Primecuts – This Week In The Journals

August 11, 2014

By Kerrilynn Carney, MD

Peer Reviewed

In global news this week, shots resume as the ceasefire expires between Israel and Hamas. Strikes in Gaza were quickly followed by those in Iraq, where President Obama authorized military strikes on Islamic state militants advancing toward the US consulate and military personnel residing in the city of Irbil. A US journalist was arrested in Iran for unknown reason and the struggle to contain Ebola marches on. Among the wave of violence and contagion abroad, at home Dr. Kent Brantley -the American missionary worker infected with Ebola- is “getting stronger everyday” and putting out messages of faith and hope from his isolation room at Emory University Hospital. In more encouraging healthcare news, a $16 billion bill passed overwhelmingly by the Congress promises veterans better access to quality healthcare. McDonald’s posted a 3.2% decrease in country-wide same-store sales, its worst month for over a decade, and primary care positions open up in Walmart as the retail giant pilots five primary care locations in South Carolina and Texas. As for the week in Primecuts, we’ll take a critical look at the clinical and histological features of statin-induced hepatotoxicity, highlight advances in the efficiency of breast cancer screening techniques, review enzalutamide, an oral androgen-receptor inhibitor providing new hope for men with metastatic castration-resistant prostate cancer, and take a look at a new diagnostic method for living patients with Creutzfeldt-Jakob disease.

Statin-induced hepatotoxicity; a rare and varied beast:

Statins are among the most frequently prescribed medications worldwide, with over 143 million prescriptions dispensed annually in the US alone[1]. Despite initial concern for their potential to cause liver injury, statins as a class are overall well-tolerated and more severe side effects including myositis and myalgias are generally dose-dependent[2]. Mild serum aminotransferase elevations seen in only 3% of patients are usually seen within the first year of therapy, and are rarely associated with clinical liver disease[2, 3]. In Hepatology this week, a prospective cohort study was published reporting the presenting features and outcomes of patients with clinically apparent liver injury due to statins(1). Among 1188 cases of drug-induced liver injury registered by the U.S. Drug-Induced Liver Injury Network (DILIN) between 2004 and 2012, only 22 were attributed to a statin. In attributing the liver injury to a statin, other causes of acute liver injury were excluded, including viral hepatitis, alcohol, pancreatic, biliary, and metabolic liver disease. Cases were also excluded if a non-statin drug was thought by expert opinion to be a more likely culprit of liver injury in each case. Almost all statins were represented in the 22 cases reviewed and the daily dose was within the recommended range. The latency (time from starting the statin to the onset of liver injury) varied widely ranging from 34 days to more than 10 years, with most cases (77%) occurring within the first year of therapy. Nineteen patients had clinical symptoms at the time of onset, most commonly jaundice (15/22, 68%) and itching (8/22, 36%). Three were asymptomatic, with liver injury detected upon routine liver tests. Each case was assigned a severity score at the onset from 1-5, ranging from serum enzyme elevation alone to death. Sixty four percent of scores (14/22) were mild to moderate (severity scores 1-2) presenting with serum enzyme elevation and jaundice without the need for hospitalization, signs of organ failure, or death. Phenotypes of liver injury were categorized based on a ratio (R ratio) of serum alanine aminotransferase (ALT) to alkaline phosphatase, those with R>5 being hepatocellular and those <2 being cholestatic, with a total of 12 hepatocellular, 7 cholestatic, and 2 mixed phenotypes. The 12 hepatocellular cases were further categorized as having prominent autoimmune features or not. Six of these 12 cases had high levels of auto-antibodies (ANA or ASMA >1:80) or a liver biopsy suggesting autoimmune hepatitis (moderate-severe lymphocytic hepatitis with plasma cells) or both.

In conclusion, clinically apparent liver injury caused by statins is extremely rare, and when it is precipitated there is no single defining pattern of either histological or phenotypic pathology. The disease can range from mild to severe, have short and long latency, and present with very cholestatic and very hepatocellular phenotypes. Clinical features neither correlated with the type of statin nor conventional clinical demographics of patients. One apparently unifying characteristic is that all cases rapidly reversed upon stopping the offending medication, unless there was an underlying diathesis for autoimmune hepatitis, in which case those patients were more likely to develop chronic liver injury.

