Steven C. Lin

Noninvasive Diagnosis of Nonalcoholic Fatty Liver Disease and Quantification of Liver Fat Using a New Quantitative Ultrasound Technique

BACKGROUND & AIMS Liver biopsy analysis is the standard method used to diagnose nonalcoholic fatty liver disease (NAFLD). Advanced magnetic resonance imaging is a noninvasive procedure that can accurately diagnose and quantify steatosis, but is expensive. Conventional ultrasound is more accessible but identifies steatosis with low levels of sensitivity, specificity, and quantitative accuracy, and results vary among technicians. A new quantitative ultrasound (QUS) technique can identify steatosis in animal models. We assessed the accuracy of QUS in the diagnosis and quantification of hepatic steatosis, comparing findings with those from magnetic resonance imaging proton density fat fraction (MRI-PDFF) analysis as a reference. METHODS We performed a prospective, cross-sectional analysis of a cohort of adults (N = 204) with NAFLD (MRI-PDFF, ≥5%) and without NAFLD (controls). Subjects underwent MRI-PDFF and QUS analyses of the liver on the same day at the University of California, San Diego, from February 2012 through March 2014. QUS parameters and backscatter coefficient (BSC) values were calculated. Patients were assigned randomly to training (n = 102; mean age, 51 ± 17 y; mean body mass index, 31 ± 7 kg/m(2)) and validation (n = 102; mean age, 49 ± 17 y; body mass index, 30 ± 6 kg/m(2)) groups; 69% of patients in each group had NAFLD. RESULTS BSC (range, 0.00005-0.25 1/cm-sr) correlated with MRI-PDFF (Spearman ρ = 0.80; P < .0001). In the training group, the BSC analysis identified patients with NAFLD with an area under the curve value of 0.98 (95% confidence interval, 0.95-1.00; P < .0001). The optimal BSC cut-off value identified patients with NAFLD in the training and validation groups with 93% and 87% sensitivity, 97% and 91% specificity, 86% and 76% negative predictive values, and 99% and 95% positive predictive values, respectively. CONCLUSIONS QUS measurements of BSC can accurately diagnose and quantify hepatic steatosis, based on a cross-sectional analysis that used MRI-PDFF as the reference. With further validation, QUS could be an inexpensive, widely available method to screen the general or at-risk population for NAFLD.

Silent virtuous teachers: anatomical dissection in Taiwan

Steven C Lin, Julia Hsu, and Victoria Y Fan describe how the dissection course at Tzu Chi College of Medicine in Taiwan has motivated and inspired people to donate their bodies for scientific endeavours, an otherwise culturally avoided gesture in the East

Assessment of treatment response in non‐alcoholic steatohepatitis using advanced magnetic resonance imaging

Magnetic resonance imaging‐derived measures of liver fat and volume are emerging as accurate, non‐invasive imaging biomarkers in non‐alcoholic steatohepatitis (NASH). Little is known about these measures in relation to histology longitudinally.

It is time to include compassion in medical training.

1 Abedini NC, Gruppen LD, Kolars JC, Kumagai AK. Understanding the effects of short-term international service–learning trips on medical students. Acad Med. 2012;87:820–828. 2 Crump JA, Sugarman J. Ethical considerations for short-term experiences by trainees in global health. JAMA. 2008;300:1456–1458. 3 Crump JA, Sugarman J; Working Group on Ethics Guidelines for Global Health Training (WEIGHT). Ethics and best practice guidelines for training experiences in global health. Am J Trop Med Hyg. 2010;83:1178–1182. 4 Stanford University Center for Global Health; Johns Hopkins University Berman Institute of Bioethics. Ethical Challenges in Short-Term Global Health Training. www. ethicsandglobalhealth.org. Accessed August 31, 2012.

Cardiovascular risk assessment in the treatment of nonalcoholic steatohepatitis: a secondary analysis of the MOZART trial

