Bridging the Gap: Screening for Nonalcoholic Fatty Liver Disease in the Primary Care Population

Abstract

Chronic liver disease (CLD) affects 1.5 billion people worldwide.1Cheemerla S. Balakrishnan M. Global epidemiology of chronic liver disease.Clin Liver Dis. 2021; 17: 365-370Crossref PubMed Scopus (47) Google Scholar Cirrhosis is the sequela of CLD2Schuppan D. Afdhal N.H. Liver cirrhosis.Lancet. 2008; 371: 838-851Abstract Full Text Full Text PDF PubMed Scopus (1492) Google Scholar and has been increasing in prevalence since 2009.3Tapper E.B. Parikh N.D. Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study.BMJ. 2018; 362k2817PubMed Google Scholar Hepatitis C virus was the leading cause of liver disease and associated mortality; however, with improved treatments leading to high sustained virologic response, alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) have been the dominant etiologies of CLD.4Kim D. Li A.A. Gadiparthi C. et al.Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016.Gastroenterology. 2018; 155: 1154-1163Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar NAFLD is associated with the metabolic syndrome including obesity, type 2 diabetes, dyslipidemia, and hypertension.5Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of nonalcoholic fatty liver disease: meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84Crossref PubMed Scopus (5088) Google Scholar As the obesity and the metabolic syndrome pandemic continues among the general population, the prevalence of NAFLD is projected to become the leading cause of liver transplantation by 2030.6Byrne C.D. Targher G. NAFLD: a multisystem disease.J Hepatol. 2015; 62: S47-S64Abstract Full Text Full Text PDF PubMed Scopus (1465) Google Scholar Therefore, identification of CLD, especially NAFLD, in the general population has become a major focus for primary care providers.7Ginès P. Castera L. Lammert F. et al.Population screening for liver fibrosis: toward early diagnosis and intervention for chronic liver diseases.Hepatology. 2022; 75: 219-228Crossref PubMed Scopus (36) Google Scholar In the primary care setting, there are no formal screening guidelines for NAFLD; however, given the increase in disease burden, this is a care gap that needs to be addressed. Although liver biopsy is the gold standard for evaluation of liver disease, it is not routinely performed given it is an invasive procedure that carries the risk, although rare, of severe complications.8Bravo A.A. Sheth S.G. Chopra S. Liver biopsy.N Engl J Med. 2001; 344: 495-500Crossref PubMed Scopus (1829) Google Scholar Furthermore, liver biopsy is not feasible nor reasonable as a screening tool in the general population. As such, noninvasive tests (NITs) have gained popularity as alternatives, which can include the Fibrosis-4 (FIB-4) index and NAFLD fibrosis score (NFS) in adjunct with transient elastography (TE) liver stiffness measurement (LSM). These NITs have reasonable accuracy and are now widely used in hepatology and gastroenterology practices. However, their use in primary care remains ill defined. To address this gap, Graupera et al9Graupera I. Thiele M. Serra-Burriel M. et al.Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population.Clin Gastroenterol Hepatol. 2022; 20: 2567-2576Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar in the current issue of Clinical Gastroenterology and Hepatology aimed to assess the accuracy of NITs and their ability to detect CLD when compared with LSM obtained by TE in a general and high-risk population. In this cross-sectional study, they looked at a cohort from 4 European countries and Hong Kong comprised of a total of 5129 patients. The cohort was then divided into 2 subgroups comprised of the general population (n = 3979) and those at high risk, defined as those with alcohol use, diabetes, or obesity (n = 1150). Of note, those from specific countries were not randomized among the groups; rather, the countries were divided into the at-risk and general population cohorts. All patients had TE and FIB-4 and NFS were calculated to assess correlation with TE scores. The primary aim was to correlate FIB-4 and NFS to TE-LSM. Secondary aims were to describe the diagnostic accuracy of FIB-4 and NFS for the detection of significant fibrosis (TE ≥8 kPa) and advanced fibrosis (TE ≥12 kPa). Thresholds to rule out or rule in significant and advanced fibrosis used were <1.3 and ≥2.67 for FIB-4 and <-1.45 and ≥0.676 for NFS, respectively. The mean age of the cohort was 55 years, 52% were female, and 30% had alcoholic liver disease. Overall, 10.8% had LSM ≥8 kPa and 4.1% had LSM ≥12 kPa. Of those with FIB-4 ≥1.3 in the general population, 6.58% and 1.9% had LSM ≥8 kPa and ≥12 kPa, respectively. Using a higher FIB-4 threshold (≥2.67), 15.9% and 8.7% had LSM ≥8 kPa and ≥12 kPa, respectively. Comparatively, of those with NFS ≥-1.45, 9.16% and 2.57% had LSM ≥8 kPa and ≥12 kPa, respectively, while using a threshold of ≥0.676; 25.7% and 13.5% had LSM ≥8 kPa and ≥12 kPa. These percentages increased in the high-risk population. Although most of those with low LSM were correctly classified, the false-negative rate was 7.2% for FIB-4 ≥1.3 and 5.7% with NFS ≥-1.45 and higher in the high-risk group compared with the general population. Conversely, the false-positive rate was 29% for FIB-4 and 28% for NFS and similar between the general population and high-risk cohort. The sensitivity and specificity to rule out fibrosis (TE <8 kPa) for FIB-4 was 37% and 69% compared with 52% and 69% for NFS in the general population, whereas it was 70% and 77% for FIB-4 and 60% and 55% for NFS in the high-risk cohort. Younger age led to more false-negative patients, whereas older age led to high false-positive patients using FIB-4. Interestingly waist circumference had higher performance (area under the curve, 0.716) compared with FIB-4 (area under the curve, 0.572) and NFS (area under the curve, 0.643) for detecting LSM ≥8 kPa. This study concluded that given the high false-positive and negative rates, FIB-4 and NFS are suboptimal NITs to use in primary care to identify significant and advanced fibrosis determined by LSM. This study has several strengths. First, it addresses a significant care gap among the primary care population: the need to screen for CLD, particularly fatty liver disease because no current screening guidelines currently exist. This results in a higher rate of diagnosis at advanced stages of liver disease (ie, decompensated cirrhosis). Second, this study included a large population. Third, this cohort was further categorized into a general population and high-risk population to offer comparison. Fourth, interestingly, this study identified waist circumference as a possible objective marker to identify those at risk for liver fibrosis. Last, this study found that among those with low FIB-4 and NFS, >95% had LSM <8 kPa and 99% had LSM <12 kPa in the general population and >80% and 93% in the high-risk cohort conferring a high negative predictive value of FIB-4 and NFS for those that do not need further diagnostic evaluation. This study also has several limitations. First, although the cohort was large and included a significant proportion of females, it was primarily European and importantly, we are not provided data on the diversity and those born of color, which may limit the generalizability, especially to a North American population. Second, there is no gold standard for comparison (liver biopsy).8Bravo A.A. Sheth S.G. Chopra S. Liver biopsy.N Engl J Med. 2001; 344: 495-500Crossref PubMed Scopus (1829) Google Scholar Additionally, Graupera et al9Graupera I. Thiele M. Serra-Burriel M. et al.Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population.Clin Gastroenterol Hepatol. 2022; 20: 2567-2576Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar defined their at-risk cohort to include those with alcohol use, diabetes, or obesity. Although other components of the metabolic syndrome were defined by prevalence in the population, they were not included in defining the cohorts. This is especially important given the association of metabolic syndrome and NAFLD. Additionally, stratifying those with 1 compared with multiple risk factors and the correlation to screening tests would be useful to determining which population to screen. Similarly, it may be beneficial to specifically target those with the previously mentioned risk factors who are between 35 and 65 years old because this is a higher risk population. Last, a sensitivity analysis for FIB-4 with a cutoff of >3.25 as mentioned in the methods would be beneficial to assess those with advanced fibrosis; these results were not found in this article. To put these results into perspective, Ginès et al7Ginès P. Castera L. Lammert F. et al.Population screening for liver fibrosis: toward early diagnosis and intervention for chronic liver diseases.Hepatology. 