Managing NAFLD in primary care
Non-alcoholic fatty liver disease (NAFLD) – a clinicopathological spectrum comprising hepatic steatosis or non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) – is the hepatic manifestation of metabolic syndrome recognized as a leading cause of liver morbidity and mortality. Dr Loo Wai Mun, Consultant at the Division of Gastroenterology and Hepatology, National University Hospital, Singapore, speaks with Audrey Abella to discuss how NAFLD can be best managed in primary care.
NAFLD is characterized by the accumulation of ≥5 percent hepatic fat, excluding other causes of NAFL and liver disease. NASH involves inflammation with hepatocyte injury (ballooning degeneration) with or without fibrosis. [Hepatology 2018;67:328-357] Up to 20 percent of NASH cases progress to fibrosis, cirrhosis, and end-stage liver complications. [Nat Rev Gastroenterol Hepatol 2013;10:307-318]
In recent times, NAFLD has emerged as the most common cause of liver disease worldwide, while NASH has become the most common cause of cryptogenic cirrhosis and hepatocellular carcinoma (HCC). The current prevalence of NAFLD in Asia is around 25 percent, similar to various Western countries. In Singapore, a prevalence of up to 40 percent has been reported. [J Hepatol 2017;67:862-873; Gastroenterol Rep (Oxf) 2016;4:131-135]
The epidemic surge in obesity and type 2 diabetes (T2D) increases the incidence and prevalence of NAFLD which could herald a future epidemic of NASH-induced HCC, potentially overtaking the role of viral hepatitis in HCC development. In the US, NASH is the most rapidly growing indication for liver transplantation in HCC patients and could be the leading indication in future. [Hepatology 2014;59:2188-2195]
NAFL generally runs a benign and non-progressive course, whereas NASH typically progresses to liver fibrosis. Fibrosis has been shown to be the most significant predictor of progression to liver-related clinical outcomes including cirrhosis and HCC. [Hepatology 2015;61:1547-1554] On average, it takes about 14 years for NAFL to progress by one fibrosis stage and 7 years for NASH. [Clin Gastroenterol Hepatol 2015;22:498-504]
NAFL patients have a low risk of disease progression while those with NASH have reduced survival. NAFLD patients have an increased mortality risk predominantly from cardiovascular disease followed by malignancy and liver complications. [Hepatology 2013;57:1357-1365]
In Singapore, obesity rates are on the rise, predominantly due to a sedentary lifestyle and unhealthy dietary habits, thus contributing to the rise in NAFLD. Subsequently, this could lead to increased disease burden and healthcare costs.
Natural history of NAFLD in Asia [J Hepatol 2017;67:862-873]
Pathophysiology of NAFLD
Its pathophysiology is a complex and incompletely elucidated process. The ‘multiple-hit’ hypothesis, which has superseded the initial ‘two-hit’ hypothesis (as it was deemed too simplistic), considers a multitude of pathways acting in parallel, thus leading to NAFLD development. [Metabolism 2016;65:1038-1048; Gastroenterol Res Pract 2016;doi:10.1155/2016/2862173]
Insulin resistance is one of the key drivers in the pathogenesis of NAFLD, resulting in increased hepatic de novo lipogenesis, adipose lipolysis, and adipocyte dysfunction with consequent release of adipokines and inflammatory cytokines like TNF-α and IL-6. Dietary, environmental, and genetic factors, as well as obesity, all play a role in the development of insulin resistance.
In the liver, high levels of free fatty acids cause triglyceride accumulation and increased lipotoxicity, which induce mitochondrial dysfunction with oxidative stress and activation of reactive oxygen species, as well as endoplasmic reticulum stress. All these mechanisms lead to hepatic inflammation, apoptosis, and fibrogenesis.
Gut dysbiosis is also a major contributing factor in NAFLD development via several mechanisms: increased production and absorption of short-chain fatty acids in the bowel, altered bile acid and choline metabolism, increased gut permeability and endotoxaemia leading to the release of inflammatory cytokines and activation of the inflammatory cascade.
Genetic variants have also been associated with NAFLD development, severity, and progression. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been associated with increased susceptibility to NAFLD.