Background: Nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular risk and mortality. No US Food and Drug Administration (FDA) approved therapies for NASH are available; clinical trials to date have not yet systematically assessed for changes in cardiovascular risk. This study examines the prospective utility of cardiovascular risk assessments, the Framingham risk score (FRS) and coronary artery calcium (CAC) score, as endpoints in a NASH randomized clinical trial, and assesses whether histologic improvements lead to lower cardiovascular risk. Methods: Secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial (MOZART) in which 50 biopsy-proven NASH patients received oral ezetimibe 10 mg daily (n = 25) versus placebo (n = 25). Biochemical profiling, FRS, CAC scores, liver biopsies were obtained at baseline and endpoint. Results: Ezetimibe improved FRS whereas placebo did not (4.4 ± 6.2 to 2.9 ± 4.8, p = 0.038; 3.0 ± 4.4 to 2.9 ± 4.2, p = 0.794). CAC scores did not change with ezetimibe or placebo (180.4 ± 577.2 to 194.1 ± 623.9, p = 0.293; 151.4 ± 448.9 to 183.3 ± 555.7, p = 0.256). Ezetimibe improved FRS and CAC scores in more patients than placebo (48% versus 23%, p = 0.079, and 21% versus 0%, p = 0.090, respectively), though not significantly. No differences were noted in cardiovascular risk scores among histologic responders versus nonresponders. Conclusions: Ezetimibe improved FRS whereas placebo did not. FRS and CAC scores improved in a greater proportion of patients with ezetimibe; this trend did not reach significance. These findings indicate the utility and feasibility of monitoring cardiovascular risk in a NASH trial. The utility of CAC scores may be higher in trials of longer duration (⩾52 weeks) and with older patients (age ⩾45). ClinicalTrials.gov registration: NCT01766713.

A comparison of the performance appraisal practices of US multinational subsidiaries with parent company and local Taiwanese practices

Purpose – The purpose of this paper is to compare the performance appraisal practices of US subsidiaries in Taiwan to those of their parent firms and to those of large Taiwanese companies in an effort to understand how foreign subsidiaries adjust to the competing demands for global integration and local responsiveness.Design/methodology/approach – A stratified random sampling scheme was employed to ensure that performance appraisal practices of manufacturing firms in similar industry sectors were compared. A mail survey was chosen over other ways of gathering data because of the wide geographical dispersion of companies, the required speed of data collection, and the length of the questionnaire.Findings – The results indicate that performance appraisal is not a uniform function, but consists of practices that differ in their relative resemblance to local practices and to parent practices. This finding suggests that the competing demands for global integration and local adaptation should not be viewed as o...

Encapsulating peritoneal sclerosis

Encapsulating peritoneal sclerosis (EPS) is a debilitating condition characterized by a fibrocollagenous membrane encasing the small intestine, resulting in recurrent small bowel obstructions. EPS is most commonly associated with long-term peritoneal dialysis, though medications, peritoneal infection, and systemic inflammatory disorders have been implicated. Many cases remain idiopathic. Diagnosis is often delayed given the rarity of the disorder combined with non-specific symptoms and laboratory findings. Although cross-sectional imaging with computed tomography of the abdomen can be suggestive of the disorder, many patients undergo exploratory laparotomy for diagnosis. Mortality approaches 50% one year after diagnosis. Treatment for EPS involves treating the underlying condition or eliminating possible inciting agents (i.e. peritoneal dialysis, medications, infections) and nutritional support, frequently with total parenteral nutrition. EPS-specific treatment depends on the disease stage. In the inflammatory stage, corticosteroids are the treatment of choice, while in the fibrotic stage, tamoxifen may be beneficial. In practice, distinguishing between stages may be difficult and both may be used. Surgical intervention, consisting of peritonectomy and enterolysis, is time-consuming and high-risk and is reserved for situations in which conservative medical therapy fails in institutions with surgical expertise in this area. Herein we review the available literature of the etiology, pathogenesis, diagnosis, and treatment of this rare, but potentially devastating disease.

Fecal microbiota transplantation for recurrent Clostridium difficile infection in patients with solid organ transplants: an institutional experience and review of the literature

Clostridium difficile, an anaerobic gram‐positive, spore‐forming bacillus, has become the most common cause of nosocomial infectious diarrhea, and is associated with increased mortality in all populations. Patients who have received solid organ transplants (SOT) are at increased risk of Clostridium difficile infection (CDI) and CDI recurrence (rCDI). This may be related to chronic immunosuppression, frequent antibiotic exposure, and increased or prolonged hospitalizations. Increased morbidity and mortality from CDI is well‐described in SOT patients. Conventional treatments for index and recurrent CDI include vancomycin and fidaxomicin. Fecal microbiota transplantation has emerged as an effective and safe alternative for treating rCDI in the general population. Reports of its safety in certain immunocompromised populations, such as those with inflammatory bowel disease, appear reassuring, but outcomes among SOT patients are less well known. Here, we summarize the experiences published to date on the treatment of rCDI with FMT in SOT patient, and also describe our detailed FMT protocol and experience in treating a series of SOT patients with rCDI. In addition to reporting the safety and efficacy of our FMT experience, we also discuss the diagnostic challenges and considerations in this population of solid organ transplant recipients.

