Ernst A,Schlattmann P,Waldfahrer F,Westhofen M
Laryngo- rhino- otologie
The BEMED study (BMJ 2016; 352: DOI 10.1136) was designed as multi-centric, double-blind, plaebo-controlled study in patients with Menière's disease. It should compare a low-level (2 × 24 mg/d) vs. high-level (3 × 48 mg/d) betahstine intake vs. placebo. The primary endpoint was the "number of vertigo attacks lasting longer than 20 min as documented in a patient's diary". The main finding of the study was that betahistine did not significantly better reduced the number of vertigo attacks than placebo. Therefore, the BEMED study should be critically discussed in the present paper.
Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis.
Yilmaz Yusuf,Dolar Enver,Ulukaya Engin,Akgoz Semra,Keskin Murat,Kiyici Murat,Aker Sibel,Yilmaztepe Arzu,Gurel Selim,Gulten Macit,Nak Selim-Giray
World journal of gastroenterology
AIM:To investigate whether serum levels of two soluble forms of extracellular cytokeratin 18 (M30-antigen and M65-antigen) may differentiate nonalcoholic steatohepatitis (NASH) from simple steatosis in patients with nonalcoholic fatty liver disease (NAFLD). METHODS:A total of 83 patients with suspected NAFLD and 49 healthy volunteers were investigated. Patients with suspected NAFLD were classified according to their liver histology into four groups: definitive NASH (n=45), borderline NASH (n=24), simple fatty liver (n=9), and normal tissue (n=5). Serum levels of caspase-3 generated cytokeratin-18 fragments (M30-antigen) and total cytokeratin-18 (M65-antigen) were determined by ELISA. RESULTS:Levels of M30-antigen and M65-antigen were significantly higher in patients with definitive NASH compared to the other groups. An abnormal value (> 121.60 IU/L) of M30-antigen yielded a 60.0% sensitivity and a 97.4% specificity for the diagnosis of NASH. Sensitivity and specificity of an abnormal M65-antigen level (> 243.82 IU/L) for the diagnosis of NASH were 68.9% and 81.6%, respectively. Among patients with NAFLD, M30-antigen and M65-antigen levels distinguished between advanced fibrosis and early-stage fibrosis with a sensitivity of 64.7% and 70.6%, and a specificity of 77.3% and 71.2%, respectively. CONCLUSION:Serum levels of M30-antigen and M65-antigen may be of clinical usefulness to identify patients with NASH. Further studies are mandatory to better assess the role of these apoptonecrotic biomarkers in NAFLD pathophysiology.
Cytokeratin 18 fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis in bariatric surgery patients.
Diab Dima L,Yerian Lisa,Schauer Philip,Kashyap Sangeeta R,Lopez Rocio,Hazen Stanley L,Feldstein Ariel E
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
BACKGROUND & AIMS:Nonalcoholic fatty liver disease (NAFLD) is extremely common among morbidly obese patients. We assessed the usefulness of plasma caspase-generated cytokeratin 18 (CK-18) fragments as a novel marker for NAFLD in a bariatric cohort. METHODS:The cohort consisted of 99 consecutive patients who underwent liver biopsy at the time of bariatric surgery. CK-18 levels were measured by using an enzyme-linked immunosorbent assay before and 6 months after surgery. Patients were subdivided into 4 histologic groups: not NAFLD (normal liver biopsy), nonalcoholic fatty liver (NAFL), borderline diagnosis, and definitive nonalcoholic steatohepatitis (NASH). RESULTS:CK-18 levels were significantly higher in subjects with NASH compared with those with not NAFLD, NAFL, or borderline diagnosis (median [25th quartile, 75th quartile], 389 U/L [275, 839] vs 196 U/L [158, 245], vs 217 U/L [154, 228], or vs 200 U/L [176, 274], respectively; P < .0001). CK-18 levels were significantly higher in subjects with moderate to severe fibrosis versus those with no or mild fibrosis (334.5 U/L [240.5, 896] vs 207 U/L [175, 275], respectively; P = .007). A significant decrease in CK-18 levels was observed in most patients 6 months postoperatively. The area under the receiver operating characteristic curve for NASH diagnosis was estimated to be 0.88 (95% confidence interval, 0.77-0.99). The values with the best combination of sensitivity and specificity were 252 U/L (sensitivity, 82%; specificity, 77%) and 275 U/L (sensitivity, 77%; specificity, 100%). CONCLUSIONS:These results support the potential utility of this test for diagnosis and staging of NAFLD before bariatric surgery.
