The Journey of a Clinician Researcher on NAFLD in Malaysia: From Epidemiology to Non-Invasive Assessment to Treatment

Dr. Chan is Associate Professor of Medicine at the University of Malaya and Consultant Physician and Gastroenterologist at the University of Malaya Medical Centre and the University of Malaya Specialist Centre. He graduated with distinction from the University of Malaya in 2005 and obtained the Membership of the Royal Colleges of Physicians of the United Kingdom in 2008. He served at the Kuala Lumpur General Hospital at the beginning of his career and subsequently returned to his alma mater in 2010 where he actively contributed to clinical, research and educational work. He completed his Ph.D. on non-alcoholic fatty liver disease (NAFLD) at the University of Malaya in 2015 and is a Member of the Academy of Medicine of Malaysia and a Committee Member for the Malaysian Society of Gastroenterology and Hepatology. He has published numerous papers in peer-reviewed journals and presented in both local and international conferences. He is also a reviewer for several international journals. His areas of special interest include diagnostic and therapeutic gastrointestinal endoscopy, viral hepatitis B and C, and non-alcoholic fatty liver disease.


Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in the liver, and is the result of over-nutrition. The prevalence of NAFLD has been increasing in recent years and parallels the increase in prevalence of obesity. Non-alcoholic steatohepatitis (NASH), the more severe form of NAFLD, is characterized by inflammation and ballooning of liver cells, and can lead to scarring of the liver. Scarring of the liver can progress to cirrhosis and eventually liver failure. NASH patients are also at increased risk of developing liver cancer, especially in the presence of excessive scarring in the liver. NAFLD is now recognized as one of the most common causes of chronic liver disease worldwide. The impact of the disease is big in countries such as Malaysia where the prevalence of obesity is high. NAFLD is also closely related to diabetes mellitus, hypertension and dyslipidemia, and patients with NAFLD are more susceptible to cardiovascular diseases as well as certain cancers.

A group of dedicated clinician researchers at the University of Malaya and the University of Malaya Medical Centre has been actively conducting research work on NAFLD for nearly a decade. Their effort has contributed to most of the published work on NAFLD in Malaysia found in the literature today, which includes the epidemiology of the disease, non-invasive methods for assessment of disease severity, and treatment. “My work on NAFLD started with a research project looking at the progression of the disease using paired liver biopsy.(1)As my interest in the subject grew, I started doing several other research projects, and the rest was history,” said Dr. Chan Wah Kheong, who is Associate Professor at the Faculty of Medicine, University of Malaya, and an instrumental figure in NAFLD research there. “It is certainly not easy to juggle clinical work, research work and teaching, but when you know that your work has made a difference, you will find that the sacrifices were worth it,” quipped Dr. Chan, who completed his PhD in NAFLD while teaching undergraduate and postgraduate students, and providing clinical service as a Consultant Physician and Gastroenterologist at the University of Malaya Medical Centre. “I hope the work that has been done will form the foundation for future work that will further enhance our understanding of NAFLD and eventually benefit all patients with the disease,” he added.

 

Epidemiology of NAFLD

The prevalence of NAFLD in the general population was estimated to be 23% based on a study using ultrasonography on health check individuals in a private medical centre in Petaling Jaya about a decade ago.(2)“The work by Professor Dato Dr. Goh Khean Lee and his colleagues, provided primary data on the estimated prevalence of NAFLD in the general population in Malaysia,” said Dr. Chan. Recently, the prevalence of NAFLD was found to be 57% based on a study using Fibroscan on health check individuals in a public medical facility in Kuala Lumpur. The study also found that 18% of the individuals had liver stiffness measurement consistent with excessive scarring in the liver.(3)“The figures from our latest work are indeed worrisome. More concerted efforts are needed to tackle obesity and obesity-related disease such as NAFLD,” he said. The group also reported that half of the patients with diabetes mellitus seen at their hospital clinic had NAFLD,(4)and 8% of the students at their faculty had NAFLD.(5)

 

