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Abstract
Objective Patients with non-alcoholic fatty liver disease (NAFLD) with ≥stage 2 fibrosis are at increased risk for liver-related mortality and are candidates for pharmacological therapies for treatment of NAFLD. The aim of this prospective cohort study is to examine the diagnostic accuracy of MR elastography (MRE) combined with fibrosis-4 (FIB-4) in diagnosing ≥stage 2 fibrosis (candidates for pharmacological therapies).
Design This is a cross-sectional analysis of a prospective cohort (University of California at San Diego (UCSD)-NAFLD) including 238 consecutive patients with contemporaneous MRE and biopsy-proven NAFLD. Non-alcoholic steatohepatitis-Clinical Research Network-Histologic Scoring System was used to assess histology. The radiologist and pathologist were blinded to clinical, pathological and imaging data, respectively. Receiver operating characteristics (ROCs) were determined to examine the diagnostic accuracy of MRE and FIB-4 for diagnosis of ≥stage 2 fibrosis in NAFLD. We then validated these findings in an independent validation cohort derived from Yokohama City University in Japan (Japan-NAFLD Cohort; N=222 patients).
Results In the UCSD-NAFLD (training) Cohort, MRE demonstrated a clinically significant diagnostic accuracy for the detection of ≥stage 2 fibrosis with an area under the ROC curve (AUROC) of 0.93 (95% CI 0.90 to 0.97) vs FIB-4 with an AUROC of 0.78 (95% CI 0.71 to 0.85), which was both clinically and statistically significant (p<0.0001). We then combined MRE with FIB-4 (MRE ≥3.3 kPa and FIB-4 ≥1.6) to develop a clinical prediction rule to rule in ≥stage 2 fibrosis patients which had positive predictive value (PPV) of 97.1% (p<0.02) in the UCSD-NAFLD cohort (AUROC of 0.90 (95% CI 0.85 to 0.95)) which remained significant at PPV of 91.0% (p<0.003) in the Japan-NAFLD Cohort (AUROC of 0.84 (95% CI 0.78 to 0.89)).
Conclusion MRE combined with FIB-4 (MEFIB) index may be used for non-invasive identification of candidates for (≥stage 2 fibrosis) pharmacological therapy among patients with NAFLD with a high PPV.
- fatty liver
- liver imaging
- liver function test
- hepatic fibrosis
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information. Data details can be provided upon request to credible investigators on verification for patient confidentiality.
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Significance of this study
What is already known on this subject?
Patients with non-alcoholic fatty liver disease (NAFLD) with ≥stage 2 fibrosis are at increased risk for liver-related mortality and are candidates for pharmacological therapies for treatment of NAFLD. However, current non-invasive tests (such as fibrosis-4 (FIB-4) and vibration-controlled-transient elastography) have a high negative predictive value but a low positive predictive value (PPV) so are unable to rule in a patient who needs to be treated. Therefore, there is a major unmet need to examine if a combination of advanced imaging tests (such as MR elastography (MRE)) and serum markers will yield a high enough PPV for a clinician to rule in clinically significant disease that needs pharmacological treatment in NAFLD.
What are the new findings?
In multivariable-adjusted models, a combination of MRE ≥3.3 kPa and FIB-4 ≥1.6 (MRE combined with FIB-4 (MEFIB) index) provided a robust PPV of 97.1% ruling in patients with ≥stage 2 fibrosis who are candidates for treatment among patients with NAFLD. The results remained significant after validation in a geographically and ethnically distinct cohort.
How might it impact on clinical practice in the foreseeable future?
MEFIB index may be used for non-invasive identification of candidates for (≥stage 2 fibrosis) pharmacological therapy among patients with NAFLD with a high PPV.
Introduction
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common liver disease that affects worldwide population and is also prevalent in the USA.1–3 NAFLD is broadly categorised into two clinical subtypes including non-alcoholic fatty liver (NAFL), which is the non-progressive form of liver disease, and non-alcoholic steatohepatitis (NASH), which is the progressive form of liver disease. NASH is a clinical-pathological diagnosis characterised by the presence of hepatic steatosis, lobular inflammation, ballooning with or without perisinusoidal fibrosis in individuals who consume little or no alcohol and do not have a secondary cause for hepatic steatosis. NASH can lead to progressive liver injury, significant fibrosis, cirrhosis and end-stage liver disease leading to liver-related morbidity and mortality.4 NASH is now the second leading indication for liver transplant in the USA.5 However, currently, there are no Food and Drug Administration (FDA)-approved therapies for the treatment of NASH and NASH-related fibrosis.
