Non-alcoholic fatty liver disease - 2019

Disclaimer: Clinical Practice Guidelines are developed to be of assistance to health care professionals by providing guidance and recommendations for particular areas of practice. The Guidelines should not be considered inclusive of all proper approaches or methods, or exclusive of others. The Guidelines cannot guarantee any specific outcome, nor do they establish a standard of care. The Guidelines are not intended to dictate the treatment of a particular patient. Treatment decisions must be made based on the independent judgment of health care providers and each patient’s individual circumstances. The Sri Lanka College of Endocrinologists or Sri Lanka Society for Gastroenterology makes no warranty, express or implied, regarding the Guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. The society shall not be liable for direct, indirect, special, incidental, or consequential damages related to the use of the information contained herein.


Introduction
This clinical practice guideline on the evaluation and treatment of non-alcoholic fatty liver disease (NAFLD) among adults is a product of a joint effort by The Sri Lanka College of Endocrinologists (SLCE) and Sri Lanka Society of Gastroenterology (SLSG). This guideline is based on extensive, up to date evidence search made by the guideline team and selected to match the clinical context and available resources. The ultimate purpose of the guideline is to increase awareness and to improve patient care of nonalcoholic fatty liver disease (NAFLD), and to assist caring physicians in the decision-making process by providing Disclaimer: Clinical Practice Guidelines are developed to be of assistance to health care professionals by providing guidance and recommendations for particular areas of practice. The Guidelines should not be considered inclusive of all proper approaches or methods, or exclusive of others. The Guidelines cannot guarantee any specific outcome, nor do they establish a standard of care. The Guidelines are not intended to dictate the treatment of a particular patient. Treatment decisions must be made based on the independent judgment of health care providers and each patient's individual circumstances.The Sri Lanka College of Endocrinologists or Sri Lanka Society for Gastroenterology makes no warranty, express or implied, regarding the Guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. The society shall not be liable for direct, indirect, special, incidental, or consequential damages related to the use of the information contained herein.

DOI: http://doi.org/10.4038/sjdem.v9i2.7402
evidence-based guidance considering the health care burden posed by the management of the disease Definitions NAFLD is defined as the presence of hepatic steatosis (HS) (fatty liver, >5% fat in the liver), in the absence of any secondary cause for HS. Exclusion of 'unsafe' alcohol consumption above Asian standards (>14 units per week for males and >7 units per week for females) is essential for the diagnosis. In appropriate situations, other causes of HS such as chronic viral hepatitis, autoimmune and hereditary liver disease, and contribution of steatogenic drugs should be also excluded . (1) HS is most commonly established by liver ultrasonography. Less commonly, other imaging modalities such as CT or MRI scanning will be required to establish HS. Liver biopsy and histology is rarely required for the diagnosis. NAFLD is a spectrum of disorders ranging from simple steatosis [non-alcoholic fatty liver (NALF)], non-alcoholic steatohepatitis (NASH) and NASH-related cirrhosis.
Incidence and Prevalence of NAFLDThe incidence and the prevalence of the NAFLD have risen exponentially in the recent past ( Figure 1).P -In Sri Lanka, the prevalence of ultrasonically detected NAFLD among urban adults is 32.6% (6) and among rural adults is 18% (7). The annual incidence of NAFLD among urban adults is 6.6% (8) Note: Fibrosis Severity Scale: F0 -No fibrosis, F1 -Mild fibrosis, F2 -Moderate fibrosis, F3 -Severe fibrosis, F4 -Cirrhosis Table 1. Definitions of NAFLD

Pathogenesis and pathophysiology
Fatty liver is considered to be the hepatic component of metabolic syndrome. Although the pathogenesis of NAFLD/ NASH is not yet fully understood, several theories are currently available to describe its development. Steatosis represents the 'first hit', which then sensitizes the liver to injury mediated by 'second hits', such as inflammatory cytokines, adipokines, oxidative stress, angiotensinogen, norepinephrine, osteopontin and mitochondrial dysfunction, leading to steatohepatitis and fibrosis. Furthermore, accumulation of FFA alone has been suggested to be sufficient to induce liver damage, without recourse for a second hit. Oxidative stress reduces the ability of mature hepatocytes to proliferate leading to increased hepatocyte death (9). Additionally, several agents including leptin, insulin, glucagon, deacylated ghrelin, selenoprotein P levels are increased while levels of adiponectin, GLP 1, acylated ghrelin are decreased in NAFLD contributing to the pathophysiology of the disease as described in (figure 2) (10).
There seems to be a genetic predisposition (11) to the development of NALFD. Some of the established association of genetic variants for development and progression of fibrosis in NAFLD include PNPLA3 (patatin-like phospholipase domain-containing protein 3), TM6SF2 (trans-membrane-6 super-family-2) and MBOAT7 (membrane bound O-acetyltransferase domain containing 7). Out of these variants PNPLA3 (12) has been proven to be associated with NAFLD in Sri Lanka.
Recently there is accumulating data that the gut microbiome may play a key role in the development and progression of NALFD via lipopolysaccharides, inflammatory cytokines and bile acid derivatives (12).  NAFLD is strongly associated with metabolic syndrome as well as its individual components.

