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ARTICLE
Nonalcoholic Steatohepatitis Is the Most Rapidly Growing Indication for Liver Transplantation in Iranian Patients

Objectives: Nonalcoholic fatty liver disease is a rapidly growing disease and is hypothesized to become the most common cause of liver cirrhosis in the near future. This study aimed to investigate trends of nonalcoholic steatohepatitis as an indication for liver transplant in Iranian patients.

Materials and Methods: Liver transplant data from all adult patients (age > 18 y) who had undergone liver transplant between 1993 and 2017 at the Shiraz Organ Transplant Center (Shiraz, Iran) were reviewed. Underlying liver diseases leading to liver transplant were stratified according to year of transplant, and trends of increase or decline were analyzed. Kaplan-Meier curves were used for analysis of posttransplant survival of patients with nonalcoholic steatohepatitis and patients with modified nonalcoholic steato­hepatitis.

Results: We evaluated 3184 liver transplant patients. Of these, 112 patients with biopsy-proven nonalcoholic steatohepatitis underwent liver transplant up to the end of 2017. Mean age of patients was 52.86 ± 9.01 years in those with nonalcoholic steatohepatitis and 51.73 ± 7.91 years in those with modified nonalcoholic steatohepatitis (P > .05). The prevalence of nonalcoholic steatohepatitis as an indication for liver transplant was 0.8% in 2011, 0.36% in 2012, 1.9% in 2013, 4.01% in 2014, 2.89% in 2015, 6.65% in 2016, and 9.97% in 2017. The prevalence of modified nonalcoholic steatohepatitis was 2.4% in 2011, 2.88% in 2012, 2.71% in 2013, 2% in 2014, 2.17% in 2015, 2.13% in 2016, and 2.28% in 2017. We found that nonalcoholic steatohepatitis as a cause of liver transplant increased significantly during recent years (P < .001).

Conclusions: Nonalcoholic steatohepatitis is a rapidly growing indication for liver transplant among Iranian patients. Health care providers should consider programs for prevention and early diagnosis of patients with nonalcoholic steatohepatitis for proper treatment.


Key words : Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, Liver cirrhosis, Liver transplant, Viral hepatitis

Introduction

Liver transplant is now considered the optimal modality of treatment for patients with end-stage liver disease and is a growing treatment option worldwide.1 Improvements in surgical techniques and medical treatments such as immunosuppressive regimens have resulted in increased short-term and long-term survival after liver transplant.1 With these improvements, liver transplant is now routinely performed not only for liver cirrhosis but also for acute liver failure, hepatocellular carcinoma (HCC), metabolic disorders, and hilar cholangiocarcinoma.2,3 However, the most prevalent indication for liver transplant is still end-stage liver diseases of various causes. Evaluation of causes of liver transplant may provide important and valuable information on the burden of chronic liver disease leading to liver cirrhosis. This will help health care authorities and clinicians plan for better prevention and treatment of chronic liver diseases by providing updated data about the epidemiology of major causes of liver cirrhosis. A vital example is the cross-sectional study showing an increase in aging patients with hepatitis C virus (HCV) on transplant wait lists and with a higher proportion having HCC.4 Su and colleagues reported a dramatic increase in age of registrants on wait lists and recipients of liver transplant from 2002 to 2014 without a detrimental impact on transplant-related survival.5 In a study using data from the United Network for Organ Sharing and Organ Procurement and Transplantation Network, Kim and associates showed a decreased number of patients with hepatitis B virus (HBV)-induced hepatic decompensation on liver transplant wait lists secondary to widespread HBV therapy.6

Nonalcoholic fatty liver disease (NAFLD) is usually considered to be the hepatic manifestation of metabolic syndrome.7 The universal rising preva­lences of metabolic syndrome and obesity are considered to be major causes of the increasing prevalence of NAFLD.8 Simple steatosis may progress to nonalcoholic steatohepatitis (NASH)/liver cirrhosis, and NASH-induced liver cirrhosis is predicted to be the predominant cause of liver transplant in the near future. Several recent studies have demonstrated a rapid growing trend for NASH as an indication for liver transplant. In 2015, Wong and associates reported that NASH was the second leading cause of liver cirrhosis in patients on liver transplant wait lists in the United States.9 Goldberg and associates reported a decreasing pattern of HCV-related cirrhosis and an increasing trend in NAFLD and alcoholic liver disease in patients on liver transplant wait lists.10 Nonalcoholic steatohepatitis has been reported to be the most rapidly growing underlying cause of liver disease for liver transplant in the United States.11 With the consideration of the high prevalence of NAFLD in Iran,12 understanding trends of NASH cirrhosis as an indication for liver transplant is of great interest. This study aimed to investigate the current status and trends of underlying liver diseases in a cohort of Iranian patients who underwent liver transplant.