An apoptosis panel for nonalcoholic steatohepatitis diagnosis.
Tamimi Tarek I Abu-Rajab,Elgouhari Hesham M,Alkhouri Naim,Yerian Lisa M,Berk Michael P,Lopez Rocio,Schauer Phillip R,Zein Nizar N,Feldstein Ariel E
Journal of hepatology
BACKGROUND & AIMS:The extrinsic death receptor-mediated pathway of apoptosis is involved in nonalcoholic steatohepatitis (NASH) development. Our aims were to create and validate a noninvasive prediction model for NASH diagnosis based on specific circulating markers of apoptosis. METHODS:Our initial cohort consisted of 95 consecutive patients undergoing a liver biopsy for clinically suspected NASH. Blood was obtained from each patient at the time of liver biopsy. Plasma caspase 3 generated cytokeratin-18 fragments (CK-18), soluble Fas (sFas), and soluble Fas ligand (sFasL) were measured. Histology was assessed by an experienced hepatopathologist. The validation cohort consisted of 82 consecutive patients that underwent liver biopsy at the time of bariatric surgery. RESULTS:Patients with NASH had significantly higher levels of CK-18 and sFas than patients in the "not NASH" group [median (25th, 75th percentile): 508 (280, 846) U/L versus 176 (131, 224) U/L (p<0.001), and 11.8 (7.8, 12.5) ng/ml versus 5.9 (4.8, 8.3) ng/ml (p<0.001), respectively]. A significant positive correlation was revealed between the apoptosis markers and liver histopathology independent of other metabolic factors. A prediction model was generated including CK-18 fragments and sFas levels that showed an AUC of 0.93 and 0.79 in the initial and validation cohorts, respectively. A cutoff value using this model predicted NASH with a sensitivity and specificity of 88% and 89%, respectively. CONCLUSIONS:Quantification of circulating levels of two apoptotic markers accurately predicts the presence of NASH, supporting the potential usefulness of these markers in clinical practice for noninvasive diagnosis of NASH.
Combined Serum Biomarkers in Non-Invasive Diagnosis of Non-Alcoholic Steatohepatitis.
Yang Mei,Xu Dongping,Liu Yuan,Guo Xiaodong,Li Wenshu,Guo Chaonan,Zhang Hongping,Gao Yinjie,Mao Yuanli,Zhao Jingmin
BACKGROUND:Non-alcoholic steatoheaptitis (NASH), the critical stage of non-alcoholic fatty liver disease (NAFLD), is of chronic progression and can develop cirrhosis even hepatocellular carcinoma (HCC). However, non-invasive biomarkers for NASH diagnosis remain poorly applied in clinical practice. Our study aims at testing the accuracy of the combination of cytokeratin-18 M30 fragment (CK-18-M30), fibroblast growth factor 21 (FGF-21), interleukin 1 receptor antagonist (IL-1Ra), pigment epithelium-derived factor (PEDF) and osteoprotegerin (OPG) in diagnosing NAFLD and NASH. METHODS:179 patients with biopsy-proven NAFLD were enrolled as training group, 91 age- and gender-matched healthy subjects were recruited at the same time as controls. 63 other NAFLD patients were separately collected as validation group. 45 alcoholic fatty liver disease (AFLD) patients, 50 hepatitis B virus (HBV) patients, 52 hepatitis C virus (HCV) patients were also included. Serum biomarker levels were measured by enzyme-linked immunosorbent assay. RESULTS:Serum levels of CK-18-M30, FGF-21, IL-1Ra and PEDF increased, while OPG decreased in a stepwise fashion in controls, non-NASH NAFLD patients and NASH patients (P < 0.01). The area under receiver-operating characteristics curve to diagnose NASH was 0.86 for CK-18-M30, 0.89 for FGF-21, 0.89 for IL-1Ra, 0.89 for PEDF and 0.89 for OPG. CK-18-M30 had 70% negative predictive value (NPV) and 79% positive predictive value (PPV) to diagnose NASH. A 5-step approach measuring CK-18-M30 followed by FGF21, IL-1Ra, PEDF and OPG gradually improved the NPV to 76% and PPV to 85%, which reached 80% and 76% respectively in the validation cohort. CONCLUSION:Compared to single biomarker, stepwise combination of CK-18-M30, FGF-21, IL-1Ra, PEDF and OPG can further improve the accuracy in diagnosing NASH.