Abbreviated breast MRI, a novel approach to screening:

MRI offers a high sensitivity for breast cancer [4], but is associated with many indirect and direct costs [5, 6]. One reason for the high cost is the fact that current breast MRI protocols are time consuming to acquire and read. MRI tends to be reserved for cases of diagnostic uncertainty or to classify with accuracy the extent of existing disease. In a prospective observational reader study published in the Journal of Clinical Oncology, a total of 443 women at mildly to moderately increased risk of breast cancer were analyzed with an abbreviated screening protocol by MRI [7]. Eligible women had normal or benign digital mammograms, and, for those with heterogeneously dense or extremely dense breasts, normal or benign ultrasounds. The imaging protocol was captured and read by an expert breast radiologist (defined as reading annual caseloads of greater than 800 breast MRIs) in a 3-stage process. First postcontrast subtracted images (FAST) images were recorded then fused into a single summation image- the maximum intensity projection (MIP), which was presented together as the abbreviated protocol (AP) to be read while patients underwent the regular full diagnostic protocol (FDP). To avoid knowledge of FDP findings from confounding the AP readings, readers read the images in the same standardized order (first MIP only; second FAST – together being the full AP; and finally FDP images). Acquisition time for the AP was 184 seconds, for the FDP it was 1,024 seconds. Average time to read the complete AP was 28 seconds, which compares favorably to batch reading of digital screening mammograms, which range between 60 and 120 seconds (40-41). Diagnostic accuracy and cancer yield were equivalent to those of regular breast MRI protocols. Sensitivity and negative predictive value were 100% for both AP and FDP readings. Specificity and positive predictive value of AP readings did not differ significantly (P=0.563) from those of the FDP (94.3% v 93.9% and 24.4 % v 23.4%, respectively). Eleven breast cancers were diagnosed for an additional cancer yield of 18.15 per 1,000 screening rounds (women-years) and a breast cancer incidence of 11 (2.5%) of 443. All invasive cancers were T1N0 cancers, with a median size of 8mm. An additional 23 breast biopsies were performed and yielded benign changes: adenosis in 21 patients and fibroadenoma and fat necrosis in one patient each. High risk but benign lesions were detected in eight of these women. Although this study proposes some interesting techniques to shorten the traditional breast MRI protocol and make it more accessible and cost-effective as a screening modality, questions remain as to the burden of false positives compared to traditional mammography and ultrasound as well as the utility of MRI in community practices utilizing non-expert readers. Additional information would be required before screening MRI could take the place of conventional mammography, and longer follow up would be needed before a true mortality benefit could be proven in cancers detected by this highly specific modality.

Enzalutamide, a new option before cytotoxic chemotherapy for castration-resistant, metastatic prostate cancer:

Prostate cancer is a legitimate fear for men as they age. Not only is it the most commonly diagnosed cancer over all, but it is also the sixth leading cause of cancer-related death among men worldwide [8] . In most patients who are treated for advanced recurrent prostate cancer with androgen-deprivation therapy, disease progression occurs despite effective suppression of serum testosterone. Preclinical evidence suggests that androgen-receptor overexpression is sufficient to confer resistance to androgen deprivation, a disease state called castration-resistance [9, 10]. Of the new treatment options targeting this phenomenon, enzalutamide is an oral androgen-receptor inhibitor featured in the NEJM this week with the support of Medivation and Astellas Pharma [11]. In this double blind, phase 3 study, 1717 men with metastatic castration-resistant prostate cancer were randomized to receive either enzalutamide at a dose of 160mg or placebo once daily. To be included in the analysis, at the time of enrollment these men could not have undergone any cytotoxic chemotherapy. Coprimary end points were radiographic progression free survival and overall survival. Secondary end points included the time until the initiation of cytotoxic chemotherapy, the time until the first skeletal-related event, decline in PSA level of 50% or more from baseline, and the time until PSA progression. The study was stopped after a planned interim analysis showed a benefit of active treatment. The rate of radiographic progression-free survival at 12 months was 65% for those treated as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared to 532 patients (63%) in the placebo group were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35) and the time until PSA progression (0.17), with a rate of decline of at least 50% in PSA (78% vs. 3%) with P<0.001 for all comparisons. The most common clinically significant adverse drug events were fatigue and hypertension, which seem a small price to pay for the significantly decreased risk of radiographic progression, death, or need for escalation to cytotoxic chemotherapy in men with metastatic prostate cancer.

