Validation of the Performance of MRE for the Detection of Advanced Fibrosis due to NASH across Multiple Clinical Trials

( Rohit Loomba ),( Naim Alkhouri ),( Mazen Noureddin ),( Jie Zhang ),( Bryan J. Mccolgan ),( C. Stephen Djedjos ),( Robert P. Myers ),( Michael Middleton ),( Zachary Goodman ),( Kris Kowdley ),( Atsus 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Magnetic resonance elastography(MRE) is a quantitative imaging biomarker for the detection of advanced fibrosis due to NASH. Our aim was to validate the performance of MRE for detection of advanced fibrosis using data from multiple clinical trials. Methods: Baseline data were pooled on 296 subjects with NASH from seven randomized, phase 2 and 3 trials including ATLAS and STELLAR-3/-4 trials. All subjects underwent 2D MRE and liver biopsy with staging of fibrosis according to NASH CRN classification. Associations between MRE-stiffness, fibrosis stage, noninvasive tests (NITs) of fibrosis (ELF, FibroTest, FIB-4, NAFLD Fibrosis Score [NFS]), and NASH activity (NAFLD Activity Score ≥5 vs <5) were determined. The discrimination of MRE for advanced fibrosis (F3-F4 vs F0-F2) and cirrhosis (F4 vs F0- F3) was evaluated using areas under receiver operating characteristic (AUROC) curves, and cutoffs from literature-based MRE thresholds (3.64 and 4.67 kPa, respectively) and optimal thresholds(defined by the maximal sum of sensitivity and specificity) were determined. Results: Among 296 subjects, fibrosis stages were F0-1(6%), F2(11%), F3(44%), and F4(40%); median MRE-stiffness was 4.71 kPa(IQR 3.52, 6.35). MRE-stiffness was correlated with fibrosis stage(Spearman ρ=0.60), and other NITs of fibrosis(ρ =0.47-0.52; all P<0.05). The AUROCs(95% CI) of MRE-stiffness for detecting advanced fibrosis and cirrhosis were 0.85(0.80, 0.90) and 0.81(0.76, 0.86), respectively. In general, cutoffs from the literature and optimal cutoffs derived from this dataset had similar performance for classification of fibrosis by 2D MRE. Among subjects with F0-F2 fibrosis on biopsy, those with MRE-stiffness ≥3.64 kPa (potential misclassification) had higher ELF and FibroSure than those with MRE-stiffness <3.64 kPa (both P<0.05). Conversely, among subjects with F3-F4 fibrosis on biopsy, those with MRE-stiffness <3.64 kPa had lower ELF, FibroSure, FIB-4, and NFS compared with those with MRE-stiffness ≥3.64 kPa(all P<0.05). Conclusions: This multi-center, multi-study validation demonstrates the clinical utility of 2D MRE for the detection of advanced fibrosis due to NASH.

Hepatocellular carcinoma surveillance in the 21st century: Saving lives or causing harm?

Ibrahim A. Hanouneh,Naim Alkhouri,Amit G. Singal 대한간학회 2019 Clinical and Molecular Hepatology(대한간학회지) Vol.25 No.3

Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. Prognosis and treatment options largely depend on tumor stage at diagnosis, with curative treatments only available if detected at an early stage. However, two thirds of patients with HCC are diagnosed at a late stage and not eligible for cure. Therefore several liver professional societies recommend HCC surveillance using abdominal ultrasound with or without alpha fetoprotein in at-risk populations, including patients with cirrhosis and subsets of those with chronic hepatitis B. Available data suggest HCC surveillance can significantly improve early tumor detection, curative treatment eligibility, and overall survival. However, the potential benefits of HCC surveillance must be considered in light a shifting HCC demographic from a viral-mediated cancer to an increasing proportion of patients having non-alcoholic steatohepatitis, which has been shown to limit ultrasound sensitivity and may mitigate observed benefits. Further, benefits of HCC surveillance must be weighed against potential physical, financial and psychological harms. Continued data for both benefits and harms of HCC surveillance in contemporary populations are necessary. In the interim, providers should continue to strive for high quality HCC surveillance in at-risk patients.