Non-invasive tests for NAFLD

Dr. Chan and his team was the first to report on the controlled attenuation parameter (CAP) for the detection and quantification of hepatic steatosis, specifically in NAFLD patients.(6)CAP is the decrease in the amplitude of ultrasound as it is propagated through liver tissue and can be estimated using the same radio-frequency data that is used for liver stiffness measurement using Fibroscan. “In our study on 101 biopsy-proven NAFLD patients, we found CAP to be excellent for the detection of significant hepatic steatosis. However, its accuracy was impaired by an increased body mass index, and it was less accurate to distinguish between the different grades of hepatic steatosis,” explained Dr. Chan. Data from the work was subsequently combined in an international, multi-centre effort led by researchers from the University of Leipzig, Germany, that produced important reference cut-offs for CAP for the diagnosis of the different grades of hepatic steatosis.(7)Together with researchers from the Chinese University of Hong Kong, the group was also the first to report on CAP obtained using the XL probe for the detection and quantification of hepatic steatosis, specifically in NAFLD patients, using histology as reference standard.(8)“In the study on 57 biopsy-proven NAFLD patients with liver stiffness measurements using both the M and XL probes, we found both probes to have comparable accuracy for the diagnosis of the different grades of hepatic steatosis. Further work on whether similar cut-offs could be used for both the M and XL probes for the diagnosis of the different stages of hepatic steatosis is currently underway,” he added excitedly.

The group also reported a 2-step approach for the assessment of the presence or absence of advanced fibrosis in NAFLD patients.(9)“The NAFLD fibrosis score has been used for identifying NAFLD patients with and without advanced fibrosis. However, 20-58% of patients would have an indeterminate score. Liver stiffness measurement using Fibroscan has been shown to have excellent accuracy for the exclusion of significant fibrosis and for the diagnosis of cirrhosis. However, it is less accurate for the diagnosis of advanced fibrosis. Moreover, it is not widely available. Patients with a low NAFLD fibrosis score are unlikely to have advanced fibrosis. Liver stiffness measurement by Fibroscan in patients with low NAFLD fibrosis score could lead to discordant results in over 30% of patients, and may lead to a liver biopsy being performed unnecessarily. Hence, we recommend using liver stiffness measurement by Fibroscan for diagnosis of advanced fibrosis only for those patients with indeterminate and high NAFLD fibrosis score. This can maintain the accuracy of identifying patients with advanced fibrosis and at the same time reduce the need for a liver biopsy. Moreover, only about one third of patients would require liver stiffness measurement by Fibroscan with this approach,” he explained.

The group has also worked on several biomarkers for the assessment of disease severity in NAFLD, including the cytokeratin-18 fragment, M30,(10)and serum Wisteria floribundaagglutinin-positive Mac-2 binding protein.(11)“The availability of stored blood samples with corresponding histological data enables us to work on future biomarkers for NAFLD. We are also currently working with an overseas company on a novel magnetic resonance imaging technology for assessment of disease severity in NAFLD and are eagerly awaiting the results of this research project,” said Dr. Chan.

 

Therapeutics for NAFLD

Recently, his team also found that silymarin may be useful for the treatment of NASH.(12)Silymarin is an extract from the milk thistle plant Silybum marianumand has been used for centuries as a herbal remedy for chronic liver disease. It consists of 6 major flavonolignans, namely silybin A and B, isosilybins A and B, silychristin and silydianin, as well as other minor polyphenolic compounds. Its anti-oxidant, anti-inflammatory and anti-fibrotic activity has been demonstrated in numerous in vitro and animal studies. Several human clinical trials have also suggested that silymarin may be useful for the treatment of NAFLD. However, robust evidence was still lacking. “Our work provides primary histological data on the potential efficacy of silymarin in improving liver fibrosis in patients with NASH,” said Dr. Chan, who is one of the main investigators of the research project. The study randomized biopsy-proven NASH patients to silymarin 700 mg three times daily or placebo for 48 weeks, and a repeat liver biopsy was performed at the end of the study. All patients received lifestyle advice. The study found that a significantly higher proportion of patients who received silymarin had fibrosis improvement compared with those who received placebo. The improvement in fibrosis was further supported by improvement in liver stiffness measurement by Fibroscan. Silymarin was safe and well tolerated with an adverse event profile that appeared no different than placebo. “There are currently limited treatment options for NASH. Although weight loss through diet restriction and physical exercise has been shown to improve NASH, only a minority of patients are able to achieve the desired amount of weight loss to have a significant impact on the disease. The findings from our study should prompt further work to better define the role of silymarin in the treatment of NAFLD,” he added.

