Discussion
This study analyzed the information from the AARC registry, the largest ACLF patients database in the Asia–Pacific region. In comparison with the previous information published by the APASL in 2014 [
4], the overall 28-day mortality rate decreased from over 50% in the previous analysis to 39.3% in the current study. This might reflect an improvement in the quality of care for ACLF patients. In terms of the CLD etiologies and precipitating causes, the trend of prevalence in each factor was similar to the study in 2014, but these differed from the first evaluation in 2009. HBV infection was the most common cause of CLD, and HBV reactivation was the most common precipitating factor in 2009. HBV prevalence was predominately found among Asian countries, whereas alcohol-related complications were the major contributing factor at both acute and chronic liver injury in Western countries [
7]. The current analysis showed that alcohol consumption surpassed others to become the major cause of CLD and liver injury, while HBV-related complications dropped to second rank (Table
1). It should be noted that the prevalence of NAFLD from our study was much increased. Furthermore, the incidence of NAFLD might be under-detected because the burnt-out NASH might be misdiagnosed as cryptogenic [
4]. Based on these situations, it might be predicted that according to the westernization of lifestyle of the Asian people and the significant changes in dietary habits, the incidence of CLD and ACLF would exponentially increase, and NAFLD might be one of the contributing factors for these epidemiological shifts in CLD etiologies. Changing trends were not only discovered in the Asia–Pacific region but also observed globally [
8,
9].
Several variables that influence ACLF prognosis has been discovered; however, there were conflicting associations between each parameter to the outcome. Apart from the presence of cirrhosis, aging and acute insult from alcohol were the pre-ACLF factors that influence ACLF mortality, while other parameters, including sex and types of CLD etiologies, which were found potentially related with prognosis by univariate analysis. These parameters were found insignificant to mortality after being adjusted with the presence of cirrhosis by multivariate analysis. Shi et al. [
10] showed that cirrhotic patients who were injured by non-liver insults, such as bacterial infection, were related with a worse prognosis than liver-related insults, such as alcohol drinking. Shalimar et al. [
11] found alcohol and cryptogenic liver insults were independent risk factors to mortality. They also found that HEV CLD patients had a significantly better prognosis than other CLD patients. In concordance with the results of most literature, the higher level of post-ACLF parameters in our study including WBC count, MELD scores, the number of organ failures and hepatic encephalopathy were associated with poorer prognosis. The presence of cirrhosis was an independent factor of mortality. However, these parameters were not observed as significant effects by prior literatures and systematic reviews [
11‐
20]. Paradoxical impacts from each variable might be explained by the small sample size and the heterogeneity of the study protocol and ACLF definition among different studies [
12].
The 28-day and 90-day mortality rates in cirrhosis patients were significantly lower than in non-cirrhosis patients. Both univariate and multivariate analyses confirmed that the presence of cirrhosis significantly impacted the prognosis among ACLF patients. Cirrhosis ACLF patients had about a 50% greater chance to survive at both 28-days and 90-days in comparison to those without cirrhosis. To compare our results with other literature, only a few studies had evaluated the effects of cirrhosis on mortality. Three studies evaluated CLD patients from any cause. They did not find noteworthy differences between the presence of cirrhosis and short-term (28-days) and long-term (after 28-days) mortalities [
17,
21,
22]. Four literatures evaluated the prognostic effects among HBV-related ACLF patients. Every study performed multivariate analysis considering the presence of cirrhosis as one of the prognostic parameters. Interestingly, none of these studies evaluated short-term mortality. Three studies did not find any critical impacts from the presence of cirrhosis to long-term mortality (equal or more than three months) [
15,
16,
19]. Another study found that liver cirrhosis was an independent risk factor for 3-month death [
14].
Although most literature did not find significant effects of the presence of cirrhosis on prognosis, which contrasted results from our study, we should take into account the fact that these results were not the primary objective of their studies, so the number of the study population might be too small to discriminate the effect of cirrhosis on mortality. The significant impact of the presence of cirrhosis was consistently observed from every evaluation in our study, in which the study protocol was specifically generated. Moreover, our database was relatively large and enrolled diverse participants from various countries and ethnicities. This was the strength of our study, reassuring that the presence of cirrhosis influenced ACLF prognosis particularly in patients who had alcohol-related liver disease.