Among patients with NAFLD, the stage of fibrosis portends a worse prognosis.6–8 Recent meta-analyses suggest that NAFLD patients with ≥stage 2 fibrosis have significantly increased risk of progression to cirrhosis and liver-related mortality.9–11 Guidance by FDA and European Medicines Agency (EMA) requires inclusion of patients who have ≥stage 2 fibrosis for the purposes of registration trials for assessment of therapeutic response among patients with NAFLD. Resolution of NASH on histology or reversal of fibrosis by 1 or more stages is required for subpart H approval of medications for the treatment of NASH-related fibrosis. Currently, there are five drugs in phase 3 trials for the treatment of NASH-related fibrosis.12 In the near future, newer therapies will become available for the treatment of NASH.
To determine whether a patient is a candidate for a pharmacological therapy for NASH-related fibrosis, we currently require a liver biopsy assessment as the gold standard.13 However, liver biopsy is limited due to sampling errors, intraobserver and interobserver variability.14 Furthermore, it is an invasive procedure and associated with adverse effects such as pain, risk of infection, bleeding, perforation and extremely rarely even death.15 Given the burden of NAFLD afflicting approximately 80–100 million Americans, liver biopsy assessment for the detection for candidacy for the treatment of NASH-related fibrosis is impractical.16 17
To address these problems, various non- invasive techniques have been proposed such as fibrosis-4 (FIB-4). FIB-4 is a blood test which uses widely available and simple variables such as age, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and platelet count to detect patients with advanced fibrosis (stage 3 and 4).18 However, FIB-4 is suboptimal in detecting lower stages of fibrosis and does not help in ruling in who needs to be treated but rather helpful in ruling out who does not need to be treated.19 20
Liver stiffness assessment by ultrasound-based modalities including vibration-controlled-transient elastography (VCTE), acoustic radiation impulse force imaging (ARFI) and shear wave elastography (SWE) have also been used to risk stratify patients with NAFLD.18 21 MRI-based assessment has also been proposed such as MR elastography (MRE). MRE is a non-invasive, imaging-based, diagnostic tool that allows quantitative measures of liver stiffness as it correlates with fibrosis stage on liver histology.6 22 23 Previous studies have also shown that MRE is more accurate than VCTE and ARFI in the detection of liver fibrosis among patients with NAFLD.23–28
As biopsy has its limitations, non-invasive identification of candidates with high positive predictive value (PPV) is a major unmet need for pharmacological treatment.29 The advantage of combining two unrelated methods, such as imaging and serum biomarkers, has been proposed for staging liver fibrosis in chronic liver diseases.30 31 In application to NAFLD, serial and paired combinations have shown promising results in diagnosing ≥stage 3 fibrosis.32 However, there are limited data for whether these may be used for identification of patients with ≥stage 2 fibrosis, and what cut-points may be used.18
Current non-invasive tests (such as FIB-4 and VCTE) have a high negative predictive value (NPV) but a low PPV so are unable to rule in a patient who needs to be treated. Therefore, there is a major unmet need to examine if a combination of advanced imaging tests (such as MRE) and serum markers will yield a high enough PPV for a clinician to rule in clinically significant disease that needs pharmacological treatment in NAFLD.
The aim of this study was to examine whether a combination of MRE plus FIB-4 may be used for non-invasive identification of candidates for (≥stage 2 fibrosis) pharmacological therapy among well-characterised patients with NAFLD with liver biopsy assessment using NASH Clinical Research Network (CRN) Histologic Scoring System as the reference standard. We then validated these findings in a geographically and ethnically diverse external validation cohort.