A test for Creutzfeldt-Jakob disease using nasal brushings:

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative spongiform encephalopathy that is uniformly fatal in humans and animals [12, 13]. Sporadic CJD, is clinically heterogeneous and includes forms characterized by psychotic symptoms, depression, and behavioral and personality changes [14, 15]. Possible or probable sporadic CJD is typically defined on the basis of clinical features, as well as periodic sharp and slow wave complexes on electroencephalograms, a positive 14-3-3 protein assay of cerebrospinal fluid samples, and altered signals on brain magnetic resonance images (MRI) [16]. Definite diagnosis of sporadic CJD requires neuropathological or immunochemical detection of the prion protein (PrPCJD) in brain tissue, which is usually acquired post mortem as there is a risk of iatrogenic transmission [17]. PrPCJD arises through the post-translational conformational conversion of the normal endogenous PrP and accumulates preferentially in nervous tissue. Although PrPCJD is the only specific marker for CJD, it has been difficult to identify a PrPCJD assay and procedure for obtaining a tissue specimen that is sufficiently sensitive, noninvasive, and practical for use in living patients, and safe for practitioners. Recent testing of cerebrospinal fluid with a new in vitro PrPCJD amplification technology, designated real-time quaking-induced conversion (RT-QuIC), has shown considerable promise as a highly specific diagnostic test for sporadic CJD; however, the sensitivity is closer to 80 or 90%[18, 19]. This week, NEJM has several articles detailing new modalities for diagnosing sporadic CJD including urine samples [20] and nasal brushings, the latter of which will be discussed further here [21]. In one study in Italy, 31 patients with rapidly progressive dementia were referred for possible or probable CJD. Through clinical history and a battery of tests including LP for Tau level, 14-3-3 level, MRI, and EEG, all 29 of 31 referrals were classified as probable CJD and 2 were diagnosed as having inherited forms of the disease. Controls were comprised of twelve patients with other neurodegenerative disorders including Alzheimer’s and Parkinson’s disease as well as 31 patients without neurological disorders referred to ENT clinic for another purpose. All enrollees underwent olfactory mucosal sampling via nasal brushing. Overall, 30 of 31 nasal brushings from patients with apparent CJD tested positive, representing an estimated sensitivity of 97% (95% confidence interval [CI], 82 to 100). All control patients tested negative, yielding a specificity of 100% (95% CI, 90 to 100). In contrast, RT-QuIC analysis of cerebrospinal fluid samples of the same patient cohort had a sensitivity of 77% (95% CI, 57 to 89), with only 23/30 positive tests from patients with apparent CJD. Without treatment options, the clinical significance of these screening test remains unclear; however, implications for transmission via contact with nasal secretions from infected patients warrants consideration when it comes to hospital infection control policies.

Other articles in brief:

-An article in JAMA found that high-protein enteral nutrition enriched with immune-modulating nutrients did not improve infectious complications and may be harmful as suggested by increased adjusted mortality at 6 months in intubated adult patients in an ICU setting[22].

-A randomized clinical trial also in JAMA showed a one-time brief intervention for problem drug use with an attempted telephone booster had no effect on drug use in patients seen in safety-net primary care settings[23].

-A model-study published in Annals of Internal Medicine reflects on the changing burden of hepatitis C infection in the United States and recommends strategies including a more aggressive 1-time universal screening method to identify a larger pool of infected patients and link them to care[24].

