Primecuts – This Week In The Journals

March 6, 2017

A_TransGender-Symbol_black-and-white_svgBy Jack Dougherty, MD

Peer Reviewed

This week in the news, Breitbart reported on a female to male transgender teenager who won the Texas girls state wrestling championship.1 According to local regulations for school sports, 17 year old Mack Beggs was only permitted to compete against other athletes that had the same gender on their birth certificates: female. But he is taking testosterone supplements and identifies as male. A lawyer hired to oppose Mack’s participation commented, “The more I learn about this, the more I realize that she’s [sic] just trying to live her life and her family is, too.” This statement, where the teen is identified using the wrong pronoun, but is simultaneously defended for his right to define his own gender, demonstrates the profound tumult much of America is feeling as transgender rights are debated nationally. This particular issue is indeed challenging. With the narrow view that Mack was assigned the female gender at birth, his participation against girls not taking hormone supplements as a medical treatment does seem unfair. By contrast, boys taking testosterone would normally be barred from wresting competitions for use of performance-enhancing drugs. Testosterone also made several headlines in the medical community this week, where it has shown again and again to be a controversial treatment.

Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone2

Previous observational studies have generated the hypothesis that testosterone supplementation may cause adverse cardiovascular outcomes, metabolic syndrome, diabetes and mortality.3,4 This trial is the first prospective, double-blinded, placebo-controlled, multicenter trial to test that hypothesis. 138 men over the age of 65 with serum testosterone levels below 275 ng/dL and with clinical signs of hypogonadism were randomized to testosterone gel or placebo gel. Participants with uncontrolled hypertension, recent MI or stroke, or who were high risk for prostate cancer were excluded. Atherosclerotic plaque volumes were measured serially on coronary CTA. Patients in the treatment arm where shown to have significantly higher volume of non-calcified coronary artery plaque (median increased plaque volume of 41 mm3; 95% CI, 14 to 67 mm3; P = .003) but similar coronary artery calcium scores. No adverse cardiac events occurred in either arm during the 12 month trial period. Previous studies have shown that non-calcified plaque volume is associated with myocardial ischemia and subsequent cardiovascular events.5,6 The authors point out that testosterone may differentially effect the various components of plaque, which may impact plaque stability, and requires further investigation. The biggest limitation of this study is its small size and short follow-up period, giving it power too limited to identify the effect of testosterone supplementation with clinical relevance. Additionally, all-comers in the trial had on average a high burden of coronary calcium, which limits the sensitivity of coronary CTA to characterize underlying atherosclerotic lesions. Overall, the study is another useful and worrisome data point regarding the safety of testosterone supplementation, but it is unlikely to convince patients and practitioners already using the medication.

Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment7 

The previous trial on testosterone supplementation and cardiovascular disease was part of the Testosterone Trials, a coordinated group of 7 trials aimed at assessing the safety and efficacy of testosterone supplementation using prospective data. The Cognitive Function Trial compared 493 men from this data set with and without age-associated memory impairment and found no significant association between testosterone use and in delayed paragraph recall, visual memory, executive function, or spatial ability.

Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis8

Obesity is a global epidemic and is now the most important driver of liver disease. Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. NAFLD is a spectrum ranging from steatosis to inflammation (nonalcoholic steatohepatitis, or NASH) causing necrosis and fibrosis. NASH will be the leading indication for liver transplantation within a few years.9 Despite the prevalence and serious morbidity and mortality associated with these diseases, there is currently no medical therapy approved to target reversal of advanced fibrosis. Previous studies identified thiazolidinediones as improving NASH but failed to show a benefit in extent of fibrosis, the only independent predictor of outcomes in NAFLD,10,11 and an effect this meta-analysis aimed to identify. The study combined data from eight randomized controlled trials enrolling a total of 516 patients with NASH. It met its primary endpoint of improving advanced fibrosis with odds ratio of 3.2 (CI 1.3-7.9), as well as secondary endpoints of improvement in fibrosis of any stage, and resolution of NASH. Similar results were obtained when only data from patients without diabetes was analyzed. Interestingly, all of the observed benefits were derived from the 5 trials that used pioglitazone, whereas the 3 trials that used rosiglitazone, which was restricted for adverse cardiac outcomes, did not show a benefit in reversal of inflammation or fibrosis. Overall, this meta-analysis makes a compelling case for the use of pioglitazone to treat NAFLD. However, important questions remain. The trials studied here ranged from only 6 to 24 months, and additional studies need to be performed to assess long-term efficacy and safety. In particular, subsets of patients at various points on the NAFLD-NASH-fibrosis spectrum should be evaluated to determine when thiazolidinedione therapy has the most clinical utility.

