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Management of NAFLD patients with advanced fibrosis

The prevalence of non alcoholic fatty liver disease (NAFLD) has increased to 25% in the general population and could double by 2030. Liver fibrosis is the main indicator of morbidity and mortality and recent estimations suggest a substantial number of individuals with undiagnosed advanced liver disease. Strategies to monitor advanced fibrosis are essential for early detection, referral, diagnosis and treatment in primary care and endocrine units, where NAFLD and consequently liver fibrosis are more prevalent. Blood‐based non‐invasive methods could be used to stratify patients according to the risk of the progression of fibrosis and combined with imaging techniques to improve stratification. Powerful new diagnostic tools such as MRE and PDFF are emerging and might prevent the need for liver biopsy in the near future. The current therapeutic landscape of NAFLD is rapidly evolving with an increasing number of molecules that treat key factors involved in its progression, but that still have a limited or no ability to effectively reverse fibrosis. Management of this disease will probably require a combination of sequential and personalized treatments as a result of its complex and dynamic pathophysiology. Lifestyle interventions are still the most effective therapeutic option and should be better integrated into patient management together with specific programs of bariatric endoscopy/surgery for morbidly obese patients.


| INTRODUC TI ON
Non-alcoholic fatty liver disease (NAFLD) is known to be the most prevalent chronic liver disease worldwide. The estimated pooled prevalence in the general population is 25% for NAFLD and ranges from 3% to 5% for non-alcoholic steatohepatitis (NASH) with wide geographical variations across the world. NAFLD has traditionally been described as a group of nosological entities characterized by a high accumulation of fat in the liver cells (steatosis) in the absence of any other cause of liver disease, alcohol consumption or steatogenic drug use. However, the last decade has provided ample evidence of a complex interplay between NAFLD and many other diseases, especially type 2 diabetes mellitus (T2DM) and obesity, with a prevalence of 55.5% which can reach up to 90% in extremely obese patients. 1 NAFLD alone is a risk factor for cardiovascular disease, the most common cause of death in these patients. NAFLD has also been associated with the development of numerous diseases including extrahepatic malignancies, chronic kidney disease, certain endocrinopathies including polycystic ovary syndrome and osteoporosis, brain aging and cognitive impairment. 2 The spectrum of NAFLD ranges from simple steatosis, a relatively benign form of the disease, to NASH, which may or may not be associated with liver fibrosis. NASH and fibrosis seem to promote the development of diabetes mellitus, dyslipidaemia and arterial hypertension in patients without baseline metabolic disturbances. 3 Because of the strong association of this disease with general metabolic disorders as well as the coexistence of metabolic risk factors with some level of alcohol consumption in a substantial proportion of the population, alternative names have recently been proposed for this disease such as metabolic associated fatty liver disease (MAFLD) or dysmetabolism-associated fatty liver disease (DAFLD). 4,5 Whatever term best defines or classifies this disease, 6 it is clear that the global increase in obesity and dysmetabolic disorders together with an ageing population makes NAFLD a serious public health problem.
Chronic injury from NAFLD inhibits the regenerative capacity of the liver because of a state of overnutrition that generates an imbalance in the hepatic lipid metabolism that promotes cellular stress, apoptosis and liver injury. In these cases, fibrosis is a result of a complex crosstalk among different organs and also among most of the different cell types in the liver, in particular hepatic stellate cells (HSCs) and immune cells, which are the key drivers of fibrosis. Diet-induced accumulation of lipid overload and intrahepatic insulin resistance are considered to be key factors that trigger NASH through persistent accumulation of lipotoxic and glucotoxic damage, which mainly takes place in hepatocytes. Lipotoxicity and glucotoxicity eventually trigger apoptosis and liver injury along with a production of pro-inflammatory cytokines, chemokines and damage-associated molecular patterns (DAMPs) which upregulate the activation of Kupffer cells and monocyte-derived macrophages. This activation further promotes the transdifferentiation of hepatic stellate cells into myofibroblasts. In the long run, dendritic cells activate CD4 + T cells, which polarize Th1 and Th17 into pro-inflammatory lymphocytes worsening liver damage and inflammation.
Hepatic fibrosis is an adaptive mechanism whose main goal is to repair damaged tissue and is characterized by an accumulation of extracellular matrix (ECM). If the insult persists chronic liver injury may lead to cirrhosis, which is characterized by a distortion of the hepatic architecture generating abnormal blood flow and, in certain cases, portal hypertension, the major cause of clinical complications, including hydropic decompensation, bleeding events and hepatic encephalopathy. Liver fibrosis also progressively restricts normal liver regeneration increasing the risk of liver failure, and generates a favourable micro-environment for the development of liver cancer through mechanisms that have not been completely clarified. 7 Although the prevalence of NAFLD is high, not all patients are at risk of developing severe complications. In 2017, one meta-analysis including 1,495 NAFLD patients evaluating the risk of all-cause mortality and liver-related mortality reported a linear increase in all-cause mortality as fibrosis progresses and a more sudden increase in liver-related mortality after stage 2. 8 A more recent metaanalysis including 4,428 biopsy-proven NAFLD patients reached a similar conclusion. It is important to note that this study did not find evidence of an additional risk of NASH compared to patients with simple steatosis or NASH and the same stage of fibrosis. 9  Overall, these data suggest that although NASH plays a key role in driving and/or accelerating the progression of fibrosis in patients with NAFLD, liver fibrosis is probably the most important factor to be taken into account when evaluating patient prognosis.
• Composite scores for the assessment of fibrosis are easy-to-use tools that help identifying patients with minimal or advanced fibrosis, and should be implemented in primary care health centres and endocrine units.
• Patient management should focus on treating comorbidities and risk factors that are more likely to worsen fibrosis and include active and well-designed standardized lifestyle interventions.