The full report of the study has been published in Clinical Gastroenterology and Hepatology, the prestigious journal of the American Gastroenterological Association, and was immediately highlighted by NEJM Journal Watch. “We are happy that our research work has received the recognition from our peers and hope to continue to contribute in the field of NAFLD. We would like to take this opportunity to thank our collaborator, Dr. Nik Raihan Nik Mustapha, Consultant Pathologist from Hospital Sultanah Bahiyah, Alor Setar, and all others who have contributed to the success of this research project, especially the patients and their family members,” said Professor Sanjiv Mahadeva, the other main investigator of the research project. The group is currently actively conducting further research in NAFLD, including a pilot study on the use of empaglifozin, a sodium-glucose co-transporter-2 inhibitor, for the treatment of NASH in patients with diabetes mellitus, and welcomes collaboration for further advancement in the field of NAFLD. “I would like to take this opportunity to thank my mentors in my work on NAFLD and my supervisors for my PhD, Professor Dato Dr. Goh Khean Lee and Professor Dr. Sanjiv Mahadeva for their guidance, without which all these work would not have been possible. I would also like to thank my wife, Lai Yong for her understanding and support in my work,” said Dr. Chan.


References

  1. Chan WK, Ida NH, Cheah PL, Goh KL. Progression of liver disease in non-alcoholic fatty liver disease: a prospective clinicopathological follow-up study. J Dig Dis 2014;15:545-552.
  2. Goh SC, Ho EL, Goh KL. Prevalence and risk factors of non-alcoholic fatty liver disease in a multiracial suburban Asian population in Malaysia. Hepatol Int 2013;7:548-554.
  3. Tan EC, Tai SM, Chan WK, Rahman R, Mahadeva S. A study on non-alcoholic fatty liver disease using transient elastography and carotid intima media thickness using ultrasonography in a middle-aged Malaysian population. J Gastroenterol Hepatol 2016;31:385.
  4. Chan WK, Tan AT, Vethakkan SR, Tah PC, Vijayananthan A, Goh KL. Non-alcoholic fatty liver disease in diabetics–prevalence and predictive factors in a multiracial hospital clinic population in Malaysia. J Gastroenterol Hepatol 2013;28:1375-1383.
  5. Chan WK, Bahar N, Razlan H, Vijayananthan A, Sithaneshwar P, Goh KL. Non-alcoholic fatty liver disease in a young multiracial Asian population: a worrying ethnic predilection in Malay and Indian males. Hepatol Int 2014;8:121-127.
  6. Chan WK, Nik Mustapha NR, Mahadeva S. Controlled attenuation parameter for the detection and quantification of hepatic steatosis in nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2014;29:1470-1476.
  7. Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Ledinghen V, Kumar M, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol 2017;66:1022-1030.
  8. Chan WK, Nik Mustapha NR, Wong GL, Wong VW, Mahadeva S. Controlled attenuation parameter using the FibroScan(R) XL probe for quantification of hepatic steatosis for non-alcoholic fatty liver disease in an Asian population. United European Gastroenterol J 2017;5:76-85.
  9. Chan WK, Nik Mustapha NR, Mahadeva S. A novel 2-step approach combining the NAFLD fibrosis score and liver stiffness measurement for predicting advanced fibrosis. Hepatol Int 2015;9:594-602.
  10. Chan WK, Sthaneshwar P, Nik Mustapha NR, Mahadeva S. Limited utility of plasma M30 in discriminating non-alcoholic steatohepatitis from steatosis–a comparison with routine biochemical markers. PLoS One 2014;9:e105903.
  11. Lai LL, Chan WK, Sthaneshwar P, Nik Mustapha NR, Goh KL, Mahadeva S. Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in non-alcoholic fatty liver disease. PLoS One 2017;12:e0174982.
  12. Chan WK, Nik Mustapha NR, Mahadeva S. A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol 2017.

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