2022; 75: 219-228Crossref PubMed Scopus (36) Google Scholar recently reviewed the availability of evidence for screening for liver fibrosis in the general population. They identified the importance of early detection of CLD because this allows for multiple disciplines to be intervened on to improve survival including but not limited to treatment of comorbid conditions, treatment of coinfections, alcohol abstinence, and so forth. They identified the difficulty for a uniform screening test because of the “spectrum effect” as varying prevalence can affect the outcomes. Because liver biopsy is not feasible in the general population, they recommended a step-wise algorithm using multiple NITs. Furthermore, they recommended a targeted approach focusing on patients with risk factors and sequential testing with NIT. Similarly, Srivastava et al10Srivastava A. Gailer R. Tanwar S. et al.Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease.J Hepatol. 2019; 71: 371-378Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar evaluated a population from the United Kingdom to assess for screening the general population for NAFLD and identified similar a 2-step pathway using FIB-4 with cutoff of <1.3 and >3.25 in adjunct with enhanced liver fibrosis, again demonstrating the increased diagnostic yield with sequential testing. Screening the primary care population for CLD is important and needs to be addressed, especially because cirrhosis is the 11th most common cause of death worldwide.7Ginès P. Castera L. Lammert F. et al.Population screening for liver fibrosis: toward early diagnosis and intervention for chronic liver diseases.Hepatology. 2022; 75: 219-228Crossref PubMed Scopus (36) Google Scholar Graupera et al9Graupera I. Thiele M. Serra-Burriel M. et al.Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population.Clin Gastroenterol Hepatol. 2022; 20: 2567-2576Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar aimed to assess the utility of NITs in comparison with TE. However, sequential testing with multiple NITs offers higher diagnostic yield at identifying those at risk.7Ginès P. Castera L. Lammert F. et al.Population screening for liver fibrosis: toward early diagnosis and intervention for chronic liver diseases.Hepatology. 2022; 75: 219-228Crossref PubMed Scopus (36) Google Scholar,10Srivastava A. Gailer R. Tanwar S. et al.Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease.J Hepatol. 2019; 71: 371-378Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar,11EASL-ALEH Clinical Practice GuidelinesNon-invasive tests for evaluation of liver disease severity and prognosis.J Hepatol. 2015; 63: 237-264Abstract Full Text Full Text PDF PubMed Scopus (1188) Google Scholar Additionally, screening those at risk (ie, alcohol consumption, metabolic syndrome) may increase the yield. Figure 1 demonstrates a proposed screening algorithm for the primary care population, excluding those with preexisting liver disease (eg, hepatitis C virus or alcoholic liver disease), starting with FIB-4 and NFS, which requires no additional equipment, relies on routine testing, and can be incorporated into electronic health records with little to no additional burden to the provider. Those patients identified that might have at least significant fibrosis should then be referred to a hepatologist and preferable a multidisciplinary clinic for TE-LSM because this has proven to improve use of resources, interprofessional team work, and help with progression of disease.12Kumar S. Wong R. Newberry C. et al.Multidisciplinary clinic models: a paradigm of care for management of NAFLD.Hepatology. 2021; 74: 3472-3478Crossref Scopus (7) Google Scholar Furthermore, patients who do not meet criteria for TE but do have persistently abnormal alanine aminotransferase or viral hepatitis should be referred to hepatology. Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the PopulationClinical Gastroenterology and HepatologyVol. 20Issue 11PreviewFibrosis-4 (FIB-4) and the nonalcoholic fatty liver disease fibrosis score (NFS) are the 2 most popular noninvasive blood-based serum tests proposed for widespread fibrosis screening. We therefore aimed to describe the accuracy of FIB-4 and NFS to detect elevated liver stiffness as an indicator of hepatic fibrosis in low-prevalence populations. Full-Text PDF Open Access