| Screening advanced liver disease in the general population
Liver biopsy is still the reference method for the diagnosis of NAFLD. It determines the grade of steatosis, necroinflammation and fibrosis simultaneously and is still the only available technique to effectively diagnose NASH. The staging of fibrosis is usually based on the NASH-CRN score, which uses the Kleiner score to classify fibrosis, with moderate accuracy for intermediate stages because of a variability in inter-and intra-observer agreement of almost 25% for overlapping stages of fibrosis. 11 Several alternative methods have been developed to provide more objective quantification of fibrosis. Morphometry provides a finite-quantitative scale of the amounts of collagen, the Collagen Proportionate Area (CPA), which has already been used in certain clinical trials for Hepatitis C but it is time consuming and has a non-linear relationship with the stage of fibrosis. 12 Q-fibrosis, a technique that has been shown to improve the underestimation of staging in suboptimal biopsies (<15 mm) and under-and over-scoring by different pathologists (P < .001), has recently been modified and applied to NAFLD to improve the discrimination between F1 and F2 patients. 13 Liver biopsy is still the best method to evaluate the progression and regression of fibrosis but it is limited by cost, accuracy, a risk of adverse events and invasiveness so that it is unsuitable for large-scale screening. which use mechanical drivers to generate shear wave and measure its velocity using sonographic Doppler or MR techniques, and shear wave elastography (pSWE 2D-SWE, 3D-SWE), which uses high frequency ultrasound impulses for shear wave generation from one or multiple frequencies in real-time using ultrasound. These methods are usually accurate enough to exclude the presence of advanced liver disease, but not to effectively classify a significant number of patients that remain in the grey zone. None of them has proven so far a robust ability to dynamically monitor disease progression over time.
The ability of NITs to rule in or rule out liver fibrosis varies significantly depending on the cut-off value, which can be modified depending on the desired endpoint. Current available NITs have usually low to moderate positive predictive values and, therefore, a limited ability to confirm significant and advanced fibrosis, which often requires additional clinical information for a clear diagnosis.
In contrast, the negative predictive value (NPV) of NITs is generally strong, allowing the clinician to confidently exclude advanced fibrosis or cirrhosis. The estimated prevalence of advanced fibrosis and cirrhosis in the population being studied, as well as certain comorbidities (diabetes, obesity, age), can influence the results of NITs for the diagnosis of advanced fibrosis. Differences in ethnicity can also influence certain NITs such as FIB-4 and NFS, whose results have been shown to be less reliable in South Asians than in Caucasians.
All of these factors should be taken into consideration in the study design as well as the conclusions. 14 Table 1 summarizes the ability of several NITs to predict significant and advanced fibrosis according to four recent metanalyses. [15][16][17][18] None of the existing NITs provides an analysis of fibrosis comparable to liver biopsy. However, NITs can be used to identify high-risk patients in the global population. Implementing targeted diagnostic screening programs in primary care and outpatient clinics could greatly reduce the number of patients with undiagnosed advanced liver fibrosis, which could represent 6-7% of the population. 19 Screening should be performed in patients with obesity, diabetes or individual components of the metabolic syndrome as well as in those with increased liver enzymes or steatosis. It is important to note that abnormal liver blood enzymes are not specific for the diagnosis or exclusion of fibrosis, so they must be incorporated into algorithms or associated with other tools to assess the extent of fibrosis.
Most of the algorithms and screening protocols proposed combine a two-stage evaluation. First, a non-invasive test with a single cut-off is performed in primary care or endocrinology units to exclude patients with a low risk of advanced fibrosis. FIB-4 or NFS are inexpensive, easy-to-perform tests with good NPV for the exclusion of advanced fibrosis using a single cut off (NFS<−1.455 and FIB4 < 1.3), and can be used as a first screening option for intermediate-tohigh-risk patients. Both these tests may be influenced by age and should use a different cut-off for patients aged > 65 (NFS < 0.12 and FIB-4 < 2.0). FIB4 is easier to perform in primary care than NFS because the latter also requires albumin. Patients with available HOMA-IR scores can also be assessed for advanced fibrosis using a single cut off with the Hepamet Fibrosis Score (HFS < 0.12). HFS has been shown to be better than NFS and FIB-4 for the exclusion of advanced fibrosis, to significantly reduce the grey zone and seems    2. High percentage in the grey zone.
3. Assesment in non-diabeƟcs requires HOMA-IR TE TE should be performed by an experienced operator (>100 examinaƟons) following a standardized protocol with the paƟent, fasƟng for at least 2 hours, in the supine posiƟon, right arm in full abducƟon, on the midaxillary line with the probe-tip placed in the 9th to 11th intercostal space with a minimum of 10 shots with > 60% valid measurementes (IQR <0.3).  16,17 Patients above the recommended thresholds should be referred to a hepatologist for a possible liver biopsy to confirm the diagnosis, or ultrasound to confirm cirrhosis. Patients below the threshold should be followed in primary care using serum-based NITs if there are no other clinical symptoms suggesting advanced liver disease (2-3 years) ( Figure 1B).

