Non-alcoholic fatty liver disease: Prevalence and management in Hong Kong
Fatty liver encompasses broad spectrum of conditions that lead to accumulation of fat in the liver. In Asia, the prevalence of non-alcoholic fatty liver disease (NAFLD) and its subsets are increasing due to altered dietary habits and lifestyle factors.1 In Hong Kong, the prevalence of NAFLD is 27.3% and in need of immediate measures to avoid further increase.2 In an interview, Professor Grace Wong from the Department of Medicine and Therapeutics, The Chinese University of Hong Kong, shared her insights on the prevalence and management of NAFLD in Hong Kong.
Shifting epidemiology of NAFLD
NAFLD and its subsets range from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC) (Figure 1).3 The prevalence of NAFLD is growing in adults and children alarmingly worldwide, with Asia leading the rise. In the United States, the prevalence increased from 15% in 2005 to 25% within 5 years.3 In Asia, the prevalence of NAFLD ranges between 20-45%.1 NAFLD was regarded as a consequence of the modern sedentary, food-abundant lifestyle prevalent in the West until its changing epidemiology to East over the past three decades.1
In a study conducted in Hong Kong in 2012, the prevalence of fatty liver was 36.8% in men and 22.7% in women.2 In men, the prevalence of fatty liver peaked at 40 years of age and remained relatively constant up to 70 years of age. In contrast, the prevalence of fatty liver remained low in women younger than 50 years old, and increased steadily after menopause.2 Overall, the population prevalence of NAFLD was 27.3%.2 Patients with fatty liver had liver stiffness ≥9.6 kPa, a level suggestive of advanced fibrosis. Together with other clinical prediction scores, the estimated prevalence of advanced fibrosis in patients with fatty liver in Hong Kong was <10%.2
In a subsequent study in 2015, people without NAFLD at baseline were followed for a median interval of 47 months.4 13.8% developed incidence of fatty liver with a mean intrahepatic triglyceride (IHTG) content of 8.9%.4 20.5% had an IHTG content 11.0%, suggestive of moderate to severe steatosis. Population incidence of NAFLD at 3–5 years was 13.5%.4
Another study conducted in Hong Kong reported a higher prevalence of NAFLD as 42.3%.5 However, among these, 17.7% had mild steatosis, 19.5% had moderate steatosis, and 5.1% had severe steatosis.5 The factors associated with NAFLD in Hong Kong included male gender, older age, and higher weight, height, BMI, waist and hip circumference, systolic and diastolic blood pressure, fasting cholesterol and glucose levels.5 In total, 1.2% and 0.002% with NAFLD had advanced liver fibrosis and cirrhosis respectively.5
The risk factors associated with NAFLD
Based on the current knowledge, it appears that a combination of genetic, demographic, clinical and environmental factors may play a role in determining the likelihood of fatty liver in a given individual (Figure 2).
Metabolic comorbidities are commonly associated with NAFLD, including obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and metabolic syndrome.3 However, NAFLD varies substantially among people with comparable lifestyle, environmental impact, and metabolic abnormalities, indicating that other factors are contributing to the pathogenesis. The heritability and interethnic variations in susceptibility suggest that genetic factors may also play an important role in determining the phenotypic manifestation and overall risk for NAFLD.6
NAFLD and its pathologically more severe form NASH, mainly occur in genetically susceptible people who are over-nourished. Asian people are particularly susceptible, partly owing to body composition differences in fat and muscle.1 There are emerging data on genetic polymorphisms that predispose Asian people to NAFLD, NASH and cirrhosis.1 In addition to genetic predisposition, associated obesity and diabetes pandemics that have occurred more recently in Asia have resulted in increasing incidence of NAFLD.1
Non-invasive diagnostic tests are recommended for NAFLD
According to the current guidelines, non-invasive investigations, such as serum-based tests, blood tests or imaging, are suggested in the diagnosis of NAFLD. Although liver enzyme profiles and plasma cytokeratin-18 fragment (CK-18) reflect the degree of hepatocellular apoptotic activity, a characteristic feature of NAFLD and NASH, a combination of imaging techniques are mandatory to arrive at a definitive diagnosis.7
Abdominal ultrasonography is the most common first-line imaging modality for patients with elevated liver enzymes or suspected NAFLD.7 Despite being a convenient and a rapid investigation to screen, it is insensitive if steatosis is ≤30%, and thus cannot be utilized in identifying simple steatosis.7
Moreover, transient elastography (FibroScan) is an efficient diagnostic tool with high sensitivity to steatosis. It can be used to assess liver steatosis by controlled attenuation parameter (CAP), concurrently with liver stiffness measurements (LSM). CAP has 80-97% sensitivity in diagnosing ≥11% steatosis, and hence is used to diagnose NAFLD by confirming the presence of steatosis, and its severity.7 In patients whose diagnosis is unclear, liver biopsy is required to diagnose NAFLD and NASH.7
The importance of screening for NAFLD
Currently, a functional screening system for liver steatosis is not available in Hong Kong. Specialists usually receive patients who have been referred due to abnormal liver enzyme profiles. With subsequent further testing, fatty liver can be diagnosed among these patients. In order to carry out further screening, high risk patients should be identified. In a study conducted in Hong Kong, the incidence of fatty liver in T2DM was reported at 72.8% (CAP) and LSM as 17.7%.8 Factors directly associated with increased CAP include female gender, higher body mass index, triglycerides, fasting plasma glucose, alanine aminotransferase and non-insulin use.8 Longer duration of diabetes, higher body mass index, increased ALT, spot urine albumin:creatinine ratio and lower high-density lipoprotein-cholesterol were the factors responsible for the increased LSM.8 It is hence recommended to screen patients whose inherent risk for liver fat is higher due to metabolic disease.