Editorial: further evidence for the use of advanced magnetic resonance imaging techniques to monitor NAFLD – authors’ reply

We thank Drs. Mansour and McPherson for their editorial summary and insightful comments on our paper exploring the utility of advanced magnetic resonance imaging (MRI) measures in assessing for treatment response in non-alcoholic steatohepatitis. 2 As they have pointed out, the increasing prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) has profound public health implications, spawning numerous clinical trials over the past decade. In order to transcend the various shortcomings of the liver biopsy and minimise the risks involved to patients, we believe MRI techniques may be the next gold standard for assessing steatosis and fibrosis. In our previous work, we have compared several novel imaging modalities to liver biopsy for the assessment of steatosis, including quantitative ultrasound and MRI-proton density fat fraction (PDFF). In a previous study, we showed that MRI-PDFF is more sensitive than liver histology for detecting incremental, longitudinal changes in hepatic fat content. Our present student expands on this trend, looking at total liver volume (TLV) and the total liver fat index (TLFI), derived from the same scan. We agree with the editorial authors that the lack of relationship between change in histological steatosis and total liver volume may be in part due to methodology, whereby our histological grade of steatosis was categorical (grade 1–3) rather than continuous (percentage steatosis). In future studies, we will consider this nuance and expand our methodology, and sample size, to further examine this relationship. We agree that fibrosis is a major determinant for classifying high-risk patients. Both the degree and trend of fibrosis in these patients with NASH – especially as we study potential therapies – is an increasingly important endpoint. Indeed, various studies are showing that the risk of liver-related mortality increase exponentially with higher fibrosis stages. While transient elastography (TE, or “FibroScan”) is generally more accessible, body habitus and volume overload (findings frequently found among this patient group often with cardiovascular comorbidities) can affect its overall accuracy. While this study did not show a statistically significant relationship between PDFF, TLV, and TLFI with histological fibrosis, we have studied in other trials the utility of MR elastography, a different type of MRI-based exam involving shear waves to evaluate liver stiffness. It has been shown to be more accurate for measuring fibrosis than TE when compared with histology, with an AUROC of 0.957 when compared with eight other clinical prediction rules for advanced fibrosis. The nuances between the various advanced MRI techniques remain to be fully elucidated. As we continue to unravel these nuances, we recently showed that 3D-MRE may be more accurate than 2D-MRE in assessing advanced fibrosis. With our present study, we believe there may be utility in assessing (changes) in liver volume and calculating total liver fat burden as well.

WE‐EF‐210‐05: Diagnosis and Quantification of Liver Steatosis with Quantitative Ultrasound Backscatter Technique

Purpose: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States, affects 30% of adult Americans and may progress to more serious diseases. Liver biopsy is the standard method for diagnosing NAFLD. MRI can accurately diagnose and quantify hepatic steatosis but is expensive. Sonography with qualitative interpretation by radiologists is lower cost, more accessible but less sensitive for detection. The objective of this study, using MRI proton density fat fraction (PDFF) as reference, is to assess the accuracy for diagnosing and quantifying steatosis with two quantitative US parameters-- backscatter coefficient (BSC) and attenuation coefficient (AC)--derived from RF signals using the calibration phantom technique. Methods: We performed a prospective, cross-sectional analysis of a cohort of adults (n=204) with NAFLD (MRI-PDFF≥5%) and without NAFLD (controls). Subjects underwent MRI-PDFF and BSC and AC US analyses of the liver on the same day. Patients were randomly assigned to training (n=102, mean age 51±17 years, mean body mass index 31±7 kg/m2) and validation (n=102, mean age 49±17 years, body mass index 30±6 kg/m2) groups; 69% of patients in each group had NAFLD. Results: BSC provided AUC 0.98 (95% CI 0.95–1.00, p<0.0001) for diagnosis of NAFLD; the optimal BSC cut-off provided sensitivity, specificity, positive and negative predictive values (PPV, NPV) of 87%, 91%, 95%, and 76%, respectively. AC provided AUC 0.89 (95% CI 0.81–0.96, p<0.0001) for diagnosis of steatosis; the optimal AC cut-off provided sensitivity, specificity, PPV, NPV of 80%, 84%, 92%, and 66%, respectively. BSC and AC both correlated significantly with MRI-PDFF (P<0.0001). Conclusion: QUS BSC and AC can accurately diagnose and quantify hepatic steatosis, using MRI-PDFF as reference. With further validation, QUS may emerge as an inexpensive, widely available tool for NAFLD assessment. General support: NIH R01 CA111289, K23 -DK090303, AmerGastroAssoc Found, TF Williams Scholarship, S3000 scanner loaned by Siemens, Sucampo, JA Hartford Found, Atlantic Philanthropies Amer Gastroenterological Assoc. Agencies had no role in design/conduct of study, collection, management, analysis or interpretation of the data; preparation, review, or approval of the manuscript.