Materials and Methods

Liver transplant data from all adult patients (age > 18 y) who had undergone liver transplant between 1993 and 2017 at the Shiraz Organ Transplant Center (Shiraz, Iran) were reviewed. Patients who had multivisceral transplant, repeat transplant, and simultaneous liver-kidney transplant were excluded from the study. All patients received liver allografts from deceased donors. The causes of chronic liver disease leading to liver transplant were identified based on the pretransplant diagnosis of liver disease by serology, liver biopsy, and clinical background. Underlying liver diseases leading to liver transplant were stratified according to the year of transplant, and trends of increases and decreases were analyzed over the study period. Data regarding posttransplant mortality of patients with diagnosis of NASH were recorded.

Nonalcoholic steatohepatitis was defined patho­logically as presence of steatosis in ≥ 5% of hepa­tocytes, hepatocyte ballooning, and inflammation in the absence of secondary causes of hepatic steatosis. Secondary causes of hepatic steatosis included history of significant alcohol consumption (> 20 g/day), HBV and HCV, autoimmune hepatitis (AIH), Wilson disease, and hemochromatosis. Patients were cate­gorized as having NASH-related cirrhosis when the pathologic criteria were fulfilled and when secondary causes of hepatic steatosis were excluded. Patients were diagnosed with cryptogenic liver cirrhosis when other known causes of liver disease were thoroughly investigated and excluded before transplant. Patients with cryptogenic liver cirrhosis with body mass

index ≥ 30 kg/m2 were defined as having modified NASH. Causes of liver diseases were classified into 6 categories: NASH, autoimmune liver diseases including AIH, cholestatic liver diseases including primary sclerosing cholangitis and primary biliary cholangitis, cryptogenic cirrhosis, metabolic liver diseases including Wilson disease, hemochromatosis and alpha-1 antitrypsin deficiency, and viral-induced liver cirrhosis including HBV and HCV.

Ethics and consent
The study protocol was approved by the institutional review board of the Organ Transplant Center, Shiraz University of Medical Sciences (Shiraz, Iran). Written informed consent was obtained from patients. The study was performed in accordance with the Helsinki Declaration as revised in Seoul 2008.

Statistical analyses
Annual trends in liver transplant numbers were stratified based on underlying causes of liver cirrhosis. Clinical characteristics of patients were recorded and are presented as frequencies and proportions. Comparisons of categorical variables were done with chi-square test, and t test was used for comparisons of continuous variables. Annual trends of underlying liver disease as the cause of liver transplant during the study period were analyzed using R-statistics and Armitage trend test. Kaplan-Meier method and log-rank test were used for analysis of overall posttransplant survival of patients with NASH and patients with modified NASH. We used SPSS software version 20.0 (SPSS Inc.; Chicago, IL, USA) for statistical analysis. P < .05 was consi­dered statistically significant.

Results

Records of 3184 adult liver recipients were reviewed (Figure 1). Table 1 outlines the frequencies of the main underlying liver diseases leading to liver transplant among adult patients. Overall, HBV-related liver cirrhosis (23.86%) was the most common cause of liver transplant followed by cryptogenic cirrhosis (18.53%). Among all years, HBV remained the most common cause of liver transplant. Annual trends of reasons for liver transplant are shown in Figure 2.

