases diagnosed between 2007 and 2008 and uninfected controls admitted to the ICU during the same time.ResultsThe total number of patients with MDR-Ab infections diagnosed between 2007 and 2014 was 128. There were also 99 patients with MDR-Ab colonization without evidence of active infection between 2011 and 2014. The incidence of MDR-Ab transmission was 315.4 cases/1000 ICU patient-days. The majority of infections were considered hospital-acquired (84%) and most consisted of respiratory infections (53.1%). The mortality rate of patients with MDR-Ab ranged from 52% to 66%.ConclusionMDR-Ab infections mostly consisted of ventilator-associated pneumonia and were associated with a very high mortality rate. Infection control measures should be reinforced to control the transmission of these organisms in the ICU.

A 27-year experience with infective endocarditis in Lebanon

Although rare, infective endocarditis (IE) continues to cause significant morbidity and mortality. Previous data from the American University of Beirut Medical Center (AUBMC) had shown predominance of streptococcal infection. As worldwide studies in developed countries show increasing trends in Staphylococcus aureus endocarditis, it becomes vital to continually inspect local data for epidemiological variations. We reviewed all IE cases between 2001 and 2014, and we performed a comparison to a historical cohort of 86 IE cases from 1987 to 2001. A total of 80 patients were diagnosed with IE between 2001 and 2014. The mean age was 61 years. The most commonly isolated organisms were streptococci (37%), compared to 51% in the previous cohort. S. aureus accounted for 11%. Only one S. aureus isolate was methicillin-resistant. In the historical cohort, 26% of cases were caused by S. aureus. Enterococci ranked behind staphylococci with 22% of total cases, while in the previous cohort, enterococcal IE was only 4%. Compared to previous data from AUBMC, the rates of streptococcal and staphylococcal endocarditis have decreased while enterococcal endocarditis has increased. This study reconfirms that in Lebanon, a developing country, we continue to have a low predominance of staphylococci as etiologic agents in IE.

Hypercalcemia in Necrobiotic Xanthogranuloma: First Reported Case and Insight into Treatment.

Necrobiotic xanthogranuloma (NXG) is a rare systemic and progressive granulomatous disease first described in 1980. Given no established first‐line therapy, treatment focuses on the control of skin lesions and associated complications. Despite it being a granulomatous disease, NXG has not been associated with hypercalcemia. About 140 cases of NXG have been reported to date but, to our knowledge, this is the first case to be complicated by hypercalcemia. Our case confirms a granulomatous disease–mediated production of 1α‐hydroxylase leading to increased synthesis of 1,25‐dihydroxyvitamin D and subsequent hypercalcemia. Based on this pathophysiology, we elected to start systemic glucocorticoids, titrated to clinical and metabolic response. Steroid‐sparing agents need to be considered to avoid long‐term complications but continue controlling this granulomatous disease.

In insulin-treated type 1 diabetes, canagliflozin increased diabetic ketoacidosis

Question In adults with type 1 diabetes mellitus treated with insulin, does canaglifozin add-on treatment increase the risk for diabetic ketoacidosis (DKA)? Methods Design Randomized placebo-controlled trial. ClinicalTrials.gov NCT02139943. Allocation Unclear allocation concealment.* Blinding Blinded* {study sites and sponsor}. Follow-up period 18 weeks. Setting Not reported. Patients 351 patients 25 to 65 years of age {mean age 42 y, 56% men} who had type 1 diabetes for 1 year, hemoglobin (Hb) A1c level 7.0% to 9.0% (53 to 75 mmol/mol), body mass index 21 to 35 kg/m2, and were receiving a stable insulin regimen (multiple daily injections or continuous subcutaneous infusion) for 8 weeks. Exclusion criteria included history of type 2 diabetes mellitus; DKA or severe hypoglycemic event in the past 6 months; myocardial infarction, unstable angina, coronary revascularization, or cerebrovascular accident in the past 12 weeks; history of New York Heart Association class III to IV cardiac disease; uncontrolled hypertension; estimated glomerular filtration rate <70 mL/min/1.73 m2; or treatment with an antihyperglycemic other than insulin in the past 12 weeks. Intervention Canagliflozin, 100 mg (n =117), canagliflozin, 300 mg (n =117), or placebo (n =117) once/d before the first meal. Outcomes Safety outcomes included ketone-related adverse events (i.e., acidosis, blood ketone body increased, blood ketone body present, DKA, diabetic ketoacidotic hyperglycemic coma, ketoacidosis, ketonemia, ketonuria, ketosis, metabolic acidosis, or urine ketone body present) and serious DKA. Patient follow-up 93% (modified intention-to-treat analysis). Main results Risks for any ketone-related adverse events and for serious DKA events requiring hospitalization were increased with canagliflozin compared with placebo (Table). Conclusion In patients with insulin-treated type 1 diabetes mellitus, canagliflozin increased diabetic ketoacidosis. Canagliflozin add-on treatment vs placebo in adults with type 1 diabetes mellitus treated with insulin Outcomes Event rates P value Canagliflozin, 100 mg Canagliflozin, 300 mg Placebo Any ketone-related adverse event 5.1% 0% 0.0146 9.4% 0% 0.0004 Serious diabetic ketoacidosis 4.3% 0% 0.0299 6.0% 0% 0.0071 Abbreviations defined in Glossary. Upper tail 1-sided P values calculated from data in article using Fisher exact test. Events requiring hospitalization. Commentary To date, pramlintide and insulin are the only medications approved to treat patients with type 1 diabetes. Since their introduction, sodiumglucose cotransporter 2 (SGLT2) inhibitors have drawn substantial interest as an add-on to insulin in type 1 diabetes. There have, however, been unexpected reports of increased incidence of ketoacidosis in patients with type 2 diabetes using these agents (1). Peters and colleagues used data from the pivotal trial of canagliflozin in type 1 diabetes (1) to evaluate the association between SGLT2 inhibitors and DKA. The results are limited by lack of precision and inadequate information about insulin dosing around each event. Aside from the reduction in daily insulin dose for patients receiving canagliflozin, 2 factors may contribute to the observed increased risk for ketoacidosis. First, despite a reduction in fasting glucose, SGLT2 inhibitors increase endogenous glucose production and glucagon levels in patients with type 2 diabetes (2). The amplitude of this paradoxical physiologic response has yet to be determined in type 1 diabetes. However, it does have a direct effect on hepatic ketone production, thus contributing to the development of ketoacidosis (3). Second, patients and clinicians may not recognize DKA without severe hyperglycemia, and this could lead to delays in diagnosis and treatment. This is especially true if patients do not have good guidance about when to look for ketonuria or when to seek medical care in the absence of hyperglycemia. In all, for most patients with type 1 diabetes, the modest reduction in HbA1c level conferred by SGLT2 inhibitors (1) may not outweigh the cost and potential risk for DKA requiring hospitalization.