Methods
University of California at San Diego-NAFLD cohort
Study design
This study includes a prospective cohort (University of California at San Diego (UCSD)-NAFLD) including 238 well-characterised, consecutively recruited patients with biopsy-proven NAFLD who had a clinical indication for a liver biopsy assessment (figure 1). After a careful exclusion of other causes for liver diseases (see inclusion and exclusion criteria section), the study participants underwent a detailed standardised research visit that included history, physical examination, biochemical validation and an advanced MRI assessment including 2-dimensional (2D)-MRE at the UCSD NAFLD Research Centre. These patients were enrolled from January 2012 to January 2020. All patients provided written informed consent prior to enrolment.
Derivation of UCSD-NAFLD cohort. *NASH CRN Histologic Scoring System was used.34 CRN, Clinical Research Network; MRE, MR elastography; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; UCSD, University of California at San Diego.
Inclusion and exclusion criteria
Patients who are at least 18 years of age with biopsy-proven NAFLD or NAFLD-related cirrhosis were included in the study. Written informed consent was required to participate in the study. Patients with evidence of alcoholic liver disease were excluded based on histological or clinical evidence. History or conditions that are associated with hepatic steatosis were used to screen patients such as short bowel syndrome, bariatric surgery, hepatitis B and C, and HIV infection. Patients with any other diseases determined by clinical investigator to confound the purpose of the study have been excluded. As the study requires MR usage, patients with claustrophobia, metallic implants, or who were not able to fit in MR chambers were excluded. Detailed exclusion criteria are provided in online supplemental materials.
Supplemental material
MR elastography
MRE was performed at UCSD MR3T Research Laboratory using GE 3T research scanner (E Signa EXCITE HDxt, GEHealthcare, Waukesha, Wisconsin, USA) as previously described.26 33 All patients were fasting for at least 4 hours before the visit. An acoustic passive driver was placed on the patient’s body anterior to the liver. It was hold in place with an elastic band and a plastic tube connected the passive driver to an active driver outside the MRI room. By producing shear waves from active to passive driver of 60 Hz, liver vibrations were measured. Specialised software processed the image for the whole liver to calculate an elastogram. Radiologists were blinded to clinical and pathology data.
Histological evaluation
All patients with a clinical indication for a liver biopsy underwent a liver biopsy procedure using a 16 gauge BioPince needle under strict aseptic precautions. All histological assessment for the training cohort were systematically assessed by an expert liver pathologist who was blinded to both imaging and clinical data. Biopsy results were scored based on the NASH CRN Histologic Scoring ystem.34 Steatosis was scored from 0 to 3 (0–3). Lobular inflammation was scored from 0 to 3 (0–3). Hepatocellular ballooning was scored from 0 to 2 (0–2). Steatosis, lobular inflammation and ballooning scores were combined to obtain the total NAFLD Activity Score ranging from 0 to 8. NASH was defined by presence of hepatic steatosis with lobular inflammation and definite ballooning with or without fibrosis. Fibrosis was staged from 0 to 4.34 Patients with stage 0 had no fibrosis. Patients with stage 1 fibrosis included those with either mild-moderate perisinusoidal or periportal fibrosis. Patients with stage 2 fibrosis included those with both peri-sinusoidal and portal/periportal fibrosis, stage 3 included those with bridging fibrosis and stage 4 included those with cirrhosis. These categories were employed prior to statistical evaluation.
Japan-NAFLD cohort
Study design
Japan-NAFLD cohort patients were recruited from Yokohama City University Hospital, Yokohama, Japan. A total of 222 patients enrolled from March 2013 to March 2019. All patients had received a biopsy paired with MRE within 6 months. Patients with history of excessive alcohol consumption (>140 g for male and >70 g for women per week), and other liver diseases such as chronic hepatitis, drugs that are associated with fatty liver, weight reduction, renal disease or thyroid disease were excluded. All subjects were provided with written consent prior to examination.
Histological evaluation
Liver biopsy samples were obtained from all patients diagnosed with NAFLD. Patients diagnosed with NASH-associated cirrhosis were defined clinically and pathologically.35 A 16 gauge needle biopsy was used according to standard protocol to obtain two specimen. An adequate liver sample was defined as >20 mm in length and/or >10 portal tracts. Pathologists were blinded to clinical and radiology data.
