Non-Alcoholic Fatty Liver Disease (NAFLD) is closely associated with metabolic risk factors such as obesity, hypertension, diabetes and dyslipidemia and has been considered the hepatic manifestation of metabolic syndrome9. The likelihood of NAFLD and specifically nonalcoholic steatohepatitis (NASH) increases as the severity and number of metabolic syndrome components increases. Obesity remains an important risk factor associated with NAFLD.

INTRODUCTION

NAFLD is defined as the excessive accumulation of fat (>5%) within the liver that is not attributable to alcohol or other drugs^{1, 2}. It is increasingly becoming the most common chronic liver disease worldwide and may be encountered by a myriad of medical personnel, ranging from family doctors, endocrinologists, cardiologists to gastroenterologists. It is a heterogeneous disease, manifesting in a spectrum of phenotypes ranging from simple steatosis, which is traditionally considered relatively benign, to the more aggressive non-alcoholic steatohepatitis (NASH), seen in 10 to 25% of the cases.

Up to one-third of the patients with NASH may progress onwards to liver cirrhosis and other liver related complications such as hepatocellular carcinoma (HCC)³. On meta-analysis, it was found that the average time needed for NAFLD patients with simple steatosis with no fibrosis to progress by one stage was 14.3 years while the time taken to progress by one fibrosis stage is shortened to 7.1 years if NASH was present⁴.

Studies have consistently demonstrated its increasing clinical burden, both as a function of increasing disease prevalence in parallel to the obesity and metabolic syndrome epidemic and also corroborated by continued emergence of natural history data. In the United States, NASH-related cirrhosis is the fastest growing indication for liver transplantation⁵. Other studies have also reported increasing trends of NASH-related HCC over time.

For one, in our local context, there is evidence to suggest that the decline of chronic hepatitis B as a risk factor for HCC may be offset by the emergence of NAFLD as a rising cause of HCC⁶. In addition, relative to the general population, patients with NAFLD have been reported to have increased mortality, with the top three causes of death attributed to cardiovascular, malignancy and liver related causes³.

From the public health perspective, the direct medical cost of caring for a patient with NAFLD has been estimated to be about $1,613 or €1,163 per patient annually in the United States and Europe respectively, representing a substantial economic burden.

PREVALENCE OF NAFLD

Pooled global prevalence of NAFLD has been estimated at 24.4%, with geographic variability seen among different regions⁷. In Asia, the reported prevalence has been reported slightly higher than overall global prevalence, at 27.4%. However, in westernised Asian populations, including in Singapore, prevalence appears to be higher, with rates as high as 40% being reported⁸.

PATIENT PROFILE

NAFLD is closely associated with metabolic risk factors such as obesity, hypertension, diabetes and dyslipidemia and has been considered the hepatic manifestation of metabolic syndrome⁹.

The likelihood of NAFLD and specifically NASH increases as the severity and number of metabolic syndrome components increases.

Obesity

Obesity remains an important risk factor associated with NAFLD. In bariatric surgery cohorts representing the extreme end of the obesity spectrum, studies have reported NAFLD and NASH in 66- 91% and 34-37% of the patients respectively¹⁰. This was consistent with a recent meta-analysis demonstrating a dose-dependent relationship between BMI and NAFLD risk and concluding that obese individuals had a 3.5 fold increased risk of developing NAFLD¹¹.

It should be emphasised that the distribution of fat may be more important than generalised obesity as reflected by BMI⁹. Central obesity correlates more with visceral adiposity and is more closely related to insulin resistance, an integral part of NAFLD/NASH pathogenesis. There have been several reports where NAFLD can occur in “lean” (as defined by low BMI) but centrally obese individuals.

This is relevant to our Asian context, as South Asians, particularly from the Indian subcontinent, have a high prevalence of central obesity, which intuitively translated into increased risk of NAFLD.

Type 2 Diabetes Mellitus
Besides obesity, type 2 diabetes mellitus is also an important factor to evaluate¹². NAFLD is more prevalent and severe in diabetics compared to non-diabetics, with DM an established independent risk factor for NASH and advanced liver fibrosis/cirrhosis. In addition, NAFLD patients with DM have a two-fold increased mortality compared to non-diabetic NAFLD patients. This takes on additional urgency in Asia where the most rapid increase in DM is being experienced.

Asian patients experience corresponding higher rates of DM and metabolic syndrome complications at lower levels of obesity compared to their western counterparts.

Other obesity or metabolic related diseases such as gout, thyroid dysfunction, polycystic ovary syndrome and obstructive sleep apnoea have been associated with increased risk of NAFLD¹³.

Other Factors
Besides metabolic risk factors, advancing age, certain genetic predispositions such as specific variant of PNPLA3 (which encodes patatin-like phospholipiase domain containing protein 3), unhealthy dietary patterns and sedentary lifestyles have also been reported to contribute to development of NAFLD¹³.

SYMPTOMS

Patients with NAFLD are commonly asymptomatic. Some patients may report vague non-specific symptoms such as lethargy, nausea or dull ache over right upper quadrant. However, patients with NAFLD who subsequently progress to cirrhosis/HCC may then develop symptoms, such as pain, jaundice, fluid retention/ascites and variceal bleeding.

Weight loss of at least 3-5% of body weight can improve steatosis and up to 10% can improve necroinflammation.