Diagnosis of Growth Hormone Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers.

Background Limited guidance exists for selecting a laboratory method for diagnosing GH deficiency (GHD) when it occurs as a late effect of radiotherapy in childhood cancer survivors (CCSs). Methods We searched Medline, Embase, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus for studies evaluating GHD that used IGF-1 or IGF-binding protein 3 (IGFBP-3) measurements compared with GH dynamic testing. Results We included 15 studies [IGF-1 (8 studies) and IGFBP-3 (7 studies)] enrolling 477 patients. Comparator tests varied widely. Overall, both IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy but were strongly correlated. The use of both tests simultaneously in the same cohort did not improve the diagnostic accuracy. Despite high variability in the testing protocols, dynamic tests remained the most accurate for appropriately identifying patients with GHD. The insulin tolerance test (ITT) appears to be the most accepted reference test when used alone or in combination with arginine; however, standardized testing strategies among practice groups are absent. GHRH and arginine stimulation performed almost similarly to the ITT; however, in one study GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT. Insufficient data were available to assess the accuracy of serial GH testing (nocturnal or over 24 hours). Conclusion The diagnostic accuracy of various dynamic tests for GHD in CCSs appears to follow the same patterns as those in non-CCSs. Interpreting GHRH stimulation is a challenge given the primarily hypothalamic dysfunction in CCSs. IGF-1 and IGFBP-3 perform poorly in this population.

Evaluation of cross-sectional and longitudinal changes in volumetric bone mineral density in postmenopausal women using single- versus dual-energy quantitative computed tomography

Central quantitative computed tomography (QCT) is increasingly used in clinical trials and practice to assess bone mass or strength and to evaluate longitudinal changes in response to drug treatment. Current studies utilize single-energy (SE) QCT scans, which may be confounded both by the amount of bone marrow fat at baseline and changes in marrow fat over time. However, the extent to which marrow fat changes either underestimate volumetric BMD (vBMD) measurements at baseline or under-/overestimate longitudinal changes in vivo in humans remains unclear. To address this issue, 197 early postmenopausal women [median age (IQR) 56.7 (54.4-58.7) years] underwent spine and hip QCT scans at baseline and 3 years using a 128-slice dual-source dual-energy (DE) scanner. The scans were analyzed as either SE scans (100 kVp) or DE scans (100 kVp and 140 kVp), with the latter accounting for bone marrow fat. At baseline, vertebral trabecular vBMD was (median) 17.6% lower (P < 0.001) while femur neck (FN) cortical vBMD was only 3.2% lower (P < 0.001) when assessed by SE vs DE scanning. SE scanning overestimated the 3 year rate of bone loss for trabecular bone at the spine by 24.2% (P < 0.001 vs DE rates of loss) but only by 8.8% for changes in FN cortical vBMD (P < 0.001 vs DE rates of loss). The deviation between SE and DE rates of bone loss in trabecular vBMD became progressively greater as the rate of bone loss increased. These findings demonstrate that SE QCT scans underestimate trabecular vBMD and substantially overestimate rates of age-related bone loss due to ongoing conversion of red to yellow marrow. Further, the greater the rate of bone loss, the greater the overestimation of bone loss by SE scans. Although our findings are based on normal aging, recent evidence from animal studies demonstrates that the skeletal anabolic drugs teriparatide and romosozumab may markedly reduce marrow fat, perhaps accounting for the disproportionate increases in trabecular vBMD by SE QCT as compared to dual-energy X-ray absorptiometry with these agents. As such, future studies using recently available DE scanning technology that has satisfactory precision and radiation exposure are needed to evaluate changes in trabecular vBMD independent of changes in marrow fat with aging and drugs that may alter marrow fat composition.

Corrigendum: Targeting cellular senescence prevents age-related bone loss in mice

This corrects the article DOI: 10.1038/nm.4385