Obesity
Obesity carries a 3.5 fold increased risk of developing NAFLD (13). Prevalence of NAFLD among obese individuals is 70%. Further, obese NAFLD, when compared to non-obese NAFLD has a higher transaminases, higher degree of hepatic steatosis and increased risk of liver fibrosis, hypertension, diabetes mellitus, and metabolic syndrome (14). However, some individuals with NALFD will have normal BMI (<23kg/m2). They are referred to as lean NALFD and accounts for up to 12% of NALFD in Sri Lanka (15).

Type 2 diabetes mellitus
The overall prevalence of NAFLD among T2DM is 70 %( 16). 2-5 times increased risk of incidental T2DM is demonstrated in NAFLD and its incidence reduces with resolution of fatty liver (17). However, T2DM and NAFLD can develop almost simultaneously in a patient due to the common risk factors for both conditions, confounding the prevalence of NAFLD in patients with T2 DM or vice versa.

Dyslipidemia
Nearly half of the patients with dyslipidemia were found to have NAFLD, with higher prevalence in those with high triglycerides and low HDL levels. (High TG: HDL ratio and/ or high Total cholesterol/HDL ratio) (18).

Malignancies
NAFLD increases the risk of hepatocellular carcinoma by 10 times. The presence of NAFLD doubles the risk of colon cancers in men and breast cancers in women (19).

Other associations
NAFLD increase the risk IHD by 1.5 times and chronic kidney disease by 2 times (20). Polycystic ovarian syndrome and hypothyroidism are other known associations of NAFLD.

Death
The leading cause of mortality among patients with NAFLD is cardiovascular disease. This is followed by cancer-related deaths and liver-related deaths. These deaths are strongly associated with the presence of significant or advanced liver fibrosis (>F2 -bridging fibrosis or cirrhosis) rather than the presence of NAFL/NASH alone (21).

Natural history and outcomes
The progression of NAFLD ranges from simple steatosis to hepatic inflammation, subsequent fibrosis with development of cirrhosis, and hepatocellular carcinoma (HCC). The time for progression from one stage to another varies according to the underlying disease stage. Natural history of the NAFLD is summarized in Figure 3. Cardiovascular disease is the leading cause of mortality in NAFLD (21). This is followed by cancer-related deaths due to extra-hepatic malignancies such as colorectal cancer in males and breast cancer in females as the second common cause of death in NAFLD. Liver-related deaths are only the third most common cause of death in NAFLD (22). This highlights the importance of screening and treating associated cardiovascular risk factors and screening for appropriate malignancies among patients with NAFLD.
Patients with NASH have six-time higher mortality compared to those with isolated NAFL (23,24). Similarly, patients with NASH and significant liver fibrosis have worse outcomes compared to those without significant liver fibrosis. Presence of significant liver fibrosis will increase all cause, cardiovascular and liver related mortality in NAFLD (25)(26)(27).

Screening
Screening for NAFLD can be recommended in 'high risk' patients such as obese and those with type 2 diabetes, dyslipidemia and metabolic syndrome, due to their strong association. Persons with persistently abnormal liver enzymes also should be screened for NAFLD (28). Some lean individuals are also prone to get NAFLD (lean NAFLD). Therefore, vigilant screening of lean individuals with other features of metabolic syndrome should be practiced (29). Routine population screening or family screening is not recommended due to lack of evidence of benefit (30).
Ultrasound abdomen is recommended as an initial investigation for screening of NAFLD as it is non-invasive, easy to perform, cheap and readily available (28,31).

Evaluation
Evaluation of NAFLD includes diagnosis and staging of the liver disease and assessment of risk factors and associated diseases.
The diagnosis of NAFLD requires the evidence of HS on imaging or histology in the absence of other causes of steatosis or liver disease (30). Initial evaluation should include detailed medical, medication and family history to evaluate for risk factors, alternative etiology for liver disease and complications. Details of daily activity, physical exercise, dietary habits, alcohol and smoking habits, medical comorbidities and current medications should be established.
General physical examination including weight, BMI to assess general obesity (23-24.9Kg/m2 -over-weight, >25kg/m2 -obesity), waist circumference to assess central obesity (>90cm in males, >80cm in females) (32), blood pressure, features of insulin resistance, findings suggestive of other etiologies of liver disease should be documented (Table 2) (28,30,33). Fasting blood sugar or HbA1c and fasting lipid profile should be performed routinely to identify those with associated diabetes and dyslipidemia.