MR elastography
A 3.0T scanner was used for MRE for all included patients (GE Healthcare, Milwaukee, Wisconsin, USA). A 2D MRE protocol was used in multiple clinical sites on Yokohama City University Campus36 between November 2013 and March 2019. Abdominal radiologists interpreted 2D-MR elastograms following protocols established in the department.37 Radiologists were blinded to clinical and pathology data.
Primary outcome
The primary outcome of the study was defined as presence of significant fibrosis (≥stage 2 fibrosis). The study cohort was dichotomised into two subgroups stratified by significant fibrosis status including stages 0–1 vs stages 2–4 fibrosis.
Patients with stages 0–1 fibrosis would be classified as lower risk and may not qualify for NASH treatment in phase 3 trials. Subsequently, any patient with ≥stage 2 fibrosis would be classified as higher risk and may qualify for NASH treatment in phase 3 trials. Histology was assessed using the NASH CRN Histologic Scoring ystem as previously noted.
Statistical analysis
Participants’ anthropometric, demographic, histological, laboratory and imaging results were summarised in a table below for both UCSD-NAFLD and Japan-NAFLD Cohort. Receiver operating characteristic (ROC) curve analyses were used to assess the diagnostic accuracy of several predictors for the prediction of ≥stage 2 fibrosis, calculating the area under the ROC curve (AUROC), the optimal thresholds, PPV and NPV. The Delong test was used to compare the AUROCs. The optimal threshold of each modality was determined using the Youden’s index. Logistic regression model was created to determine factors associated with ≥stage 2 fibrosis and its diagnostic accuracy. A two-tailed p≤0.05 was considered statistically significant. An experienced biostatistician analysed the data using SAS software V.9.4 (SAS Institute).
Results
Patient characteristics of UCSD-NAFLD cohort
The UCSD-NAFLD cohort had 238 patients (54.2% female) with mean (±SD) age and body mass index (BMI) of 51.0 years (±13.7) and 31.3 kg/m2 (±4.4), respectively. Patient characteristics are summarised in table 1. A total of 170 patients diagnosed with stage 0, 1 fibrosis were aged 48.9 years (±13.7) with BMI of 31.0 kg/m2 (±4.2). There were 101 patients with stage 0 fibrosis and 69 patients with stage 1 fibrosis. Sixty-eight patients diagnosed ≥stage 2 fibrosis were aged 56.4 years (±12.4) and had a BMI of 32.3 kg/m2 (±4.8). Twenty-seven patients were diagnosed with stage 2 fibrosis, 23 patients with stage 3 fibrosis and 18 patients with stage 4 fibrosis. The median time interval (IQR) between MRE and biopsy in UCSD-NAFLD cohort was 34.0 days (57.0). MRI-PDFF, MRE imaging data collected are shown in table 1. Blood tests were done to all enrolled patients and with age, platelet count, AST, and ALT, FIB-4 score was calculated.
Demographic, histologic, biochemical and imaging results at baseline visit in UCSD-NAFLD cohort and Japan-NAFLD cohort
Patient characteristics of Japan-NAFLD cohort
The Japan-NAFLD Cohort had 222 patients (44.1% female) with mean (±SD) age and BMI of 55.5 years (±15.1) and 28.8 kg/m2 (±5.1), respectively. Patient characteristics are summarised in table 1. Eighty-seven patients diagnosed with stage 0–1 fibrosis who were aged 49.3 years (±14.9) with BMI of 28.8 kg/m2 (±5.0), respectively. There were seven patients with stage 0 fibrosis and 80 patients with stage 1 fibrosis. One hundred and thirty-five patients diagnosed with ≥stage 2 fibrosis were aged 59.5 years (±13.9) and had a BMI of 28.8 kg/m2 (±5.3), respectively. Forty-six patients were diagnosed with stage 2 fibrosis, 60 patients with stage 3 fibrosis and 29 patients with stage 4 fibrosis. The median time interval (IQR) between MRE and biopsy in Japan-NAFLD Cohort was 54.5 (68.0) days.