Hypocaloric diet to promote weight-loss should be encouraged. Mediterranean-type diet such as high consumption of fibres and antioxidants- rich fruits and vegetables, low carbohydrate and saturated fat intake, and avoidance of fructoseenriched soft drinks can be beneficial. Coffee may be considered as an adjunct in NAFLD as it is associated with improved outcomes.

Sedentary lifestyle must be avoided. It is recommended that NAFLD patients should commit to at least 150 minutes of moderate to vigorous aerobic physical activities a week.

Aggressive control of metabolic risk factors such as dyslipidemia, hypertension and diabetes in NAFLD patients is prudent: ischemic heart disease is a major cause of mortality in these patients. Optimising diabetes control with insulin sensitizers such as metformin or glitazones, controlling hypertension with ACE-I/ ARB and treating dyslipidemia with statins and ezetimibe have been shown to benefit NAFLD as well. Cessation of smoking is advocated because it is associated with more severe NASH.

WHAT ARE THE LIKELY TREATMENT OPTIONS BY GPs?

GPs play a pivotal role as frontline medical practitioners managing a myriad of chronic diseases, which would also include uncomplicated NAFLD. All NAFLD patients should undergo interventions aimed at promoting healthier lifestyles and strict control of metabolic risk factors^{1, 14}. Lifestyle modification including weight loss, dietary changes and physical exercise is first-line treatment.

WHEN SHOULD GPs REFER TO SPECIALISTS?

Selected groups of NAFLD such as those with advanced liver fibrosis or cirrhosis should be referred to specialist care¹⁴. These higher risk patients may require further investigation and more intensive therapy.

Non-invasive methods such as NAFLD fibrosis score or transient elasto graphy (Fibroscan), if available, can be utilised to identify these high-risk patients. The NAFLD fibrosis score calculator that can be found on website: www.nafldscore.com is a reliable risk stratification tool. This score uses age, hyperglycemia, body mass index, platelet count, albumin, and AST/ALT ratio to predict advanced liver fibrosis in NAFLD. A score of < -1.455 could exclude advanced fibrosis with high accuracy with negative predictive value of 93%. NAFLD patients with high NAFLD fibrosis score may benefit from specialist care.

Any NAFLD patient with clinical or radiological evidence of cirrhosis should also be referred to a specialist unit for further assessment. In addition, further evaluation by specialists may be considered for patients with persistently elevated liver enzymes despite attempts at lifestyle modification or if there was uncertainty in the diagnosis of the liver disease.

WHAT ARE THE LIKELY TREATMENT OPTIONS BY SPECIALIST?

Management at the Fatty Liver/Metabolic Liver Clinic based at Singapore General Hospital follows a team-based approach, incorporating expertise ranging from gastroenterologists, endocrinologists, dietitians and weight management professionals. This clinic provides a platform for in-depth assessment of NAFLD severity and identification of any concomitant occult chronic liver disease. Initiation of liver directed therapies would be in line with most current available evidence-based practices.

Weight loss of 7-10% has consistently been shown to control or even resolve NASH, but is difficult to achieve without support. With close collaboration with LIFE centre, our weight loss management centre in SGH, our patients will have access to the full spectrum of weight loss management, from dietary regimes, exercise programs to bariatric surgical interventions. This may be useful to NAFLD patients that have difficulty losing weight by themselves without a supportive structured program.

Treatments such as vitamin E and pioglitazone have demonstrated effectiveness¹⁵, but remain controversial in the context of potential side effects with long-term use. We offer close monitoring and adjustments of these medications to be used for the right considerations.

In addition, our unit is currently actively participating in several worldwide multicentre phase 3 trials using novel agents in patients with NASH, thus providing patients the opportunity to experience innovative, potentially effective therapies to ameliorate their disease. This may be particularly pertinent for those who have failed other treatment options. In the setting where patients are found to have NASH-related cirrhosis, HCC/variceal surveillance and optimisation of cirrhosis can be implemented.

WHEN WILL THE PATIENT BE REFERRED BACK TO THE GP?

GPs play an important role in shared care for successful management of NAFLD patients, particularly the optimisation and follow-up for the various metabolic diseases commonly intertwined with it.

Patients without NASH or assessed to have low probability of having advanced fibrosis can be referred back to GPs for continued follow-up, where they can be monitored with regards to maintenance of their lifestyle interventions and control of their related metabolic diseases. In addition, it may be prudent for GPs to use non-invasive risk markers or scores such as NFS on an annual basis to screen for potential disease progression, which may then necessitate referral back to the gastroenterologist.

GPs can call for appointments through the GP Appointment Hotline at 6321 4402 or scan the QR code for more information.

By: Dr George Goh, Consultant, Departmet of Gastroenterology & Hepatology, Singapore General Hospital

Dr. George Goh is a Consultant Gastroenterologist and Hepatologist with the Department of Gastroenterology & Hepatology at the Singapore General Hospital. He underwent advanced subspecialty training in Hepatology at the Cleveland Clinic (USA), with a research focus on non-alcoholic fatty liver disease (NAFLD). He returned to establish a dedicated Metabolic Liver Clinic with multi-disciplinary involvement that helps to identify, prognosticate and manage patients with severe NAFLD.

He remains actively involved in research and is the local Principal Investigator of several ongoing international NAFLD trials. He is an appointed Adjunct Assistant Professor at Duke-NUS Medical School and Clinical Lecturer at Yong Loo Lin School of Medicine, National University of Singapore. He is the current Chairman of the National Foundation of Digestive Disease (NFDD).

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