Table 2. Common causes for hepatic steatosis and liver disease
Risk stratification to determine the stage of NAFLD will help to predict the progression of the disease, prognosis and identify the treatment candidates. This should be initially undertaken non-invasively with locally available tests (Table 3). High risk patients may be subjected to further evaluation including liver biopsy (28, 30, and 33).

Liver biopsy
Liver biopsy is the only method to reliably diagnose NASH and is the only investigation that reliably differentiates the stages of NAFLD. However it is invasive, expensive, requires expertise for interpretation and carries some morbidity and rarely mortality related to the procedure (28,30,33,34).
Liver biopsy may be considered in NAFLD/NASH in the following settings:1.To exclude competing or coexisting etiologies for liver diseas2. Advanced fibrosis which is suggested by serum based scores and/or imaging3.To establish the diagnosis of NASH in patients with poor response to therapy

Histology
Clinically useful pathology report should distinguish between simple steatosis and steatohepatitis. NAFLD encompasses: steatosis alone, steatosis with lobular or portal inflammation without ballooning or steatosis with ballooning but without inflammation. The diagnosis of NASH requires the joint presence of steatosis, ballooning and lobular inflammation. A comment on severity based on specific scoring systems such as NAFLD activity score (NAS) is useful. The presence of fibrosis should be described, and if present, a further statement related to location, amount and parenchymal remodeling is warranted (28, 30, 33, and 34).
Management strategies Management of NAFLD should ideally be via a multidisciplinary approach (30). This will increase the rate of diagnosis, improve metabolic measures and hepatic/ non-hepatic outcomes and reduce severity, which will be cost effective. This multi-disciplinary team will include Gastroenterologists/ Hepatologists, Endocrinologists, Cardiologists, Bariatric Surgeons, Nutritionists, Behavioral experts and specialist nurses. Whenever possible, patients should be managed by such Multidisciplinary team (MDT).
A successful management strategy should be tailor-made to the stage of the disease in the spectrum of NAFLD and may include following key components:

1.
Non-Pharmacological treatment Non pharmacologic managementNon-pharmacological management in the form of healthy lifestyle modifications is the cornerstone in management of NAFLD and prevention of its progression. A comprehensive lifestyle approach to management of NAFLD focuses on three key areas; weight loss, dietary modifications and exercise which in combination will provide the optimum benefit in all patients with NAFLD.The sustainability and consistency of this lifestyle approach over a long period of time should be ensured through persistent motivation and cognitive behavioral therapy.

Weight Loss
Weight loss has shown a significant improvement of clinical and histological parameters of NAFLD. 5-7% weight loss will result in resolution of steatosis. 7-10% weight loss will result in resolution of steatohepatitis. More than 10% weight loss will result in regression of fibrosis. Thus, a target weight loss of at least 5-10% is recommended to be achieved via a combination of diet and exercise (28).
Degree of weight reduction in an individual is positively associated with the resolution and improvement of liver histology ( Figure 6) (35,36,37,38).

Dietary modifications
The primary aim of dietary modifications is to achieve the target weight loss through a hypo-caloric diet. However, macronutrient and micronutrient composition in diet have also shown to improve biochemical and histological manifestations of NAFLD independent of weight loss.

Exercise and Physical Activity
Moderate-intensity exercise for 30 -60 minutes on 3-5 days per week is recommended (28,41). However, the intensity, duration and type of exercise should be individualized based on patient's baseline cardiovascular fitness, preference and lifestyle. (Algorithm 2) Exercise helps to reduce NAFLD progression by reduction of mean hepatic triglyceride composition, peripheral adipose tissue volume, free fatty acid concentration and increase of hepatic glucose sensitivity. The level of cardiovascular fitness at baseline is shown to be the most important factor to affect the degree of hepatic steatosis and it is shown to predict the improvement in NAFLD following lifestyle interventions (44). Benefits of exercise in NAFLD depend on the duration, intensity and type of exercise, independent on the degree of weight loss. Vigorous intensity exercise (Annexure 1) is beneficial in reducing the likelihood of developing NASH and its progression and moderate intensity exercise has shown to have some benefits as well (45,46) . Aerobic exercise and resistant training have shown similar benefits in reduction of progression of NASH (47) . Apart from improvement of NAFLD, exercise leads to reduction in the overall cardiovascular risk.