Correlation between serum cytokeratin-18 and the progression or regression of non-alcoholic fatty liver disease.
Kawanaka Miwa,Nishino Ken,Nakamura Jun,Urata Noriyo,Oka Takahito,Goto Daisuke,Suehiro Mitsuhiko,Kawamoto Hirofumi,Yamada Gotaro
Annals of hepatology
BACKGROUND:Diagnosis of non-alcoholic fatty liver disease (NAFLD) is limited by the need for liver biopsies. Serum cytokeratin 18 (CK-18) levels have been investigated as potential biomarkers for the presence of NAFLD and non-alcoholic steatohepatitis (NASH). Herein, we assessed the correlation between CK-18 levels and NAFLD progression. MATERIAL AND METHODS:Serum CK-18 levels were estimated using the M30 antibody enzyme-linked immunosorbent assay in 147 patients diagnosed with NAFLD. In 72 patients, disease progression was evaluated by repeated liver biopsy, which was conducted after 4.3 ± 2.6 years. The relationship between the CK-18 levels and liver histological findings was assessed. RESULTS:The CK-18 levels were useful for identifying NAFLD patients with NAFLD activity scores (NAS) ≥ 5 (NAS ≥ 5 vs. ≤ 4: 675.1 U/L vs. 348.7 U/L; p < 0.0001). A cut-off value of 375 U/L was calculated using the receiver operating characteristic curve approach, with a specificity and sensitivity of 81.5 and 65%, respectively, for the diagnosis of NASH. Among the 72 patients who underwent repeated liver biopsy, 11 patients with a progressed NAS also had significantly increased serum CK-18 levels (p < 0.01); in 30 patients with an improved NAS, there was a significant improvement in the mean CK-18 levels (p < 0.0001). The 31 patients with static NAS had static CK-18 levels. CONCLUSIONS:In conclusion, serum CK-18 levels can predict NAS ≥ 5 in NAFLD patients. In NAFLD patients, serum CK-18 levels reflect NAS values and correlate with histological changes, and they appear to be useful indicators of progression and improvement.
Performance of Serum microRNAs -122, -192 and -21 as Biomarkers in Patients with Non-Alcoholic Steatohepatitis.
Becker Philip P,Rau Monika,Schmitt Johannes,Malsch Carolin,Hammer Christian,Bantel Heike,Müllhaupt Beat,Geier Andreas
OBJECTIVES:Liver biopsies are the current gold standard in non-alcoholic steatohepatitis (NASH) diagnosis. Their invasive nature, however, still carries an increased risk for patients' health. The development of non-invasive diagnostic tools to differentiate between bland steatosis (NAFL) and NASH remains crucial. The aim of this study is the evaluation of investigated circulating microRNAs in combination with new targets in order to optimize the discrimination of NASH patients by non-invasive serum biomarkers. METHODS:Serum profiles of four microRNAs were evaluated in two cohorts consisting of 137 NAFLD patients and 61 healthy controls. In a binary logistic regression model microRNAs of relevance were detected. Correlation of microRNA appearance with known biomarkers like ALT and CK18-Asp396 was evaluated. A simplified scoring model was developed, combining the levels of microRNA in circulation and CK18-Asp396 fragments. Receiver operating characteristics were used to evaluate the potential of discriminating NASH. RESULTS:The new finding of our study is the different profile of circulating miR-21 in NASH patients (p<0.0001). Also, it validates recently published results of miR-122 and miR-192 to be differentially regulated in NAFL and NASH. Combined microRNA expression profiles with CK18-Asp396 fragment level scoring model had a higher potential of NASH prediction compared to other risk biomarkers (AUROC = 0.83, 95% CI = 0.754-0.908; p<0.001). Evaluation of score model for NAFL (Score = 0) and NASH (Score = 4) had shown high rates of sensitivity (91%) and specificity (83%). CONCLUSIONS:Our study defines candidates for a combined model of miRNAs and CK18-Asp396 levels relevant as a promising expansion for diagnosis and in turn treatment of NASH.