The Effect of Predialysis Fistula Attempt on Risk of All-Cause and Access-Related Death12

It is well-established that type of vascular access is associated with mortality in patients with end-stage renal disease (ESRD). Catheters are associated with higher mortality than arteriovenous fistulas, but it is debated whether this difference is related to patient characteristics or as a results of catheters themselves; that is, sicker patients requiring more urgent dialysis are more likely to undergo catheter placement. But are catheters themselves more dangerous than fistulas? In this study, investigators retrospectively evaluated all patients across five dialysis centers over an eight year period, excluding those who received peritoneal dialysis, kidney transplant or had end-stage heart, liver or lung disease. The remaining 2,300 patients were stratified based on an attempt at fistula creation prior to initiation of dialysis, or not (79% versus 21%, respectively). 617 patients died during the study period. The most common causes were sudden out of hospital death (n=230, 37%), cardiovascular disease (n=127, 21%) and infectious complications (n=93, 15%). Fourteen deaths (2%) were related to vascular access. Of these fourteen deaths, 10 were related to central catheters, 3 were related to fistulas, and 1 was related to a peritoneal catheter. Thus, excess mortality due to catheter use was associated with 0.1 deaths per 1000 patient years. Although an upfront fistula attempt was associated with improved mortality, the low attributable mortality suggests that unmeasured comorbidities and treatment selection were much more significant contributors to mortality. One limitation of this study is significant crossover. Some patients in the upfront fistula group had failed attempts or had fistulas that later failed, and some patients initially managed with catheters spent a significant proportion of the study period being dialyzed by fistulas that were created after the study began. Regardless, no deaths were attributed to access-related issues in these crossed-over patients. This study is also limited by its retrospective, non-blinded, uncontrolled design. Overall, the cohort is convincing though not definitive evidence that dialysis catheters are probably less inherently dangerous than is commonly thought. Better understanding the risks of vascular access is important to helping patients make informed clinical decisions when faced with kidney failure.

A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia13

Iron deficiency anemia is a very common result of many disease processes, and it has a straight-forward cure: iron supplementation (in addition to reversing the underlying cause, of course). However, non-compliance with oral iron is common due gastrointestinal side effects. Additionally, oral iron may be ineffective in patients with a primary absorption problem, such as inflammatory bowel disease or after bariatric surgery. Other common etiologies include malignancy, infection, heart failure, chronic kidney disease and heavy menstrual bleeding. These patients may benefit from intravenous iron, which comes in several different formulations. Iron sucrose is commonly used in patients on dialysis. These patients have frequent contact with healthcare providers and have regular intravenous access, making frequent dosing of IV iron relatively simple. Patients with other causes of anemia, such as menstrual bleeding, may benefit from formulations that require less frequent dosing. Iron isomaltoside is one option, as it contains iron bound to a complex carbohydrate that sustains a longer release in the blood. In addition to less frequent dosing, there is a theoretical lower risk of toxicity related to free iron release at the time of administration. Patients with active infections may be put at risk with IV iron administration to due upregulation of hepcidin. In this prospective, randomized, open-label trial, 511 patients with iron-deficiency anemia were randomized to receive infusions of iron sucrose or iron isomaltoside. Patients were selected based on clear biochemical evidence of iron-deficiency anemia without other major causes of anemia present. Patients receiving iron isomaltoside more rapidly achieved significant improvement in hemoglobin (increase ≥2 g/dL at week 12 in 65.8% of patients versus 53.6% of those receiving iron sucrose). These patients were more likely to have cutaneous adverse reactions, but less likely to have gastrointestinal reactions. Overall, both treatments were well-tolerated. In conclusion, iron isomaltoside may be a reasonable choice for iron supplementation is patients that cannot be successfully treated for iron-deficiency anemia with oral iron. However, the risk may be marginal, and there are trade-offs in side effect profiles. Cost should also be considered when deciding to use this new agent.