Systemic inflammatory response after liver injury is a major contributing mechanism in the pathogenesis of ACLF. There are two types of triggers that are able to stimulate inflammatory responses. Exogenous triggers, such as bacterial infection stimulate different types of inflammatory cells and cytokine pathways that give rise to inflammation. Endogenous triggers originating from necrotic hepatocytes and products from extracellular matrix breakdown induce inflammation to promote tissue restoration. Two types of inducers act synergistically in response to the liver injury to stimulate inflammatory cascade and repair mechanisms; however, excessive inflammation could adversely bring about organ failure and death [
23]. Besides the inappropriate immune response after liver injury, gut dysbiosis and bacterial translocation found in many CLD situations also play a role in the development of ACLF. They additionally activate inflammatory responses and interact with the precipitated-inflammatory cascade. As a result, the inflammatory response that was already dysregulated would be more heavily damaged [
5,
6,
24].
Two possible reasons might explain why patients with non-cirrhosis had a worse prognosis than patients with cirrhosis after ACLF development in alcohol-related liver disease. First, non-cirrhosis had a more inappropriate and exaggerated immune response than cirrhosis. Although ACLF patients did not have cirrhosis, they still developed systemic inflammation, which repetitively or continuously provoked an immune response. The study showed that white blood cell count was higher in alcoholic CLD patients with non-cirrhosis, demonstrating a higher degree of systemic inflammatory response. Additionally, patients with non-cirrhosis had more cerebral, coagulation, renal, and circulatory failure than patients with cirrhosis. Systemic inflammation is a distinct characteristic of ACLF, and it is significantly more prevalent in alcoholic liver disease-ACLF [
25‐
27]. An alteration in intestinal microbiomes, which is the supported mechanism of ACLF, was also observed in patients with non-cirrhosis CLD and alcohol-related liver disease by many recent literatures [
28‐
30]. Increasing evidence of an imbalance of gut microbiota and bacterial translocation was frequently found in alcoholic CLD [
31‐
33]. These might be the possible explanations for why non-cirrhosis had a poorer prognosis in patients with alcoholic CLD. However, we have no data on the inflammatory parameters in both groups of ACLF, and this hypothesis needs further studies to confirm. Second, the limitation of ACLF definition, patients with decompensated cirrhosis who were likely to have poorer outcomes, had been excluded. These might lead to the lower mortality in ACLF patients who had the background of liver cirrhosis.
Our study demonstrated that although non-cirrhosis CLD patients had a lower chance of liver-related complications, they were equally or at higher risk of poor outcome in cases with complications than patients with cirrhosis. While most physicians focused their concerns on cirrhosis patients, we recommended increasing the level of attention to CLD patients particularly alcoholic CLD. At ACLF presentation, non-cirrhosis patients should be concerned that they might have serious systemic inflammation. We encourage including the presence of cirrhosis with the type and number of organ failures at an initial evaluation for severity grading.
Our study had some limitations. First, there was marked heterogeneity in treatment protocols between each institution. We did not include treatment effects, particularly liver transplantation, in prognosis assessment. In addition, only a small number of patients (0.8%, n = 13) underwent liver transplantation, resulting in difficulty in analyzing its relation with prognostic outcomes. Second, we did not collect and compare inflammatory biomarkers between cirrhosis and non-cirrhosis ACLF patients to confirm our hypothesis. Hence, we suggest collecting inflammatory biomarkers for future research, which might help establish the hypothesis of the exaggerated inflammation and identify correlations with prognosis.