MRE accurately diagnoses patients with ≥ stage 2 fibrosis compared with FIB-4
Diagnostic accuracy was compared between MRE and FIB-4 in diagnosing ≥stage 2 fibrosis in UCSD-NAFLD (training) Cohort and Japan-NAFLD (validation) Cohort. AUROC was calculated and compared for statistical significance using p value (figure 2). In both training and validation cohort, MRE outperformed FIB-4 in assessing fibrosis stage. In the UCSD-NAFLD (training) cohort, MRE demonstrated a robust and clinically significant diagnostic accuracy for the detection of ≥stage 2 fibrosis with an AUROC of 0.93 (95% CI 0.90 to 0.97) vs FIB-4 alone with an AUROC of 0.78 (95% CI 0.71 to 0.85), which was both clinically and statistically significant (p<0.0001). The diagnostic accuracy of MRE remained statistically significant (p<0.005) in the Japan-NAFLD (validation) cohort with an AUROC of 0.89 (95% CI 0.85 to 0.93) compared with diagnostic accuracy of FIB-4 (AUROC, 0.79; 95% CI 0.73 to 0.85) (figure 2). The differences in the MR elastogram and liver histology of representative patients are shown in figure 3.
MRE is more accurate than routinely available clinical prediction rule, FIB-4. Comparison of diagnostic accuracy between MRE and FIB-4 in detecting ≥stage 2 fibrosis in UCSD-NAFLD cohort and Japan-NAFLD cohort. Left: in UCSD-NAFLD cohort, the AUROC for MRE was 0.93 which was statistically significant compared with FIB-4 which was 0.78 (p<0.0001). Right: the diagnostic accuracy of MRE (AUROC=0.89) in Japan—NAFLD cohort was also statistically significant compared with FIB-4 (AUROC=0.79). The p value is provided. AUROC, area under the receiver operating characteristic curve; FIB-4, fibrosis-4; MRE, MR elastography; NAFLD, non-alcoholic fatty liver disease; UCSD, University of California at San Diego.
Representative patient characteristics by MRE image and liver biopsy. Patient A had a FIB-4 of 1.03; patient B had a FIB-4 of 2.62. *Trichrome stain highlights normal collagen surrounding the central hepatic venule (No significant fibrosis, ×40 magnification, patient A) and bridging fibrosis (×10 magnification, patient B). FIB-4, fibrosis-4.
Univariate predictors of ≥stage 2 fibrosis in UCSD-NAFLD training cohort
We not only analysed MRE and FIB-4 but also clinically relevant parameters such as ALT, AST, platelet counts and age to see which parameters show significance in predicting ≥stage 2 fibrosis in the training cohort (table 2). Each predictor’s AUROC and diagnostic OR were obtained and compared with see if there are any additional factors associated with predicting ≥stage 2 fibrosis. Diagnostic OR assists binary classification as being a measure for effectiveness of a diagnostic test.38
Univariate assessment of continuous predictors in detecting ≥stage 2 fibrosis in UCSD-NAFLD Cohort
MRE had an OR of 13.60 (95% CI 6.71 to 27.56) and FIB-4 4.36 (95% CI 2.72 to 7.00). Other factors such as AST, age, platelet count, ALT had lower OR, respectively (≈1.0). Thus, we chose MRE and FIB-4 to calculate the Youden’s Index to determine cut-points to predict ≥stage 2 fibrosis. The cut-points for MRE was 3.3 kPa and FIB-4 1.6, respectively, for the training cohort.
Combination of MRE and FIB-4 for ruling in ≥stage 2 fibrosis (MRE combined with FIB-4 (MEFIB) index)
Using these cut-points, we looked at the diagnostic accuracy of MRE alone, FIB-4 alone and both together in a model to predict ≥stage 2 fibrosis in the UCSD-NAFLD cohort (table 3). In the training cohort, we observed our multivariable model with MRE ≥3.3 kPa and FIB-4 ≥1.6 to have a higher AUROC of 0.90 (95% CI 0.85 to 0.95) compared with each diagnostic tool alone and it was statistically significant (p<0.02). MRE coupled with FIB-4 had high PPV of 97.1% ruling in patients with ≥stage 2 fibrosis for candidacy of treatment.
Diagnostic test characteristic of MRE, FIB-4 and MRE+FIB-4 (MEFIB index) in detecting ≥stage 2 fibrosis in UCSD-NAFLD cohort and Japan-NAFLD cohort
We then applied these cut-points to the Japan-NAFLD Validation Cohort (table 3). The results remained significant in Japan-NAFLD Cohort that yielded a robust PPV of 91.0% and the results were both clinically and statistically significant (p<0.003). Online supplemental material table 2 shows recalculated AUROC, PPV, and NPV based on the Youden’s Index from the Japan-NAFLD Cohort.