Point-of-care ultrasonography for evaluation of acute dyspnea in the emergency department14

In this prospective study of 2683 consecutive patients presenting to the emergency department with a chief complaint of dyspnea, diagnosis from usual ED care was compared to diagnosis using point-of-care ultrasound by an independent operator. Overall, agreement on diagnosis was high. Ultrasound was more sensitive than the ED workup for a diagnosis of heart failure. No difference was found in the diagnosis of ACS, pneumonia, pleural effusion, pericardial effusion and pneumothorax. ED workup was more sensitive for making the diagnoses of COPD, asthma and PE.

Detection of Occult Hepatitis C Virus Infection in Patients Who Achieved a Sustained Virologic Response to Direct-Acting Antiviral Agents for Recurrent Infection After Liver Transplantation15

In this study of 134 patients with recurrent HCV infection after liver transplantation, 129 achieved sustained virologic response after treatment with direct-acting antiviral therapy with or without ribavirin. Of these patients, 14 had persistently abnormal LFTs, and 5 were found to have occult HCV infection by detection of negative strand viral genetic material, despite persistently negative HCV PCR.

Dr.  Jack Dougherty is an internal medicine resident at NYU Langone Medical Center

Peer reviewed by Neha Jindal, MD, Attending Physician, Hospitalist Medicine at NYU Langone Medical Center

Image courtesy of Wikimedia Commons 


  1. Gwinn, Dylan. Breitbart News. Transgender Wrestler Receives Testosterone Treatments, Wins Girls State Wrestling Championship. 27 Feb 2017.
  2. Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA. 2017;317(7):708-716.
  3. Oh JY, Barrett-connor E, Wedick NM, Wingard DL. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care. 2002;25(1):55-60.
  4. Smith GD, Ben-shlomo Y, Beswick A, Yarnell J, Lightman S, Elwood P. Cortisol, testosterone, and coronary heart disease: prospective evidence from the Caerphilly study. Circulation. 2005;112(3):332-40.
  5. Gaur S, Øvrehus KA, Dey D, et al. Coronary plaque quantification and fractional flow reserve by coronary computed tomography angiography identify ischaemia-causing lesions. Eur Heart J. 2016;37(15):1220-7.
  6. Miszalski-jamka T, Klimeczek P, Banyś R, et al. The composition and extent of coronary artery plaque detected by multislice computed tomographic angiography provides incremental prognostic value in patients with suspected coronary artery disease. Int J Cardiovasc Imaging. 2012;28(3):621-31.
  7. Resnick SM, Matsumoto AM, Stephens-shields AJ, et al. Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment. JAMA. 2017;317(7):717-727.
  8. Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis: A Meta-analysis. JAMA Intern Med. 2017.
  9. Singal AK, Guturu P, Hmoud B, Kuo YF, Salameh H, Wiesner RH. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation. 2013;95(5):755-60.
  10. Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61(5):1547-54.
  11. Angulo P, Kleiner DE, Dam-larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015;149(2):389-97.e10.
  12. Quinn RR, Oliver MJ, Devoe D, et al. The Effect of Predialysis Fistula Attempt on Risk of All-Cause and Access-Related Death. J Am Soc Nephrol. 2017;28(2):613-620.
  13. Derman R, Roman E, Modiano MR, Achebe MM, Thomsen LL, Auerbach M. A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia. Am J Hematol. 2017;92(3):286-291.
  14. Zanobetti M, Scorpiniti M, Gigli C, et al. Point-of-care ultrasonography for evaluation of acute dyspnea in the emergency department. Chest. 2017.
  15. Elmasry S, Wadhwa S, Bang BR, et al. Detection of Occult Hepatitis C Virus Infection in Patients Who Achieved a Sustained Virologic Response to Direct-Acting Antiviral Agents for Recurrent Infection After Liver Transplantation. Gastroenterology. 2017;152(3):550-553.e8.

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