This retrospective study is the first to examine the clinical course of CC, while excluding NASH patients with a history of obesity as far as possible, after LT in Japan. In the course of post-LT, there were no histopathological findings that could identify the primary disease such as autoimmune hepatitis, primary biliary cholangitis and so on. There were also no findings of liver allograft rejection. Interestingly, despite excluding patients with a history of obesity from our cohort of patients with CC, we observed that patients with CC had a high prevalence of steatosis after LT. This explains that there is a possibility that most cases with CC are actually cases with non-obese NASH. We also observed that an increase in the BMI one year after LT for CC was associated with steatosis after LT. Furthermore, a young age, relatively maintained muscle quality at the time of LT, and short postoperative hospitalization period were identified as the novel risk factors for steatosis development after LT. In particular, young age was a risk factor for steatohepatitis among patients with post-LT steatosis. Our findings can help predict patients at a high risk of liver steatosis development on the basis of the postoperative course, and are useful for the post-LT management of CC.
Some studies have reported that the incidence of nonalcoholic fatty liver disease (NAFLD) after LT ranges between 18% and 40% [15, 24–26]. In the general population of Western countries, the prevalence of NAFLD is reported to be 19.0–31.3%; thus, there is no difference between its prevalence after LT and in the general population  . However, among LT patients with NASH or CC, the prevalence of post-LT NAFLD is reported to be 33–63%, which is higher than the prevalence in patients with LTs for other etiologies and in the general population [2, 3, 15, 29–31]. Obesity, pre- and post-LT diabetes mellitus, hyperlipidemia, arterial hypertension, tacrolimus-based regimen, pretransplant liver graft steatosis, and the PNPLA3 genotype GG of the recipient are the risk factors for liver steatosis after LT [13, 14, 32–34]. Similar to in these reports, in this study, 61% and 39% of the patients developed liver steatosis and steatohepatitis, respectively, after undergoing LT for CC. The median times to the diagnosis of simple steatosis and steatohepatitis after LT were 12 months and 27 months, respectively. In our previous studies, among 100 patients with LT in our institution, 33% developed steatosis and 9% developed steatohepatitis after LT, and the average time to steatosis development after LT was 3.81 ± 2.46 years [26, 35]. Compared to this, the incidences of simple steatosis and steatohepatitis after LT for CC were significantly higher (P = 0.03 and P = 0.003, respectively) and the times to steatosis development were shorter in our study. Even though we separated and excluded patients with a history of obesity from the patients with CC to rule out patients suspected with NASH, the incidence of post-LT NAFLD was still high in patients with CC. This indicates that a majority of the patients with CC may actually have non-obese NASH. In Western countries, patients with CC comprise 4% of the patients with liver cirrhosis . However, the number of LTs performed for patients with CC at our institution increased from 4% (3/78) between 1997 and 2007 to 10% (20/202) between 2008 and 2018. In Asian countries, the prevalence of non-obese NAFLD was reported to be twice of that in the Western countries . These data also support our conclusion that the patients with CC in our study might have non-obese NASH.
Regarding the characteristics of our patients with CC, the prevalence of the PNPLA3 rs738409 genotype GG was 61%, which is higher than that in the general population in Japan . This genetic factor is associated with an increase in the liver fat and hepatic inflammation. Previous studies have reported that the rs738409 GG genotype was an important risk factor for the development and progression of non-obese NAFLD . Furthermore, the proportion of subjects with the rs738409 GG genotype was higher among those with non-obese NAFLD than among those with obese NAFLD (47.8% vs 36.5%), and the GG genotype was identified as an independent predictor of NAFLD in the non-obese cohort . Thus, it seems right to presume that CC should actually be diagnosed as non-obese NASH. PNPLA3 genotype GG is considered to be one of the factors of post-LT steatosis in patients with CC.
As for gender differences in the present study, there were no gender differences in the entire cohort—all patients with CC—or in the group who developed liver steatosis after LT, which was assumed to be non-obese NASH. A systematic review reported that women have a higher risk of NASH and advanced fibrosis than men . However, our study is based on LT recipients; therefore, there is a selection bias and hence, we cannot evaluate the gender difference. Furthermore, according to previous reports, there is no evidence of gender differences in CC or non-obese NASH [13, 41].
Regarding the progression after LT, patients in the steatosis group in this study showed a significant increase in the BMIs 1 and 2 years after LT. The median times to the diagnosis of simple steatosis and steatohepatitis after LT were 12 months and 27 months, respectively, and relatively early. Although CC and NASH are hypothesized to be belonging to the same spectrum of liver diseases associated with the metabolic syndrome, CC seems to be more aggressive . The study of non-obese NAFLDs has also reported that fibrosis progression was faster in patients with non-obese NAFLD than in patients with NAFLD with a higher BMI . This might indicate that the period to the onset of post-LT steatosis, especially the progression time to steatohepatitis, is short in patients with CC. Therefore, an early initiation of treatment for steatosis after LT is required.
Regarding donor characteristics, although Miyaaki et al.  reported that donor steatosis is a risk factor for liver steatosis after LT, in our study, donor factors did not have a significant effect. In case of patients with CC, the influence of the recipient factors was strong, and that of the donor factors may have been relatively small.
Previous studies have reported that the muscle composition is associated with NAFLD, hepatocellular carcinoma, and the prognosis after LT [43–46]. The quality or quantity of the patient’s muscles is an important factor in liver disease. In the present study, a higher muscle attenuation was significantly associated with the prevalence of post-LT steatosis. High muscle attenuation indicates a low intramuscular fat deposition, which thereby indicates that the quality of muscle is maintained. The muscle attenuation, which indicates a poor prognosis for hepatocellular carcinoma, is reported to be ≤ 39.3 HU in women . Therefore, the muscle attenuation in the steatosis group, though low at 33.3 HU, was higher than that in the non-steatosis group. This finding suggests that the quality of muscle at the time of LT is an indicator of post-LT steatosis. Interestingly, patients who developed post-LT steatosis and those who had high muscle attenuation were discharged early after LT. This is consistent with previous reports that have shown that patients with higher muscle attenuation have a better postoperative course and prognosis after LT or resection of hepatocellular carcinoma [44, 45]. Moreover, in the post-LT steatosis group, younger patients were more likely to progress to NASH. The results of this study suggest that post-LT NASH is more likely to occur in young patients with a relatively well-maintained muscle quality and a favorable postoperative course. Such cases with a favorable postoperative course are more likely to have NAFLD because they are no longer restricted in their lives due to their good physical condition after LT.
The limitations of our study need to be acknowledged. Our study was retrospective; therefore, annual liver biopsy specimens were not available for some patients and this may have caused a selection bias. Our study sample was taken from a single center and was small in size. Therefore, our conclusions and the interpretation of results are limited, and to validate our conclusions, a study with a larger sample size is needed.