Discussion
Main findings
Using a uniquely well-characterised contemporaneous liver biopsy and MRE study cohort, we demonstrated clinical utility of MRE and FIB-4 in detecting ≥stage 2 fibrosis as a non-proprietary biomarker panel for high-risk NASH patients and those who need to be treated in registrational trial based on FDA guidance. In multivariable-adjusted models, a combination of MRE ≥3.3 kPa and FIB-4 ≥1.6 called the MEFIB index provided a robust PPV of 97.1% ruling in patients with ≥stage 2 fibrosis who are candidates for treatment among patients with NAFLD. The results remained significant after validation in a geographically and ethnically distinct cohort.
The study provides specific cut-points for clinical use that may have an impact in clinical care and would be easy to use. It is important to note that these result stayed consistent between geographically and ethnically diverse cohorts. With these thresholds, this study helps providers to rule in patients for pharmacological registrational trial without needing a liver biopsy. High PPV of 97.1% helps by giving providers a much needed non-invasive guideline to screen patients for candidacy for treatment of NASH-related fibrosis. Liver biopsy assessment for detecting NASH-related fibrosis patient candidates for pharmacological therapy is impractical due to its unavoidable risks and complications and these data suggest MRE paired with FIB-4 may help reduce the burden for patients in avoiding the risk in a subset of patients.18 Further studies are needed to non-invasively assess change in liver histology post pharmacological treatment.
In context of published literature
Liver fibrosis stage has been clinically important as higher stages of fibrosis were shown to be linked with liver-related morbidity and mortality.9 36 Various non-invasive biomarkers have been proposed and evaluated to diagnose advanced fibrosis as a result such as MRE, FIB-4 and VCTE. As FDA accepted critical inclusion criteria to have fibrosis score greater than 1 for purposes of registration trial, the importance of assessing not only advanced fibrosis but also stage 2 fibrosis rose. Previously, it has been shown MRE is accurate in diagnosing liver fibrosis not only in mild fibrosis but also for any, advanced fibrosis and cirrhosis.27 However, limited research has been done in using FIB-4 to diagnose patients other than advanced fibrosis but has been shown to be less accurate compared with MRE.39 This study confirms that MRE is more accurate than FIB-4 in diagnosing patients with ≥stage 2 fibrosis and provides new data that combination of MRE with FIB-4 can be clinically actionable. MEFIB index correctly ruled in 34 out of 68 patients in the UCSD-NAFLD cohort and 81 out of 135 patients in the Japan-NAFLD Cohort with 56% who were correctly classified, and 44% who were missed (online supplemental material table 1). The patients who were missed would still need a liver biopsy assessment. Hence, one can avoid 56% of liver biopsies in patients who need to be treated. This appears to be better than FAST score where sensitivity was 48% with a significant lower PPV of 83%.40 Further studies with head-to-head comparison are needed to compare MEFIB index versus FAST score in future. In a recent cost-effectiveness study comparing various non-invasive modalities for detection of cirrhosis, Vilar-Gomez et al found that FIB-4 followed by MRE yielded the highest diagnostic accuracy versus FIB-4 followed by VCTE in order to avoid liver biopsy for the diagnosis of cirrhosis.41 Our study provides prospective validation with an actionable cut-point for its clinical application using the MEFIB index (defined as FIB-4 ≥1.6 and MRE ≥3.3 kPa) to rule in patients who have ≥stage 2 fibrosis in patients with NAFLD.
Strengths and limitations
There are following notable strengths of this study. This is a prospective study derived from a uniquely well-characterised cohort residing in San Diego, California, USA, and these data have been validated in an ethnically and geographically distinct cohort residing in Yokohama, Japan. This underscores the generalisability and clinical applicability of these data across both Western and Eastern population. This non-proprietary biomarker panel and its cut-points are available to all without any cost and freely available to the world for clinical use.