NAFLD patients typically remain asymptomatic given the predominantly silent nature of the disease. A proportion of patients may complain of fatigue and vague right upper abdominal discomfort. Physical findings include hepatomegaly due to fatty infiltration of the liver. In more advanced cases, some may exhibit stigmata of chronic liver disease suggestive of cirrhosis.
Diagnosis requires exclusion of secondary causes, significant alcohol consumption (ie, >14 standard drinks/week in men; >7 standard drinks/week in women), and other causes of liver disease. It is vital to ensure that other secondary aetiologies of fatty liver (ie, medications) are excluded before making a diagnosis. Other aetiologies such as chronic viral hepatitis, autoimmune liver disease, drug-induced liver injury, and Wilson’s disease should be excluded.
Ultrasonography is the usual first-line screening tool for NAFLD to detect steatosis. Other imaging tools include computed tomography, magnetic resonance imaging, or controlled attenuation parameter.
Liver enzyme levels including transaminases (ie, alanine transaminase [ALT], aspartate transaminase [AST]) and/or gamma-glutamyltransferase (GGT) are routinely elevated in NAFLD. However, a large proportion of NAFLD patients have normal transaminase levels; thus, liver enzymes are not accurate or sensitive diagnostic parameters. Liver enzymes do not adequately correlate with the degree of histological disease and may not be the most helpful in diagnosis. [Hepatology 2003;37:1286-1292] However, if transaminase levels normalize with weight loss and lifestyle intervention, a diagnosis of NAFLD is very likely.
Unfortunately, to date, there is no serum biomarker that can accurately diagnose NASH and differentiate it from NAFL in clinical practice.
Liver biopsy remains the gold standard in identifying the presence of NASH and degree of inflammation and fibrosis but is limited by sampling error and procedural complications. It should be considered in subjects with diagnostic uncertainty or if non-invasive staging is indeterminate. [BMJ 2011;343:d3897]
Fibrosis staging is essential to detect individuals with advanced fibrosis who are at risk of liver-related complications. This can be assessed via non-invasive modalities such as transient elastography (fibroscan) and fibrosis scoring systems.
The NAFLD fibrosis score (NFS), which evaluates age, body mass index (BMI), hyperglycaemia, albumin level, platelet count, and AST/ALT levels, is reliable and easy to use and has been validated in detecting advanced fibrosis. [Hepatology 2007;45:846-854] The Fibrosis-4 (FIB-4) score is another validated test using age, platelet count, and ALT/AST levels to exclude advanced fibrosis. [Hepatology 2006;43:1317-1325] These scores can be calculated in primary care to aid in risk stratification. For patients with low NFS or FIB-4 scores, management and follow-up in primary care may be sufficient; those with high scores may require referral to a tertiary centre for specialist care.
Causes of secondary fatty liver
· Excessive alcohol
· Chronic liver disease (eg, hepatitis C, Wilson’s disease)
· Medications (eg, methotrexate, corticosteroids, tamoxifen, amiodarone, valproate, antiretroviral medications)
· Parenteral nutrition
· Pregnancy-related diseases (eg, acute fatty liver of pregnancy; haemolysis, elevated liver enzyme levels, and low platelet levels [HELLP] syndrome)
According to the American Association for the Study of Liver Diseases (AASLD) guidelines, routine screening for NAFLD is not advised for the general population due to knowledge gaps in various aspects of NAFLD including diagnosis, natural history and treatment, and cost-effectiveness of screening.
‘Non-obese’ or ‘lean’ NASH refers to a subset of non-obese/overweight NAFLD patients (8–19 percent) with relatively normal BMI. These individuals possess metabolic risk factors ie, increased waist circumference and body fat percentage, insulin resistance, hyperglycaemia, dyslipidaemia, and hypertension. Given their risk of developing fibrosis and liver complications, recognition of this group of patients is important in general practice.
Clinicians should have a high index of suspicion for NAFLD in patients with T2D and metabolic risk factors, and recognize that liver enzymes in suspected patients can be normal. Evaluation should aim to identify the severity of liver fibrosis and stratify individual risk accordingly.
To aid in the diagnosis and management of NAFLD, clinicians can refer to practice guidelines from the AASLD, European Association for the Study of the Liver (EASL), and Asia-Pacific Working Party on NAFLD. However, some of the guideline recommendations (eg, fibrosis assessment using fibroscan or certain pharmacological treatments) may not be applicable as these are not readily available in general practice.