A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH).
Younossi Zobair M,Jarrar Mohammed,Nugent Clare,Randhawa Manpreet,Afendy Mariam,Stepanova Maria,Rafiq Nila,Goodman Zachary,Chandhoke Vikas,Baranova Ancha
BACKGROUND:Within the spectrum of nonalcoholic fatty liver disease (NAFLD), only patients with nonalcoholic steatohepatitis (NASH) show convincing evidence for progression. To date, liver biopsy remains the gold standard for the diagnosis of NASH; however, liver biopsy is expensive and associated with a small risk, emphasizing the urgent need for noninvasive diagnostic biomarkers. Recent findings suggest a role for apoptosis and adipocytokines in the pathogenesis of NASH. The aim of this study was to develop a noninvasive diagnostic biomarker for NASH. METHODS:The study included 101 patients with liver biopsies who were tested with enzyme-linked immunosorbent assay (ELISA)-based assays. Of these, 69 were included in the biomarker development set and 32 were included in the biomarker validation set. Clinical data and serum samples were collected at the time of biopsy. Fasting serum samples were assayed for adiponectin, resistin, insulin, glucose, TNF-alpha, IL-6, IL-8, cytokeratin CK-18 (M65 antigen), and caspase-cleaved CK-18 (M30 antigen). RESULTS:Data analysis revealed that the levels of M30 antigen (cleaved CK-18) predicted histological NASH with 70% sensitivity and 83.7% specificity and area under the curve (AUC) = 0.711, p < 10(-4), whereas the predictive value of the levels of intact CK-18 (M65) was higher (63.6% sensitivity and 89.4% specificity and AUC = 0.814, p < 10(-4)). Histological NASH could be predicted by a combination of Cleaved CK-18, a product of the subtraction of Cleaved CK-18 level from intact CK-18 level, serum adiponectin, and serum resistin with a sensitivity of 95.45% sensitivity, specificity of 70.21%, and AUC of 0.908 (p < 10(-4)). Blinded validation of this model confirmed its reliability for separating NASH from simple steatosis. CONCLUSIONS:Four ELISA-based tests were combined to form a simple diagnostic biomarker for NASH.
Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers.
Shen Jiayun,Chan Henry Lik-Yuen,Wong Grace Lai-Hung,Choi Paul Cheung-Lung,Chan Anthony Wing-Hung,Chan Hoi-Yun,Chim Angel Mei-Ling,Yeung David Ka-Wai,Chan Francis Ka-Leung,Woo Jean,Yu Jun,Chu Winnie Chiu-Wing,Wong Vincent Wai-Sun
Journal of hepatology
BACKGROUND & AIMS:The diagnosis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is limited by the need for liver biopsy. We aimed at testing the accuracy of cytokeratin-18 fragment (CK-18), adipocyte fatty acid binding protein (AFABP) and fibroblast growth factor 21 (FGF21) for the diagnosis of NAFLD and NASH. METHODS:146 patients with biopsy-proven NAFLD and 74 age- and gender-matched healthy controls were included. Serum CK-18, AFABP and FGF21 levels were determined by enzyme-linked immunosorbent assay. RESULTS:Serum CK-18, AFABP, and FGF21 increased in a stepwise fashion in control subjects (median 103 U/L, 15.4 ng/ml, and 104 pg/ml), patients with non-NASH NAFLD (263 U/L, 18.9 ng/ml, and 249 pg/ml) and NASH (418 U/L, 19.4 ng/ml, and 354 pg/ml) (p<0.001, 0.060, and 0.016, respectively). The area under receiver-operating characteristics curve to diagnose NAFLD and NASH was 0.91 and 0.70 for CK-18, 0.66 and 0.59 for AFABP, and 0.84 and 0.62 for FGF21. At cut-offs of 203 and 670 U/L, CK-18 had 71% negative predictive value (NPV) and 77% positive predictive value (PPV) to exclude and diagnose NASH. A 2-step approach measuring CK-18 followed by FGF21 further improved the NPV to 74% and PPV to 82%. In a validation cohort of 51 patients with paired liver biopsies, the NPV and PPV of the 2-step approach were 67% and 78%, respectively. CONCLUSIONS:CK-18 is the most accurate biomarker for NAFLD and NASH. A two-step approach using CK-18 and FGF21 further improves the accuracy in diagnosing NASH.
Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis.
Kamada Yoshihiro,Fujii Hideki,Fujii Hironobu,Sawai Yoshiyuki,Doi Yoshinori,Uozumi Naofumi,Mizutani Kayo,Akita Maaya,Sato Motoya,Kida Sachiho,Kinoshita Noriaki,Maruyama Nobuhiro,Yakushijin Takayuki,Miyazaki Masanori,Ezaki Hisao,Hiramatsu Naoki,Yoshida Yuichi,Kiso Shinichi,Imai Yasuharu,Kawada Norifumi,Takehara Tetsuo,Miyoshi Eiji
Proteomics. Clinical applications
PURPOSE:Mac-2 binding protein (Mac-2 bp) is one of the major fucosylated glycoproteins, which we identified with glycol-proteomic analyses. We previously reported that fucosylated glycoproteins are secreted into bile, but scarcely secreted into sera in normal liver and hypothesized that the fucosylation-based sorting machinery would be disrupted in ballooning hepatocytes due to the loss of cellular polarity. In the present study, we investigated the availability of Mac-2 bp for differential diagnosis of nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD) as a biomarker. EXPERIMENTAL DESIGN:Serum Mac-2 bp levels were determined with our developed ELISA kit. Our cohort of 127 patients with NAFLD had liver biopsy to make a histological diagnosis of NASH and simple fatty liver. RESULTS:Mac-2 bp levels were significantly elevated in NASH patients compared with non-NASH (simple steatosis) patients (2.132 ± 1.237 vs. 1.103 ± 0.500 μg/mL, p < 0.01). The area under the receiver-operating characteristic curve for predicting NASH by Mac-2 bp was 0.816. Moreover, multivariate logistic regression analyses showed Mac-2 bp levels could predict the fibrosis stage and the presence of ballooning hepatocytes in NAFLD patients. CONCLUSIONS AND CLINICAL RELEVANCE:These results support the potential usefulness of measuring Mac-2 bp levels in clinical practice as a biomarker for NASH.
Serum Fucosylated Haptoglobin as a Novel Diagnostic Biomarker for Predicting Hepatocyte Ballooning and Nonalcoholic Steatohepatitis.
Kamada Yoshihiro,Akita Maaya,Takeda Yuri,Yamada Shin,Fujii Hideki,Sawai Yoshiyuki,Doi Yoshinori,Asazawa Hitomi,Nakayama Kotarosumitomo,Mizutani Kayo,Fujii Hironobu,Yakushijin Takayuki,Miyazaki Masanori,Ezaki Hisao,Hiramatsu Naoki,Yoshida Yuichi,Kiso Shinichi,Imai Yasuharu,Kawada Norifumi,Takehara Tetsuo,Miyoshi Eiji
UNLABELLED:Nonalcoholic fatty liver disease (NAFLD) is a growing medical problem around the world. NAFLD patients with nonalcoholic steatohepatitis (NASH) can develop cirrhosis and hepatocellular carcinoma. The ability to distinguish NASH from simple steatosis would be of great clinical significance. Ballooning hepatocytes are characteristic of typical pathological NASH; here, the polarized secretion of proteins is disrupted due to destruction of the cytoskeleton. We previously reported that fucosylated glycoproteins are secreted into bile, but not into sera in normal liver. Therefore, we hypothesized that the fucosylation-based sorting machinery would be disrupted in ballooning hepatocytes, and serum fucosylated glycoproteins would increase in NASH patients. To confirm our hypothesis, we evaluated serum fucosylated haptoglobin (Fuc-Hpt) levels in biopsy-proven NAFLD patients (n = 126) using a lectin-antibody ELISA kit. Fuc-Hpt levels were significantly increased in NASH patients compared with non-NASH (NAFLD patients without NASH) patients. Interestingly, Fuc-Hpt levels showed a significant stepwise increase with increasing hepatocyte ballooning scores. Multiple logistic regression analysis showed that Fuc-Hpt levels were independent and significant determinants of the presence of ballooning hepatocytes. Moreover, Fuc-Hpt levels were useful in monitoring liver fibrosis staging. Next, to investigate the significance of serum Fuc-Hpt in a larger population, we measured Fuc-Hpt levels in ultrasound-diagnosed NAFLD subjects (n = 870) who received a medical health checkup. To evaluate NAFLD disease severity, we used the FIB-4 index (based on age, serum AST and ALT levels, and platelet counts). Fuc-Hpt levels increased stepwise with increasing FIB-4 index. CONCLUSION:Measurement of serum Fuc-Hpt levels can distinguish NASH from non-NASH patients, and predict the presence of ballooning hepatocytes in NAFLD patients with sufficient accuracy. These results support the potential usefulness of measuring Fuc-Hpt levels in clinical practice.