Although this study is performed by experienced investigators with expertise in non-invasive MRI assessment, there are some notable limitations. As our study aimed to develop a combination of non-invasive tests to rule in patients with significant fibrosis, low sensitivity may have rooted from a trade-off in reducing false-positives by inevitably increasing false-negatives. However, high PPVs in both cohorts provide evidence for clinicians to use the MEFIB index to identify patients with ≥stage 2 fibrosis without needing a liver biopsy assessment. These thresholds are recommended for usage in a hepatology clinic setting to determine potential candidates for treatment of NASH. It is likely that cut-points may be different in primary care population. Therefore, further studies are needed in patients in the primary care setting and those derived from diabetes clinic. It is important to note that patients were enrolled consecutively which underscores the entire spectrum of liver disease in a liver clinic and provides a context of use for these cut-points. While we excluded clinically relevant biomarkers, such as AST, ALT, platelet count, and age, based on univariate analysis, there might be a more comprehensive multivariate logistic model that could further improve its accuracy. However, the MEFIB index uses readily available FIB-4 and MRE results so it is clinically actionable without deriving yet another score. Moreover, this study uses MRE which might not be readily available at all centres. Hence, further studies are needed to examine the role of combination of other elastography methods along with clinical prediction rules.26
Conclusions
There is a major unmet need to identify patients who have ≥stage 2 fibrosis and are candidates for pharmacological therapy without needing a liver biopsy assessment. All currently available clinical prediction rules such as FIB-4 and elastography methods that are routinely available have a high NPV and there is a need for a combination of biomarkers that have a high PPV. Further studies are needed to establish cut-points for VCTE, ARFI and SWE along with FIB-4 in risk stratification of patients with NAFLD. This study provides evidence that MEFIB index (MRE ≥3.3 kPa and FIB-4 ≥1.6) can yield a high PPV to rule in patients with ≥stage 2 fibrosis without needing a liver biopsy assessment in the context of a liver clinic.
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information. Data details can be provided upon request to credible investigators on verification for patient confidentiality.
Ethics statements
Ethics approval
The study was approved by UCSD Institutional Review Board as well as the UCSD Clinical and Translational Research Institute. Ethics Committee of Yokohama City University Hospital approved the study protocol.
Acknowledgments
A part of this work was presented at the Digestive Disease Week, 2020 and European Association for the Study of the Liver, 2020.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors JJ: analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, approved final submission. RRL: analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, approved final submission. KI: data analysis, critical revision of the manuscript, approved final submission. EM: patient visits, critical revision of the manuscript, approved final submission. SG: data collection, critical revision of the manuscript, approved final submission. RB: data analysis, critical revision of the manuscript, approved final submission. SS: data collection, critical revision of the manuscript, approved final submission. CH: patient visits, critical revision of the manuscript, approved final submission. MAV: data analysis, critical revision of the manuscript, approved final submission. CB: data analysis, critical revision of the manuscript, approved final submission. LR: patient visits, critical revision of the manuscript, approved final submission. KF: data analysis, critical revision of the manuscript, approved final submission. CBS: data analysis, critical revision of the manuscript, approved final submission. AN: data analysis, critical revision of the manuscript, approved final submission. RL: study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, obtained funding, study supervision, approved final submission
Funding RL receives funding support from NIEHS (5P42ES010337), NCATS (5UL1TR001442), NIDDK (U01DK061734, R01DK106419, P30DK120515, R01DK121378, R01DK124318), NHLBI (P01HL147835) and DOD PRCRP (W81XWH-18-2-0026).
Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Competing interests RL serves as a consultant or advisory board member for Arrowhead Pharmaceuticals, AstraZeneca, Bird Rock Bio, Boehringer Ingelheim, Bristol-Myer Squibb, Celgene, Cirius, CohBar, Conatus, Eli Lilly, Galmed, Gemphire, Gilead, Glympse bio, GNI, GRI Bio, Intercept, Ionis, Janssen, Merck, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prometheus, Sanofi, Siemens, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer-Ingelheim, Bristol-Myers Squibb, Cirius, Eli Lilly and Company, Galectin Therapeutics, Galmed Pharmaceuticals, GE, Genfit, Gilead, Intercept, Grail, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, NuSirt, Pfizer, pH Pharma, Prometheus, and Siemens. He is also cofounder of Liponexus.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.