Dr. Kerrilynn Carney is a 1st year resident at NYU Langone Medical Center

Peer Reviewed Karin Katz, M.D., Internal Medicine Resident, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

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2. Beltowski J, Wojcicka G, Jamroz-Wisniewska A. Adverse effects of statins – mechanisms and consequences. Curr Drug Saf 2009;4:209-228. http://www.eurekaselect.com/69865/article

3. Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005;41:690-695. http://onlinelibrary.wiley.com/doi/10.1002/hep.20671/abstract

4. Mahoney MC, Gatsonis C, Hanna L, DeMartini WB, Lehman C. Positive predictive value of BI-RADS MR imaging. Radiology 2012;264:51-58. http://bit.ly/1kv9m4e

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7.Kuhl CK, Schrading S, Strobel K, Schild HH, Hilgers RD, Bieling HB. Abbreviated Breast Magnetic Resonance Imaging (MRI): First Postcontrast Subtracted Images and Maximum-Intensity Projection-A Novel Approach to Breast Cancer Screening With MRI. J Clin Oncol 2014;32:2304-2310. http://jco.ascopubs.org/content/32/22/2304.long

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10. Knudsen KE, Scher HI. Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res 2009;15:4792-4798. http://clincancerres.aacrjournals.org/content/15/15/4792.long

11. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424-433. http://www.nejm.org/doi/full/10.1056/NEJMoa1405095

12. Prusiner SB. Prions. Proc Natl Acad Sci U S A 1998;95:13363-13383. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9811807

13. Caughey B, Baron GS, Chesebro B, Jeffrey M. Getting a grip on prions: oligomers, amyloids, and pathological membrane interactions. Annu Rev Biochem 2009;78:177-204. http://bit.ly/1ug1VRI

14. Krasnianski A, Schulz-Schaeffer WJ, Kallenberg K, Meissner B, Collie DA, Roeber S, Bartl M, et al. Clinical findings and diagnostic tests in the MV2 subtype of sporadic CJD. Brain 2006;129:2288-2296. http://brain.oxfordjournals.org/content/129/9/2288.long

15. Puoti G, Bizzi A, Forloni G, Safar JG, Tagliavini F, Gambetti P. Sporadic human prion diseases: molecular insights and diagnosis. Lancet Neurol 2012;11:618-628. http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(12)70063-7/fulltext

16. Zerr I, Kallenberg K, Summers DM, Romero C, Taratuto A, Heinemann U, Breithaupt M, et al. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain 2009;132:2659-2668. http://brain.oxfordjournals.org/content/132/10/2659.long

17. Budka H, Aguzzi A, Brown P, Brucher JM, Bugiani O, Gullotta F, Haltia M, et al. Neuropathological diagnostic criteria for Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathol 1995;5:459-466. http://bit.ly/1yl8a4n

18. Atarashi R, Sano K, Satoh K, Nishida N. Real-time quaking-induced conversion: a highly sensitive assay for prion detection. Prion 2011;5:150-153. https://www.landesbioscience.com/journals/prion/article/16893/?nocache=1811687284

19. McGuire LI, Peden AH, Orru CD, Wilham JM, Appleford NE, Mallinson G, Andrews M, et al. Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Ann Neurol 2012;72:278-285. http://onlinelibrary.wiley.com/doi/10.1002/ana.23589/abstract

20. Moda F, Gambetti P, Notari S, Concha-Marambio L, Catania M, Park KW, Maderna E, et al. Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 2014;371:530-539. http://www.nejm.org/doi/full/10.1056/NEJMoa1404401

21. Orru CD, Bongianni M, Tonoli G, Ferrari S, Hughson AG, Groveman BR, Fiorini M, et al. A test for Creutzfeldt-Jakob disease using nasal brushings. N Engl J Med 2014;371:519-529. http://www.nejm.org/doi/full/10.1056/NEJMoa1315200?query=featured_home

22. van Zanten AR, Sztark F, Kaisers UX, Zielmann S, Felbinger TW, Sablotzki AR, De Waele JJ, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. Jama 2014;312:514-524. http://jama.jamanetwork.com/article.aspx?articleid=1892247

23. Roy-Byrne P, Bumgardner K, Krupski A, Dunn C, Ries R, Donovan D, West, II, et al. Brief intervention for problem drug use in safety-net primary care settings: a randomized clinical trial. Jama 2014;312:492-501. http://jama.jamanetwork.com/article.aspx?articleid=1892226

24. Kabiri M, Jazwinski AB, Roberts MS, Schaefer AJ, Chhatwal J. The changing burden of hepatitis C virus infection in the United States: model-based predictions. Ann Intern Med 2014;161:170-180. http://annals.org/article.aspx?articleid=1892615

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