Use of Ledipasvir/Sofosbuvir (LDV/SOF) in Patients with Advanced Chronic Kidney Disease (eGFR ≤30ml/min): A Case Series

( Meghan E. Sise ),( Naim Alkhouri ),( Brian Borg ),( Sooji Lee ),( Thomas Mcquaid ),( Joseph Llewellyn ),( Macky Natha ),( Shampa De-oertel ),( Diana M. Brainard ),( Marc Carp ),( Michael Fuchs ),( H 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Little is known about the safety and efficacy of LDV/SOF in patients with advanced chronic kidney disease (CKD) with eGFR ≤ 30 ml/min or on hemodialysis. Yet, off-label use of LDV/SOF in this population occurs. Methods: Providers proactively reporting such off-label use to Gilead Sciences were asked to submit de-identified case reports. Demographics, clinical characteristics at baseline, during, and after LDV/SOF treatment, and adverse events were collected. Summary statistics and paired sample t-tests are presented. Results: Twenty-one case summaries were submitted. Median Age was 59 (range 26-71). Eleven patients (52%) were black, 20 had genotype 1 (13-1a, 4-1b) and one patient had genotype 3. Median pretreatment viral load was 1,680,000 IU (range 133,000-37,200,000 IU). Twelve patients (56%) were on hemodialysis and 9 had CKD Stage 4 (eGFR 15-29 ml/min), 13 (62%) had cirrhosis, 11 (50%) had diabetes, 5 had history of organ transplantation (4 kidney, 1 liver). All patients received full dose LDV/SOF for 12 weeks with one patient also receiving 200 mg Ribavirin every other day in combination. Eight adverse events were reported; 2 patients (10%) with anemia, 1 case of insomnia, nausea/vomiting, headache, and chest pain (5%) each. Of the 9 patients with CKD stage 4, 2 experienced an increase in eGFR and 5 a decrease in eGFR post treatment. All 21 patients achieved SVR 12 (100%). No patient discontinued treatment due to an adverse event. Conclusions: In this small case series describing the use of ledipasvir/sofosbuvir in Patients with Advanced Chronic Kidney Disease: 62% had cirrhosis, 52% had diabetes mellitus, and 57% were on hemodialysis. All 21 patients achieved SVR12 including 12 patients on hemodialysis. LDV/SOF was relatively well tolerated and there were no treatment discontinuations. Most patients had stable renal function before and after treatment with LDV/SOF.

Low Serum Potassium Levels Associated with Disease Severity in Children with Nonalcoholic Fatty Liver Disease

Tabbaa, Adam,Shaker, Mina,Lopez, Rocio,Hoshemand, Kazem,Nobili, Valerio,Alkhouri, Naim The Korean Society of Pediatric Gastroenterology 2015 Pediatric gastroenterology, hepatology & nutrition Vol.18 No.3

Purpose: Recent studies have suggested that decreased serum potassium level may contribute to various metabolic disorders in adult patients including nonalcoholic fatty liver disease (NAFLD). We aimed to study the correlation between serum potassium levels and the histologic severity of NAFLD in children. Methods: Pediatric patients with biopsy-proven NAFLD were included in this study. Demographic, clinical, and histopathological data were obtained. Multivariable logistic regression analysis was used to assess whether potassium levels are associated with the presence of nonalcoholic steatohepatitis (NASH) or fibrosis after adjusting for possible confounders. A p-value <0.05 was considered statistically significant. Results: Among 125 biopsies, 49.6% (62) had evidence of NASH while 66.4% (83) had some degree of fibrosis (stage 1-3). Mean serum potassium was significantly lower in NASH group as compared to non-NASH group ($4.4{\pm}0.42mmoL/L$ vs. $4.8{\pm}0.21$, p<0.001). Higher potassium level had negative correlation with presence of steatosis, ballooning, lobular inflammation, fibrosis and NAFLD activity score (p<0.05). On multivariable analysis and after adjusting for the metabolic syndrome and insulin resistance, higher potassium level was significantly associated with lower likelihood of having a histological diagnosis of NASH on biopsy (odds ratio [OR], 0.12; 95% confidence interval [95% CI], 0.05-0.28; p<0.001). Similarly, the likelihood of having fibrosis decreases by 76% for every 0.5 mmoL/L increase in potassium (OR, 0.24; 95% CI, 0.11-0.54; p<0.001). Conclusion: Our study shows an inverse relationship between serum potassium levels and the presence of aggressive disease (NASH and fibrosis) in children with NAFLD.