What is the prognosis of NAFLD?
Simple liver fat or liver steatosis can be reversed with lifestyle modifications, but NAFLD subtypes have the potential to progress into advanced fibrosis, end-stage liver disease and HCC.3 The increasing prevalence of NAFLD or NASH with advanced fibrosis is a concern, because patients appear to experience higher liver-related and non-liver-related mortality than the general population.3 The increased morbidity, mortality and healthcare costs, and declining health related quality of life associated with NAFLD make it a formidable disease.3
The management of NAFLD and its subsets
The Asia-Pacific Working Party on the NAFLD Guidelines 2017 emphasized on the management of NAFLD with weight control and dietary modifications.9 An improvement of NAFLD histologically has been observed with a 7% reduction in body weight.9 It is also highlighted that even exercise itself improves hepatic steatosis without weight loss, but for resolution of NASH weight loss is required.9 A clear dose-response relationship between weight loss and resolution of NASH-related liver histology has been demonstrated, with 90% of patients having resolution of NASH by achieving weight loss of >10%.9 However, in order to reverse fibrosis stage, weight reduction should be greater than 10% . Most importantly, combined diet/exercise strategies are more effective in reducing liver fat than either modality alone.9
Individuals with NAFLD tend to consume foods high in energy density, rich in saturated fat and cholesterol, or sugar-sweetened beverages, which are deficient in micronutrients that usually found in fresh fruit, fiber and green vegetables, and omega-3-polyunsaturated fatty acids.9 Therefore, dietary plans should be made to address these imbalances which are important in preventing or managing the co-existing metabolic and cardiovascular disease. And gradual weight loss (up to 1 kg/week) with a hypocaloric diet (500-1,000 kcal deficit) should be adopted as crash diets can worsen NASH.9 Several different diet protocols have been proposed, such as low carbohydrate, low fat, or Mediterranean diet. In general, the optimal diet should include foods with a low glycemic index.9 A very slow release of sugar into the blood stream has proven to reduce fat amount in the liver.
For the general population, Asia-Pacific Working Party on the NAFLD 2017 guidelines recommend 30 minutes/day of moderate-intensity exercise for ≥ 5 days/week or a total of ≥ 150 minutes of per week or vigorous-intensity exercise for ≥ 20 minutes/day on ≥ 3 days/week (≥ 75 minutes/week).9 Resistance exercise on 2-3 days/week and flexibility exercises > 2 days/week are also suggested.9 A dose-response relationship between exercise volume and reduction in liver fat has been observed, with a greater response in people exercising over 250 minutes/week as compared with those exercising for less than 150 minutes/week.9 Bariatric surgery is considered in individuals who morbidly obese and are resistant to lifestyle modification for reducing the amount of body fat.9
The role of general practitioners in managing NAFLD
General practitioners offer the much-needed care in patients with chronic diseases. These patients may be at higher metabolic risk in developing fatty liver. If there are suspicions, it is advisable to arrange a FibroScan. Only if both the CAP and LSM values are high can patients be referred to specialists. In situations where there are slight increases in CAP values, it is recommended to follow up the patient with lifestyle modifications and controlling metabolic risk factors.
Altered lifestyle and increasing metabolic syndrome have resulted in the higher prevalence of NAFLD in Hong Kong. Awareness of the condition must be spread to curb the progression into liver cirrhosis or hepatocellular carcinoma. In patients at risk for NAFLD, non-invasive screening is mandatory. In simple steatosis without complications, lifestyle modifications can reverse the disease completely. Therefore, monitoring and early diagnosis are the most effective measures to reduce the incidence of NAFLD in Hong Kong.