Declarations
Collaborators The following members of the DUCA group were collaborators in this study: Shiv Kumar Sarin, Ashok Choudhury, Manoj K. Sharma1,
Rakhi Maiwall1 (Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India); Mamun Al Mahtab, Salimur Rahman (Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh); Sanjiv Saigal, Neeraj Saraf, A. S. Soin (Department of Hepatology, Medanta The Medicity, Gurgaon, India); Harshad Devarbhavi (Department of Internal Medicine, Hallym University College of Medicine, Seoul, South Korea); Dong Joon Kim (Department of Internal Medicine, Hallym University College of Medicine, Seoul, South Korea); R. K. Dhiman, Ajay Duseja, Sunil Taneja (Department of Hepatology, PGIMER, Chandigarh, India); C. E. Eapen, Ashish Goe (Department of Hepatology, CMC, Vellore, India); Q. Ning (Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China); Tao Chen (Translational Hepatology Institute Capital Medical University, Beijing You’an Hospital, Beijing, China); Ke Ma (Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China); Z. Duan, Chen Yu (Translational Hepatology Institute Capital Medical University, Beijing You’an Hospital, Beijing, China); Sombat Treeprasertsuk (Department of Medicine, Chulalongkorn University, Bangkok, Thailand); S. S. Hamid, Amna S. Butt, Wasim Jafri (Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan): Akash Shukla (Department of Gastroenterology, Lokmanya Tilak Municipal General Hospital and Lokmanya Tilak Municipal Medical College, Sion, Mumbai, India); Vivek Saraswat (Department of Gastroenterology, SGPGIMS, Lucknow, India); Soek Siam Tan (Department of Medicine, Hospital Selayang, Bata Caves, Selangor, Malaysia); Ajit Sood, Vandana Midha, Omesh Goyal (Department of Gastroenterology, DMC, Ludhiana, India), Hasmik Ghazinyan (Department of Hepatology, Nork Clinical Hospital of Infectious Disease, Yerevan, Armenia), Anil Arora (Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital and GRIPMER, New Delhi, Delhi, India), Jinhua Hu (Department of Medicine, 302 Millitary Hospital, Beijing, China); Manoj Sahu (Department of Gastroenterology and Hepatology Sciences, IMS & SUM Hospital,
Bhubaneswar, Odisha, India); P. N. Rao (Asian Institute of Gastroenterology, Hyderabad, India); Guan H. Lee, Seng G. Lim (Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore); Laurentius A. Lesmana, Cosmas Rinaldi Lesmana (Digestive Disease and GI Oncology Centre, Medistra Hospital, Jakarta, Indonesia); Samir Shah (Department of Hepatology, Global Hospitals, Mumbai, India); V. G. Mohan Prasad (Department of Gastroenterology, VGM Hospital, Coimbatore, India); Diana A. Payawal (Fatima University Medical Center Manila, Manila, Philippines); Zaigham Abbas (Department of Medicine, Ziauddin University Hospital, Karachi, Pakistan); A. Kadir Dokmeci (Department of Medicine, Ankara University School of Medicine, Ankara, Turkey); Jose D. Sollano, Gian Carpio (Department of Medicine, University of Santo Tomas, Manila, Philippines); Ananta Shresta (Department of Hepatology, Foundation Nepal Sitapaila Height, Kathmandu, Nepal); G. K. Lau (Department of Medicine, Humanity and Health Medical Group, New Kowloon, Hong Kong, China); ·Md. Fazal Karim (Department of Hepatology, Sir Salimullah Medical College, Dhaka, Bangladesh); Gamal Shiha (Egyptian Liver Research Institute And Hospital, Cairo, Egypt); Rino Gani, Kemal Fariz Kalista (Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia); Man-Fung Yuen (Department of Medicine, Queen Mary Hospital Hong Kong, The University of
Hong Kong, Hong Kong, China); Seema Alam, Rajeev Khanna, Vikrant Sood, Bikrant Bihari Lal (Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New