Noninvasive predictors of nonalcoholic steatohepatitis in Korean patients with histologically proven nonalcoholic fatty liver disease.
Kim Young Seok,Jung Eun Sun,Hur Wonhee,Bae Si Hyun,Choi Jong Young,Song Myeong Jun,Kim Chang Wook,Jo Se Hyun,Lee Chang Don,Lee Young Sok,Choi Sang Wook,Yang Jin Mo,Jang Jeong Won,Kim Sang Gyune,Jung Seung Won,Kim Hee Kyung,Chae Hee Bok,Yoon Seung Kew
Clinical and molecular hepatology
BACKGROUND/AIMS:The aims of this study were (1) to identify the useful clinical parameters of noninvasive approach for distinguishing nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD), and (2) to determine whether the levels of the identified parameters are correlated with the severity of liver injury in patients with NASH. METHODS:One hundred and eight consecutive patients with biopsy-proven NAFLD (age, 39.8±13.5 years, mean±SD; males, 67.6%) were prospectively enrolled from 10 participating centers across Korea. RESULTS:According to the original criteria for NAFLD subtypes, 67 patients (62.0%) had NASH (defined as steatosis with hepatocellular ballooning and/or Mallory-Denk bodies or fibrosis ≥2). Among those with NAFLD subtype 3 or 4, none had an NAFLD histologic activity score (NAS) below 3 points, 40.3% had a score of 3 or 4 points, and 59.7% had a score >4 points. Fragmented cytokeratin-18 (CK-18) levels were positively correlated with NAS (r=0.401), as well as NAS components such as lobular inflammation (r=0.387) and ballooning (r=0.231). Fragmented CK-18 was also correlated with aspartate aminotransferase (r=0.609), alanine aminotransferase (r=0.588), serum ferritin (r=0.432), and the fibrosis stage (r=0.314). A fragmented CK-18 cutoff level of 235.5 U/L yielded sensitivity, specificity, and positive and negative predictive values of 69.0%, 64.9%, 75.5% (95% CI 62.4-85.1), and 57.1% (95% CI 42.2-70.9), respectively, for the diagnosis of NASH. CONCLUSIONS:Serum fragmented CK-18 levels can be used to distinguish between NASH and NAFL. Further evaluation is required to determine whether the combined measurement of serum CK-18 and ferritin levels improves the diagnostic performance of this distinction.
Detection of hepatic steatosis using the controlled attenuation parameter: a comparative study with liver biopsy.
Yilmaz Yusuf,Yesil Atakan,Gerin Fatma,Ergelen Rabia,Akin Hakan,Celikel Çigdem Ataizi,Imeryuz Nese
Scandinavian journal of gastroenterology
OBJECTIVE:Measurements of controlled attenuation parameter (CAP) with transient elastography (FibroScan®; EcoSens SA, Paris, France) may provide an accurate noninvasive assessment of hepatic steatosis. Herein, we prospectively determined the accuracy of liver fat quantification with CAP values in patients with chronic liver diseases and compare the results with those of histological assessment of steatosis as reference standard. MATERIALS AND METHODS:We enrolled 50 Turkish patients with various forms of chronic liver diseases. All patients underwent both CAP assessment and ultrasonography-guided liver biopsy. RESULTS:On liver biopsy, 16 (32%) patients had S0, 12 (24%) had S1, 9 (18%) had S2, and 13 (26%) had S3. The CAP values increased significantly (p<0.001) for each steatosis stage on liver biopsy: S0, 222 dB/m; S1, 250 dB/m; S2, 270 dB/m; and S3, 318 dB/m. A cutoff value of 257 dB/m could distinguish significant steatosis (S2-S3) from S0 (Sn 89%, Sp 83%, positive likelihood ratio 5.33, negative likelihood ratio 0.13, AUROC=0.93). Multivariable analysis indicated that neither liver fibrosis (p=0.58) nor disease etiology (p=0.96) had a significant impact on the association between CAP and the stage of steatosis. CONCLUSION:The determination of CAP using transient elastography can represent an important step forward toward the goal of an "imaging liver biopsy".
