NAFLD and the interface between primary and secondary care

Non-alcoholic fatty liver disease (NAFLD) has a prevalence of 25-30% in unselected populations and has become the main reason for referrals to hepatology services. From a liver point of view, NAFLD is a disease of high prevalence but relatively low severity. Screening studies in people at risk show a prevalence of advanced fibrosis of 5%, which underlines the need for robust pathways for risk stratification in primary care with subsequent referrals as required. In this review, we discuss the interface between primary and secondary care with regard to risk stratification and management of patients with NAFLD. We focus on selected issues of epidemiology and natural history and discuss the burden of disease in primary care, the evidence on screening for NAFLD, the rationale for testing for advanced fibrosis and the optimal management in primary care. Introduction Non-alcoholic fatty liver disease (NAFLD) has a prevalence of 25-30% in the general population and has thus become the main reason for referrals to hepatology services1,2. The number of patients diagnosed and referred is projected to rise further secondary to the growing epidemic of obesity and diabetes but also the increasing awareness of the disease. NAFLD is a systemic disease and is often perceived as an inconsequential hepatic manifestation of the metabolic syndrome; although some patients will develop progressive liver disease that can lead to cirrhosis and liver cancer, the majority of those affected will never develop hepatic complications. Indeed, cardiovascular disease is the main cause of mortality in patients with NAFLD followed by non-liver related malignancies3. Therefore, from a liver point of view, NAFLD is a disease of high prevalence but relatively low severity. It is therefore critical that primary care physicians are actively involved in the screening and management of patients, with community pathways in place for selecting patients at risk of liver disease for secondary care referral and adequate education for following up and treating those deemed at low risk. In this review, we discuss the interface between primary and secondary care as regards risk stratification and management of patients with NAFLD. We focus on selected issues of epidemiology and natural history and discuss the burden of disease in primary care, the evidence on screening for NAFLD, the rationale for testing for advanced fibrosis and the optimal management in primary care. This review is relevant for primary care and/or other specialties that make the first diagnosis of NAFLD or treat the majority of people at risk of NAFLD. Parts of the manuscript on screening and testing are also relevant for secondary care clinicians developing services for NAFLD and for commissioners of those services. We further highlight areas of uncertainty and needs for future research. Search strategy and selection criteria We searched MEDLINE (2005-2017) using the search term "NAFLD" or “NASH” combined with the terms “non-invasive fibrosis tests” or “primary care” or “prevalence” or “incidence” or “treatment”. Articles were also selected through searches of the authors’ own files. We selected further relevant publications from the reference lists of articles identified by this search strategy. We largely selected publications in the past 5 years, but did not exclude highly relevant older publications. Review articles are cited to provide more details and references than this Seminar has room for. Epidemiology NAFLD is an increasingly common global entity which is defined by the presence of hepatic steatosis and varying degrees of liver injury and fibrosis, occurring in the absence of any other aetiological factors notably alcohol excess4. Its emergence over the past 20 years has been driven by the dramatic rise in levels of obesity and type 2 diabetes mellitus with which it is closely linked5. Population and other studies have used different methods to diagnose NAFLD, which in turn has a major impact on the prevalence figures generated; in general studies requiring abnormal liver blood tests to make the diagnosis of NAFLD generate much lower figures compared to those utilising imaging modalities. The observation that patients with NAFLD, and indeed those with significant liver damage, may have entirely normal liver blood tests is widely accepted but has impacted on case-finding in clinical practice6. In addition, NAFLD refers to patients with the full spectrum of the condition, ranging from indolent steatosis through to progressive inflammation, non-alcoholic steatohepatitis (NASH), and fibrosis culminating in cirrhosis7. As the distinction often requires recourse to additional investigations, some invasive such as liver biopsy, there are more limited data on the prevalence of NASH and progressive fibrosis. This is relevant as there is a growing recognition that complications related to liver disease arise only after many years and predominantly in those