Delhi, Delhi, India; Viniyendra Pamecha (Department of Hepatobilliary Pancreatic Surgery and Liver Transplant, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India); Ankur Jinda (Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan); V. Rajan, Vinod Arora (Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India); Osamu Yokosuka (Professor Emeritus, Chiba University, Chiba, Japan); Madunil A. Niriella (Department of Medicine, University of Kelaniya, Ragama, Sri Lanka); Hai Li (Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China); Xiaolong Qi (CHESS Frontier Center, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, China); Atsushi Tanaka (Department of Medicine, Tokyo University School of Medicine, Tokyo, Japan); Satoshi Mochida (Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan); Dominic Ray Chaudhuri, Ed Gane (New Zealand Liver Transplant Unit, Auckland Hospital, Auckland, New Zealand); Khin Maung Win (Yangon GI and Liver Centre, Pabedan, Yangon, Myanmar); Wei Ting Chen (Division of Hepatology, Department of Gastroenterology and Hepatology, Chang
Gung Medical Foundation, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan); Mohd. Rela (Department of Liver Transplant Surgery, Dr. Rela Institute and Medical Centre, Chennai, India); Dharmesh Kapoor (Department of Hepatology, Global Hospitals, Mumbai, India); Amit Rastogi (Department of Hepatology, Medanta The Medicity, Gurgaon, India); Pratibha Kale (Department of Microbiology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India); Archana Rastogi, Chhagan Bihari Sharma (Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India); Meenu Bajpai (Department of Immunohematology and Transfusion Medicine, Institute of Liver
and Biliary Sciences, New Delhi, Delhi, India); Virender Singh, Madhumita Premkumar (Department of Hepatology, PGIMER, Chandigarh, India); Sudhir Sudhir · A. Olithselvan (Division of Liver Transplantation and Hepatology, Manipal Hospitals, Bangalore, India); Cyriac Abby Philips (The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, India); Anshu Srivastava, Surender K. Yachha (Department of Pediatric Gastroenterology, SGPGIMS, Lucknow, India); Zeeshan Ahmad Wani (Noora Hospital in Srinagar, Shrinagar, India); B. R. Thapa (Department of Gastroenterology and Pediatric Gastroenterology, PGIMER, Chandigarh, India); Anoop Saraya, Shalimar (Department of Gastroenterology and Human Nutrition, AIIMS, New Delhi, India); Ashish Kumar (Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital and GRIPMER, New Delhi, Delhi, India); Manav Wadhawan (Department of Gastroenterology, Hepatology and Liver Transplant, B L K Hospital, New Delhi, India); Subash Gupta (Centre for Liver and Biliary Science, Max Hospital, New Delhi, India); Kaushal Madan (Department of Gastroenterology, Hepatology and Liver Transplant, Max Hospital, New Delhi, India); Puja Sakhuja (Department of Pathology, GB Pant Hospital, New Delhi, India); Vivek Vij (Department of Liver Transplant and Hepatobilliary Surgery, Fortis Hospital, New Delhi, India);Barjesh C. Sharma (Department of Gastroenterology, GB Pant Hospital, New Delhi, India); Hitendra Garg, Vishal Garg (Department of Gastroenterology, Hepatology and Liver Transplant, Apollo Hospital, New Delhi, India); Chetan Kalal (Department of Hepatology, Sir H N Reliance Hospital and Research Centre, Mumbai, India); Lovkesh Anand (Department of Gastroenterology and Hepatology, Narayana Hospital, Gurugram, India); Tanmay Vyas (Department of Hepatology, Parimal Multi-Speciality Hospital, Ahmedabad, India); Rajan P. Mathur (Department of Nephrology, Institute of Liver and Biliary Sciences, New Delhi, India); Guresh Kumar, Priyanka Jain, Samba Siva Rao Pasupuleti (Department of Statistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India); Yogesh K. Chawla (Department of Hepatology and Gastroenterology, Kalinga Institute of Med Sciences, KIIT University, Bhubaneswar, India); Abhijit Chowdhury (Department of Hepatology, Institute of Post Graduate Medical Education and Research, Kolkata, India); Shahinul Alam (Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh); Do Seon Song, Jin Mo Yang (Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea); Eileen L. Yoon (Department Of Internal Medicine, Inje University College of Medicine, Busan, South Korea).