Bariatric (Metabolic) intervention
Bariatric intervention (endoscopic or surgical) could be considered in patients aged between 18-65 years with a BMI ≥ 30kg/m2 with NAFLD. Although not to be used solely for the treatment of NALFD, bariatric surgery can be useful in management of obese patients with other comorbidities or indications.
Weight reduction is associated with significant improvement in liver histology in patients with NAFLD by several postulated mechanisms (Figure 7) (48). Bariatric surgery is more efficacious in achieving weight loss of 10 to 30% in morbidly obese patients when compared to diet, lifestyle modifications and anti-obesity medications (49). Bariatric surgery related weight loss resolved NASH in up to 85% of patients (50,51,52 ) and improved liver fibrosis in 34% at 1 year post operatively (50). NAFLD is considered as an important comorbidity when deciding on bariatric surgery in morbidly obese individuals (6,10,11). The presence of cirrhosis is a relative contraindication for bariatric surgery, as it might lead to increased mortality (48,53,54).

Pharmacologic management
Liver-directed pharmacological therapies are only considered for patients with NASH with or without advanced fibrosis. Pharmacological treatment lack evidence in phase III trials, hence not approved for NAFLD by any regulatory authorities. Several categories of pharmacological treatments are available with variable degree of evidence (Table 5). Off label use of pharmacologic therapy might be considered in following stages of NAFLD depending on the excess mortality (27,55) safety and tolerability.1. NASH with fibrosis.2. NASH with high necro-inflammatory activity3. NASH with increased risk of progressing to fibrosis (Age>50years, Diabetes mellitus, Metabolic syndrome, persistently increased ALT).

Management of risk factors and associations
Management of type 2 diabetes mellitus, dyslipidemia and metabolic syndrome according to available guidelines is of paramount importance to reduce the associated cardiovascular risk. Apart from the lipid lowering effects and cardiovascular risk reduction, statins have shown benefits in improving liver histology including fibrosis (68). Statins are safe to be used in patients with less than 3 fold elevation of transaminases, however routine prescription is not recommended in patients with decompensated cirrhosis and acute liver failure (69) (70). In addition to well established cardiovascular disease prevention, aspirin has shown to reduce NAFLD related fibrosis (71).

Liver Transplantation
NASH poses unique challenges in liver transplantation. NASH-related cirrhosis is the fastest growing indication for liver transplantation worldwide (72). At present, NASH related cirrhosis is the most common indication for liver transplant in Sri Lanka (73). Deceased and live donor grafts will be limited by the increasing prevalence of NALFD in the general population (74).When compared to non-NASH cirrhosis liver transplant recipients, NASH cirrhosis recipients show similar survival rates at 1, 3, and 5 years. However, they are more likely to die from cardiovascular diseases or sepsis (75). Recurrence of NASH in the graft following liver transplant is not uncommon (76).

Pre-transplant considerations
A transplant recipient with NASH tends to be older,with higher BMI and metabolic comorbidities (77). Obesity is strongly associated with sarcopenia, which is an independent predictor of post -transplant mortality and graft loss (78). When corrected for ascites, higher BMI does not appear to independently confer an increased risk of mortality or allograft failure (79). Considering the high cardiovascular risk, non-invasive and invasive cardiac assessment is recommended as appropriate (79). Both statins and aspirin could be safely used in patients with decompensated cirrhosis and coronary artery disease undergoing liver transplant evaluation (80). Outcomes of NASH-related or cryptogenic cirrhosis appear to be similar to that of alcohol-related cirrhosis without liver transplantation (81).

Post-transplant considerations
Immunosuppressive protocols which include short term and low dose steroids and calcineurin-inhibitors are preferred (77). NASH cirrhosis liver transplant recipients are at high risk of metabolic syndrome, recurrent/ de novo NAFLD and cardiovascular diseases in comparison to general population (82). All transplant recipients should be counselled to continue adherence to the life style modifications.

Recurrent and de novo NAFLD
De novo (20-40%) and recurrent (30-100%) graft steatosis after liver transplant is common (83). Recurrent disease may present more frequently and may progress more rapidly than de novo disease, but the development of allograft NASH cirrhosis is rare (<2% at 10 year follow up) (84). Management is similar to native NAFLD (83).

Donor Hepatic steatosis
When persons with NAFLD are considered for liver allograft donation, severely (>60 %) steatotic grafts are associated with increased risk of poor graft function, whilst moderate -severe (>30 %) steatotic grafts are associated with reduced graft survival (85).
Follow up The optimal follow-up of patients with NAFLD is yet to be determined. Therefore, follow up should be individualized considering the risk of progression, and underlying metabolic conditions. Monitoring should include routine biochemistry (ALT, AST), assessment of co-morbidities, complications and non-invasive monitoring of fibrosis.
Follow up should be every three to six months if major therapeutic changes are done. Six-monthly for patients with advanced fibrosis. Six to twelve monthly, if stable on therapy. Yearly, if young and having low risk of fibrosis. Patients with NASH-related cirrhosis should be offered standard care for cirrhosis in addition to management of comorbidities.