In general, NAFLD without advanced fibrosis can be routinely managed in the primary care setting. Lifestyle modification is the cornerstone of NAFLD management. Lifestyle interventions consisting of weight loss, dietary changes, and exercise are first-line measures for NAFLD patients. A structured and individually tailored programme promoting a healthier lifestyle and weight loss should be implemented.
Data has shown that losing 3–5 percent body weight can improve steatosis, and that a 7–10 percent loss can lead to resolution of NASH and regression in fibrosis. [Gastroenterology 2015;149:367-78] Patients should thus be encouraged to achieve these targets. Caloric restriction is essential; a hypocaloric diet reduced by 500–1,000 kcal/day to induce a weight loss of 500–1,000 g/week is advised.
Diet type is also important. Physicians should advocate a diet that is lower in carbohydrate and saturated fat and higher in fibre, vegetables, and antioxidant-rich foods, or adherence to the Mediterranean diet. Studies have demonstrated that coffee drinking has protective benefits in reducing liver fibrosis and liver-related outcomes. Patients should also be advised to consume less processed food and fructose which have been associated with NAFLD. A minimum of 150–200 minutes/week of moderately intense aerobic physical activities coupled with resistance training is effective in managing NAFLD. [J Hepatol 2016;64:1388-1402]
There is a lack of effective pharmacological treatment for NAFLD, and due to the multifactorial and complex nature of this disease, there is no ‘one-size-fits-all’ approach or drug that can provide a cure at present.
Nonetheless, pharmacologic therapy for NAFLD remains suboptimal and should not be first line. It can be considered in patients with NASH with significant or advanced fibrosis and at high risk of disease progression. Vitamin E (800 IU/day), pioglitazone, and pentoxifylline have been used with varying results in improving NASH, but their long-term benefits remain inconclusive. Given concerns regarding the safety profile of high-dose vitamin E (ie, increase in overall mortality, haemorrhagic stroke, prostate cancer), these should be reserved for selected patients with biopsy-proven NASH, and they should ideally be managed in tertiary care. Other newer drugs including elafibranor, obeticholic acid, selonsertib, and cenicriviroc – which are in phase III development – have shown promising results. Although there are ongoing studies, more in-depth evaluations are needed to develop optimal pharmacological options.
Aggressive control of metabolic risk factors (ie, hyperlipidaemia, T2D, hypertension) is vital. Treatment of hyperlipidaemia with statins and ezetimibe, control of hypertension, and optimizing diabetes control has been shown to improve NASH. Data has shown that a decrease in HbA1c is associated with an improvement in liver enzymes and fibrosis.
The use of statins in NAFLD is safe with no increased risk of hepatotoxicity and should not be stopped when a patient develops abnormal liver enzymes secondary to NAFLD. [J Hepatol 2015;63:705-712]
Another obstacle is a knowledge gap on the natural history of NAFLD and the lack of consensus on optimal follow-up of patients with NAFLD. There is no available biomarker as of yet that can provide patient-risk stratification for tailored surveillance.
As the mainstay of treatment is lifestyle intervention, adherence may be an issue and, more importantly, sustainability of such measures after an initial successful attempt.
It is important to ensure that patients are well-educated on their condition, the interplay with other metabolic risk factors, and the long-term outcomes (eg, increased risk of cardiovascular disease and liver-related morbidity). There should also be constant encouragement and positive reinforcement to ensure adherence.
The online NFS calculator for identifying advanced liver fibrosis in NAFLD patients may be used as a disease management tool. Patients are also encouraged to use apps (eg, HealthHub app by the Singapore Health Promotion Board) that could track lifestyle modification and weight loss measures.
Given our increasingly sedentary and unhealthy lifestyles, NAFLD is rapidly on the rise in Singapore, along with the diabetes and obesity scourge. Therefore, clinicians should be vigilant in appropriately recognizing and screening for NAFLD due to the risk of metabolic implications, liver cirrhosis, and related complications. Aggressive treatment of the metabolic risk factors is as vital as encouraging lifestyle modification and weight loss.