The first patient with NASH underwent liver transplant in 2011. Afterward, 112 patients with NASH underwent liver transplant at our center. After 2011, 442 patients with cryptogenic cirrhosis received liver transplants. We found that 64 patients fulfilled the criteria for modified NASH. Mean age of patients was 52.86 ± 9.01 years in those with NASH and 51.73 ± 7.91 years in those with modified NASH (P > .05). Mean Model for End-Stage Liver Disease score was 24.27 ± 7.42 in patients with NASH and 23.82 ± 5.66 in those with modified NASH (P > .05) (Table 2). Patients with NASH and modified NASH were significantly older than other patients (P < .001). Patients with NASH had higher mean BMI versus other patients (28.30 ± 4.84 kg/m2 vs 26.65 ± 7.44 kg/m2; P < .001). Diabetes mellitus was more frequently diagnosed in patients with NASH (51%) than in patients with modified NASH (25%) and other patients (12.5%) (P < .001).

The prevalence of NASH as an indication for liver transplant was 0.8% in 2011, 0.36% in 2012, 1.9% in 2013, 4.01% in 2014, 2.89% in 2015, 6.65% in 2016, and 9.97% in 2017 (Figure 3). The prevalence of modified NASH (cryptogenic cirrhosis with BMI ≥ 30 kg/m2) was 2.4% in 2011, 2.88% in 2012, 2.71% in 2013, 2% in 2014, 2.17% in 2015, 2.13% in 2016, and 2.28% in 2017 (Figure 3). Comparisons of trends of NASH versus modified NASH are depicted in Figure 3.

We analyzed trends in causes of liver diseases in 4 groups from 2007 to the end of 2017. Group 1 included patients with NASH, group 2 included patients with cryptogenic cirrhosis, group 3 included patients with viral cirrhosis (HBV- and HCV-related cirrhosis), and group 4 consisted of autoimmune liver diseases, including AIH, primary sclerosing cholangitis, and primary biliary cholangitis. Although the overall number of NASH patients as an underlying cause of cirrhosis and liver transplant has remained low, the number of patients with NASH has increased significantly during recent years as shown by Armitage test (P < .001). Trends in autoimmune liver diseases and cryptogenic cirrhosis have also increased but not significantly (for autoimmune liver disease, P = .237; for cryptogenic cirrhosis, P = .503). The proportion of patients with viral hepatitis as a cause of liver cirrhosis and liver transplant has recently significantly decreased as shown by Armitage trend test (P = .003) (Figure 4).

Using Kaplan-Meier analysis, we found that mean survival after liver transplant was 57.49 ± 2.78 months in NASH patients and 44.91 ± 2.91 in modified NASH patients (P = .796). Survival rates at 6 months, 1 year, and 5 years after liver transplant in patients with NASH and those with modified NASH are outlined in Figure 5.

Discussion

We found that NASH is an increasing cause of liver transplant among Iranian patients. Traditionally, HBV-induced liver cirrhosis and HCV-induced liver cirrhosis have been the most common indications for liver transplant in Iran, similar to that shown in other transplant centers. Our study showed that, although viral hepatitis-induced liver cirrhosis is still the most common cause of liver transplant,13 the numbers of patients with HBV and HCV cirrhosis have been decreasing significantly throughout recent years.

The decreasing trend in viral hepatitis-induced liver cirrhosis is anticipated and justified for several reasons. The decreasing pattern in HBV infection in recent years may be due to the national vaccination program in neonates from 1993 and also to the increased awareness among the population about HBV risk factors.14 Subsequently, the predominant mode of transmission has been changed from

vertical to horizontal, and there is reduced reported carrier state among children.15 As a result, it is hypothesized that current patients with HBV cirrhosis are those who had been infected before establishment of our national vaccination program. The decreasing pattern of HCV cirrhosis is also anticipated, especially after introduction and availability of direct-acting antiviral agents against HCV infection, which may lead to elimination of HCV worldwide especially among high-risk populations.16

Nonalcoholic fatty liver disease is defined as the presence of hepatic steatosis in the absence of secondary causes of fatty liver. It is usually subdivided into nonalcoholic fatty liver and NASH based on the presence or absence of hepatocyte inflammation and/or ballooning.17 Several recent studies have shown a global steady rise in the prevalence of NAFLD, including NASH.18 The prevalence of NASH has been reported to be over 25% in a meta-analysis, with the highest reported prevalence in the Middle East and South America.19 With the consideration of the rapid increase in NAFLD prevalence, the aging population, and the increased burden of diabetes mellitus and obesity, it has been estimated that chronic liver diseases and mortality related to NAFLD will increase.20,21 Nonalcoholic steatohepatitis has been reported to be the most common growing indication for liver transplant in the United States.9,10,22 Holmer and associates reported that NAFLD is an increasing cause of liver transplant in Nordic countries.23