individuals with NASH and fibrosis. The global data on prevalence of NAFLD and NASH have been reviewed recently by Younossi et al8; 86 studies from 22 countries included 8,515,431 patients and established a global prevalence of 25.24% (95% CI: 22.10-28.65) with the highest prevalence found in the Middle East and South America. Nevertheless, there were broadly similar prevalence figures across the different geographical regions, with prevalence plateauing after the age of 40 before rising further beyond the age of 70. Pooled overall prevalence estimate in those patients with NAFLD being 59.10% (95% CI: 47.55-69.73), but extrapolating this to the population prevalence of NASH is more difficult given the inherent biases in such figures, which are commonly generated in specialist centres. Modeling data, again from Younossi and colleagues, suggests a prevalence of 2-5% of NASH across the US and major European countries8. Finally data on the prevalence of NASH with advanced fibrosis are even sparser yet of greater clinical importance. Population based studies report lower prevalence figures than those from specialist centres highlighting ascertainment bias in the latter. Nonetheless these figures conservatively suggest a prevalence of 0.3-1% for NASH with advanced fibrosis in the US and Europe8. Natural History There is an uncertain understanding of the progression of liver damage in the setting of NAFLD/NASH; in the main this is due to the reliance on liver biopsy to track changes in liver injury. Moreover, most of the datasets reported are single centre studies from specialist units where repeat biopsy occurred in response to clinical events – inevitably this results in a bias as repeat biopsy will be driven by clinical concerns in many patients providing a non-representative understanding of the overall rate of change. When analysed, Singh and colleagues, determined that rate of histological progression differed depending on severity of baseline NAFLD9; those with more indolent disease at the outset appeared to progress more slowly, whereas those with NASH progressed more rapidly. These data are helpful in informing the field but it should be noted though that the rates of progression were still slow; the time taken to advance by one stage of liver fibrosis was 7 years in `fast` progressors versus 14 years in `slow` progressors9. A relevant consideration is the method of evaluating changes in fibrosis in patients with NASH. This uses the established NASH Clinical Research Network (CRN) classification which stages fibrosis from 0 to 4 depending on the histological pattern observed7. This system whilst useful has some limitations; the fibrosis is graded categorically yet analysed as if it was a continuous variable. Moreover, the staging system is not linear with absolute differences in fibrosis between the earliest stages being modest whereas later stages have more marked increases in collagen. This is relevant as in the systematic review by Singh most patients had fibrosis within the earliest categories of fibrosis and hence the reported changes in stage represent relatively small changes in fibrosis9. Of note these studies also demonstrate that there is a significant amount of spontaneous improvement in fibrosis seen at these early stages in NASH highlighting the dynamic nature of disease. To understand which factors predicted histological change Singh and colleagues undertook logistic regression followed by a multi-variate analysis. A number of features were observed as predicting progression at univariate analysis, although notably only hypertension remained as a predictive factor after multivariate analysis9. This could represent a chance finding, although there may be logic in the link between activation of the renin angiotensin axis and ongoing liver fibrogenesis, as highlighted by the potential beneficial role of angiotensin converting enzyme inhibition in liver fibrosis10. Whilst there is an understandable focus on liver morbidity and mortality in patients with NASH, analysis of outcomes in such cohorts demonstrates that deaths from cardiovascular disease and non-liver malignancy are the top two causes11,12. Given the co-existence of often multiple metabolic syndrome factors in patients with NASH this is not surprising. This knowledge is of particular relevance for the shared management of such patients in primary care where there should be a clear focus on the optimal management of the metabolic syndrome. Identification of the factors predicting the development of overall and liver-related mortality has been the focus of many recent studies, with the finding that metabolic factors such as diabetes mellitus and HMG co-A reductase usage are important prognostic factors. Similarly the presence and severity of liver fibrosis has been reported in several studies to be a strong predictor of overall and liver-related mortality. The link with liver-related mortality is to be expected, and the data by Dulai et al suggest that the risk man