Limited utility of plasma M30 in discriminating non-alcoholic steatohepatitis from steatosis--a comparison with routine biochemical markers.
Chan Wah-Kheong,Sthaneshwar Pavai,Nik Mustapha Nik Raihan,Mahadeva Sanjiv
INTRODUCTION:The utility of Cytokeratin-18 fragment, namely CK18Asp396 (M30), for the diagnosis of non-alcoholic steatohepatitis (NASH) is currently uncertain. We aimed to provide further data in this area among multi-ethnic Asian subjects with NAFLD. MATERIALS AND METHODS:The accuracy of M30 for detecting NASH was compared with serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (GGT) levels in consecutive adult subjects with biopsy-proven non-alcoholic fatty liver disease (NAFLD). RESULTS:Data for 93 NAFLD subjects (mean age 51.0 ± 11.1 years old and 51.6% males) and 20 healthy controls (mean age 50.2 ± 16.4 years old and 33.3% males) were analyzed. There were 39 NASH subjects (41.9%) and 54 non-NASH subjects (58.1%) among the NAFLD subjects. Plasma M30 (349 U/L vs. 162 U/L), and serum ALT (70 IU/L vs. 26 IU/L), AST (41 IU/L vs. 20 IU/L) and GGT (75 IU/L vs. 33 IU/L) were significantly higher in NAFLD subjects than in healthy controls. Serum ALT (86 IU/L vs. 61 IU/L), AST (58 IU/L vs. 34 IU/L) and GGT (97 IU/L vs. 56 IU/L) were significantly higher in NASH subjects compared to non-NASH subjects, but no significant difference was observed with plasma M30 (435 U/L vs. 331 U/L). The accuracy of plasma M30, and serum ALT, AST and GGT was good for predicting NAFLD (AUROC 0.91, 0.95, 0.87 and 0.85, respectively) but less so for NASH (AUROC 0.59, 0.64, 0.75 and 0.68, respectively). Serum ALT and AST, but not plasma M30 showed a significant trend with increasing grades of ballooning and lobular inflammation. CONCLUSION:The utility of M30 in the detection of NASH in clinical practice appears limited, in comparison to routine biochemical markers.
Poor Inter-test Reliability Between CK18 Kits as a Biomarker of NASH.
Pimentel Carolina F M G,Jiang Zhenghui G,Otsubo Takeshi,Feldbrügge Linda,Challies Tracy L,Nasser Imad,Robson Simon,Afdhal Nezam,Lai Michelle
Digestive diseases and sciences
BACKGROUND AND AIM:Nonalcoholic fatty liver disease (NAFLD) affects 15-40% of the general population; 10-20% of those patients have a more severe form of the disease known as nonalcoholic steatohepatitis (NASH). Cytokeratin-18 (CK18), released during apoptosis and one of the most studied biomarkers in NASH, can be measured by a number of commercially available kits. We compared serum measurements of the CK18 M30 from two different kits using the same cohort to evaluate the reliability between two test kits. METHODS:We measured serum levels of CK18 M30 from 185 patients with biopsy-proven NAFLD from a single center from 2009 to 2015, using two different ELISA kits, Test 1 (T1) and Test 2 (T2). Advanced fibrosis was defined as fibrosis stages 3-4 and NASH defined by NAS score ≥ 5. RESULTS:Mean age was 50.2 years (SD 12.6), 61.1% male and 87% White; 49.6% had NASH and 32.2% advanced fibrosis. There was no significant correlation between measurements from the two kits (p = 0.86, r = 0.01). While T2 predicted NASH and advanced fibrosis, T1 did not. The area under ROC curve for the prediction of NASH was 0.631 for T2 versus 0.500 for T1. CONCLUSIONS:Measurements from two different CK18 M30 test kits did not correlate with each other. One kit showed statistically significantly higher levels of CK18 M30 in patients with advanced fibrosis and NASH, while the other kit did not. With the increasing use of CK18 as a biomarker in NASH, it is important to standardize the different kits as it could greatly bias the results.