| Weight loss: a key cornerstone in NAFLD management
Interventions of diet and exercise as well as other strategies to induce weight loss have been shown to be useful for the treatment of both NASH and fibrosis, as well as to improve many of the comor- Nevertheless, diet-and exercise-based interventions have several important limitations. The difficulty of long-term adherence and the maintenance of initial weight loss are probably one of the major drawbacks of this approach, and strategies to improve it are needed. A meta-analysis including 49 studies identified several energy intake-reducing behaviours and energy expenditure-increasing behaviours associated with long-term adherence and found consistent evidence that demographic factors were not predictive of weight-loss maintenance. On the other hand, behavioural and cognitive factors that promote a reduction in energy intake, an increase in energy expenditure and monitoring this balance were predictive factors. Specifically, self-monitoring factors were found to have a PPV for the maintenance of weight loss. Moreover, several cognitive-psychological factors also indirectly influence the maintenance of weight loss, ie high personal efficacy for exercise and weight management. 25 Another major limitation is the lack of a general consensus for diet and exercise recommendations and of methods to assess whether patients are actively following intervention programs.
Lifestyle protocols are usually at the discretion of the researcher and vary from study to study. There is also a risk of site-specific differences that confound study outcomes even when the same standard-  Finally, this surgery with its associated risk factors cannot be indicated on a large scale to treat a disease as prevalent as NASH thus, dietary and exercise-based approaches remain the best strategy to manage this disease.

| Therapeutic landscape for NAFLD
Treatments for NASH and liver fibrosis differ in their mode of action but tend to result in one or more of these outcomes: Elafibranor, a PPARα and δ dual agonist, has been shown to resolve NASH without worsening fibrosis in a stage 2 trial, but has no effect on liver fibrosis. In addition, a recent press release from the Golden The numerous reasons for the high rate of failure in these large trials were recently reviewed. 31,32 There are currently more than 30 on-going trials (≥ stage2) of new therapies for NAFLD with a histological evaluation of fibrosis (Table S2). Thus far, obeticolic acid, an FXR agonist, is the only compound that has been found to modestly improve fibrosis in a phase III clinical trial interim analysis (resolution of fibrosis by at least 1 stage without worsening of NASH 23% 25 mg dose vs 12% in placebo).
This improvement was not accompanied by a resolution of NASH, although several components of the histological NAFLD activity score did improve [NCT01473524]. Pioglitazone is a PPARγ analogue that been shown to promote the resolution of NASH in prediabetic and diabetic patients [NCT00994682] but has not been found to significantly improve fibrosis in randomized studies (Table S1). However, a recent meta-analysis including data from 5 trials suggest that this compound could also improve advanced fibrosis (OR, 3.15; 95% CI,

| Concluding remarks
The management of NAFLD requires a multidisciplinary approach to increase detection and referral of patients with advanced fibrosis from primary care centres and non-specialist units, mainly endocrine to hepatology clinics. Patient management should focus on treating comorbidities and risk factors that are more likely to worsen fibrosis and include active and well-designed standardized lifestyle interventions. This disease also requires educational programs to improve awareness of the impact of this silent disease with long-term asymptomatic periods on quality of life and survival. Educational programs, tools and information to central laboratories and outpatient clinics as well as strategies to facilitate easy referral of patients between professionals are needed.

ACK N OWLED G EM ENTS
We would like to apologise to all authors whose work has not been cited directly in this review owing to the restriction applied to the maximum number of references allowed.