Nonalcoholic steatohepatitis can progress to advanced liver fibrosis leading to cirrhosis, can reverse to isolated steatosis, or can have a stable clinical course without significant regression or progression.24 The rate of fibrosis progression is variable among patients; however, progression from one stage to a higher stage will usually take 10 years or more.25 On the other hand, NASH is an increasing diagnosis in those with primary HCC. It has been estimated that 1% to 2% of patients with NASH-related cirrhosis will develop HCC annually26; in addition, HCC can occur in NASH patients without liver cirrhosis.27

It has been estimated that about 40% of NAFLD patients have progressive hepatic fibrosis, and the remaining 60% have stable smoldering disease or even some degree of regression.28 In patients with NAFLD and progressive fibrosis, the disease has a rapid clinical course in about 20% of patients, leading to advanced fibrosis or cirrhosis. The remaining 80% of patients will have a much lower rate of disease progression.29 The reasons for these different clinical courses and the person-to-person variabilities in disease progression and regression are not yet clear. It should be noted that NAFLD is a multifactorial disease, and several environmental, epigenetic, and genetic causes are involved in its pathogenesis. Therefore, progression or regression of NASH is determined by a constellation of environmental and genetic factors, including level of alcohol con­sumption, lifestyle, including physical activity and dietary regimen, gut microbiota, components of metabolic syndrome, and genetic mutations.30-32 A major contributing factor to the rising prevalence of NASH is probably the increased prevalence of obesity, diabetes, and metabolic syndrome. In Asian countries, urbanization and a gradual transition to a Western diet and lifestyle have been suggested to contribute to the increasing prevalence of metabolic syndrome.33 These metabolic derangements may also be responsible for development of advanced fibrosis and liver cirrhosis among patients with NAFLD.34

Severity of hepatic steatosis, progression of fibrosis, and liver cirrhosis in patients with NAFLD may also be due to several susceptibility genes and certain polymorphisms.35,36 Polymorphisms of patatin-like phospholipase domain-containing 3 and transmembrane 6 superfamily member 2 are 2 major genetic abnormalities that not only predispose to NAFLD but that may contribute to disease severity, progression, and even response to therapy.37-39 Some studies have suggested a protocol to screen the general population for advanced liver fibrosis using noninvasive markers of hepatic fibrosis. Poynard and associates have estimated the prevalence of advanced fibrosis by the FibroTest (Biopredictive, Paris, France) to be 2.8% in a general population of those older than 40 years.40 A systematic review showed that reliance only on simple liver function tests may under diagnose most patients with significant liver fibrosis and suggested the use of transient elastography and/or the FibroTest to diagnose liver fibrosis in the general population.41 In a population-based European study that analyzed transient elastography for estimation of liver fibrosis in a population without liver disease, a high prevalence of silent liver disease and fibrosis mainly attributed to NAFLD was shown.42 However, the cost-effectiveness and clinical application of this practice are still controversial and need further investigation and validation.

Conclusions

Understanding the environmental and genetic risk factors may help clinicians to identify a subgroup of NAFLD patients with progressive fibrosis phenotype versus those with a more benign course. This knowledge could be used to apply preventive and therapeutic measures in these patients, including lifestyle modifications and the use of new gen­erations of antifibrotic medications, to slow the future need for liver transplant.


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DOI : 10.6002/ect.2019.0205


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From the Avicenna Transplant Hospital, Avicenna Center for Medicine and Organ Transplant, Shiraz University of Medical Sciences, Shiraz, Iran
Acknowledgements: The authors have no conflict of interest and no sources of financial support to declare.
Corresponding author: Ahad Eshraghian, Avicenna Transplant Hospital, Avicenna Center for Medicine and Organ Transplant, PO Box 71994-67985, Shiraz, Iran
Phone: +98 71 3628 1442
E-mail: Eshraghiana@yahoo.com