Inhibition of hypoxia-induced macropinocytosis in future cancer therapeutic strategies
In general, the prognosis for liver cancer is poor because patients are often diagnosed with liver cancer in advanced stage, while its cancer cells can still survive in hypoxia.1,2 In a recent study conducted by Wong CL and colleagues from the Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, published in Nature Communications, it was found that hypoxia-induced macropinocytosis is a new metabolic mechanism in liver cancer cells, by which causing the engulfment of extracellular fluid and the subsequent protein digestion to support the unlimited growth of hepatocellular carcinoma (HCC).1 The breakthrough discovery indicates that inhibiting hypoxia-induced macropinocytosis could be a novel and effective therapeutic approach for HCC.1 This study could also be applied to other solid cancer types with hypoxia.1
Caution: The risk of severe hypoglycemia is elevated in diabetic adults with NAFLD
Hypoglycemia, the most reported adverse event in the management of type 2 diabetes, can be life-threatening and may require emergency hospital admission.1 Therefore, it is of paramount importance to identify high-risk patients early and protect them from detrimental consequences through individualized therapy. Given that liver plays a pivotal role in regulating serum glucose levels via glucogenesis and glycogenolysis, the presence of chronic liver disease such as cirrhosis is likely to disrupt the balance of glucose metabolism.1 Previous studies have already shown that about 12% to 16% of patients with both diabetes and cirrhosis developed hypoglycemia.1 However, the data regarding the association between non-alcoholic fatty liver disease (NAFLD), which is estimated to be present in 55.5% of the diabetic population, and severe hypoglycemia in patients with type 2 diabetes are still lacking.1 In a recent, large, population-based longitudinal study that included about 2 million individuals with type 2 diabetes, the correlation between the presence of NAFLD and the occurrence of severe hypoglycemia was established.
New findings suggest that NAFLD may be an independent risk factor for CVD
Non-alcoholic fatty liver (NAFLD) is the most common chronic liver disorder increasing morbidity and mortality worldwide with cardiovascular disease (CVD) being the main cause of death.1 Recent findings from a meta-analysis of observational studies demonstrated an increased cardiovascular risk with NAFLD, especially with advanced fibrosis.2 Therefore, with several studies highlighting this association, it may be important to consider cardiovascular screening in NAFLD patients in addition to the management of liver disease due to its potential in decreasing the disease burden.3
Results of CHECKMATE 040 COHORT 5: Long-term efficacy, safety and biomarker analysis of nivolumab
Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) cirrhosis have a poor prognosis and are often excluded from clinical trials.1 The overall survival (OS) of sorafenib-treated patients with CPB and aHCC is approximately 4 months.1 Based on the CheckMate 040 trial, which was an open-label, multicohort and phase 1/2 study, nivolumab received accelerated approval in the United States for sorafenib-treated patients with aHCC.1 At a median follow-up of 16.3 months, the investigator-assessed objective response rate (ORR) and median OS were 12% and 7.6 months in CPB (cohort 5) patients, respectively.1 The National Comprehensive Cancer Network (NCCN) guidelines thus recommended nivolumab as a treatment option for certain CPB and aHCC patients.1 The long-term efficacy, safety and biomarker analyses for this CPB cohort were presented, which was probably the first prospective immunotherapy trial in this population.
Potential clinical benefits of ATEZO plus BEV in HCC patients with prior LRTS: update of the IMBrave150
The global incidence of Hepatocellular carcinoma (HCC) has been rising.1 In the meantime, treatment with atezolizumab (ATEZO) plus bevacizumab (BEV) has gained approval in more than 70 countries for unresectable HCC patients who have not received prior systemic therapies.2 Evidence has shown that the combination of ATEZO and BEV significantly improved the overall survival (OS) and the progression-free survival (PFS).3 From the previous primary analysis of IMbrave150, ATEZO plus BEV successfully prolonged the survival safely in unresectable HCC.4 The recent update of IMbrave150 reported on the efficacy and safety of ATEZO plus BEV in patients with prior locoregional therapies (LRTs).
A case of patient with advanced hepatocellular carcinoma - maximizing clinical benefits through timely switching away from failing regimen
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and accounts for approximately 5.7% of all new cancer cases annually.1 In Hong Kong, HCC is the fourth and seventh most common cancer in men and women, respectively, and is the third leading cause of cancer-related death.2 In a
Direct-acting antivirals reduce the need for liver transplantation in HCV-HCC patients
Compared to patients without hepatitis C virus (HCV) infection, those with HCV are associated with a 15 to 20-fold increase in risk of developing hepatocellular carcinoma (HCC) as well as being the most common reason for liver transplantation in Europe and the United States (US).1,2 Prior to 2011, H
Overcoming challenges to eliminate HBV infection in Hong Kong
Chronic Hepatitis B Virus (HBV) infection is a global public health challenge in the same scale as tuberculosis, HIV, or malaria.1 Globally, HBV infection causes considerable amount of liver-related morbidity and mortality. In Hong Kong, 7.8% of the population suffers from HBV infection,
Obeticholic acid improves liver fibrosis related to non-alcoholic steatohepatitis
Non-alcoholic steatohepatitis (NASH) is an increasingly common liver disease that lacks a cure with pharmacological therapies.1,2 Recently released findings from the phase 3 REGENERATE trial demonstrated a significant improvement in NASH related liver fibrosis by obeticholic acid,