Low Serum Potassium Levels Associated with Disease Severity in Children with Nonalcoholic Fatty Liver Disease

Adam Tabbaa,Mina Shaker,Rocio Lopez,Kazem Hoshemand,Valerio Nobili,Naim Alkhouri 대한소아소화기영양학회 2015 Pediatric gastroenterology, hepatology & nutrition Vol.18 No.3

Purpose: Recent studies have suggested that decreased serum potassium level may contribute to various metabolic disorders in adult patients including nonalcoholic fatty liver disease (NAFLD). We aimed to study the correlation between serum potassium levels and the histologic severity of NAFLD in children. Methods: Pediatric patients with biopsy-proven NAFLD were included in this study. Demographic, clinical, and histo-pathological data were obtained. Multivariable logistic regression analysis was used to assess whether potassium levels are associated with the presence of nonalcoholic steatohepatitis (NASH) or fibrosis after adjusting for possible confounders. A p-value <0.05 was considered statistically significant. Results: Among 125 biopsies, 49.6% (62) had evidence of NASH while 66.4% (83) had some degree of fibrosis (stage 1-3). Mean serum potassium was significantly lower in NASH group as compared to non-NASH group (4.4±0.42mmoL/L vs. 4.8±0.21, p<0.001). Higher potassium level had negative correlation with presence of steatosis, balloon-ing, lobular inflammation, fibrosis and NAFLD activity score (p<0.05). On multivariable analysis and after adjusting for the metabolic syndrome and insulin resistance, higher potassium level was significantly associated with lower likelihood of having a histological diagnosis of NASH on biopsy (odds ratio [OR], 0.12; 95% confidence interval [95% CI], 0.05-0.28; p<0.001). Similarly, the likelihood of having fibrosis decreases by 76% for every 0.5 mmoL/L increase in potassium (OR ,0.24; 95% CI, 0.11-0.54; p<0.001).Conclusion: Our study shows an inverse relationship between serum potassium levels and the presence of ag-gressive disease (NASH and fibrosis) in children with NAFLD.

Race Does Not Affect the Performance of Noninvasive Tests for the Discrimination of Advanced Fibrosis due to Non-Alcoholic Steatohepatitis(NASH)

( Won Young Tak ),( Vincent Wai-sun Wong ),( George Boon Bee Goh ),( Pin-nan Cheng ),( Eric J. Lawitz ),( Zobair M. Younossi ),( Raj Vuppalanchi ),( Natalie H. Bzowej ),( Ziad Younes ),( Naim Alkhouri 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Background: Routinely available noninvasive tests of fibrosis (NITs) can be used to identify patients with advanced fibrosis due to NASH, but their performance may vary by race. Our aim was to evaluate the effect of patient race on the diagnostic performance of NITs using data from the global phase 3 STELLAR studies of selonsertib. Methods: The STELLAR studies (NCT03053050 and NCT03053063) enrolled patients with bridging fibrosis (F3) or compensated cirrhosis (F4) due to NASH (NAFLD Activity Score [NAS] ≥3). Baseline liver biopsies were centrally read using the NASH Clinical Research Network classification and NITs, including the NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by transient elastography (LS by TE) were measured. The performance of these tests to discriminate advanced (F3-F4) fibrosis by self-reported patient race was evaluated using areas under the receiver operating characteristics curves (AUROCs) with 5-fold cross-validation repeated 100x. Results for White and Asian patients are presented; data for other races (5% of patients screened) are excluded. Results: Among 3202 patients screened for the STELLAR studies with evaluable liver histology, 24% were Asian and 71% were White. The median age was 58 years in both groups; 47% of Asians and 57% of Whites were female (p<0.0001). The prevalence of F3-F4 fibrosis was 67% in Asians and 72% in Whites (p=0.01). AUROCs for each of the NITS for the discrimination of advanced fibrosis were similar between Asian and White patients (Table). In general, literature-based thresholds for the NITs had similar sensitivity and specificity among the specific racial subgroups. Conclusion: In these large, global phase 3 trials, the diagnostic performance of routinely available NITs for the discrimination of advanced fibrosis due to NASH was acceptable and similar between Asian and White patients.