De novo non-alcoholic fatty liver disease after liver transplantation – as diagnosed by magnetic resonance
Ľubomír Skladaný1, Svetlana Adamcová-Selčanová1, Jana Čiefová1, Natalia Bystrianska1, Beata Škvarková1, Beata Bachová1, Tomáš Koller2,3
1 HEGITO (Division of Hepatology, Gastroenterology and Liver Transplantation), Department of Internal Medicine II, Slovak Medical University, F. D. Roosevelt University Hospital, Banska Bystrica, Slovak Republic
2 Klinika hepatogastroenterologie, Transplantcentrum, IKEM, Praha
3 Gastroenterologické a hepatologické oddelenie, V. interná klinika LF UK a UN Bratislava
Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of and indications for chronic liver disease and liver transplant (LTx). NAFLD arising after LTx for another indication is called de novo NAFLD. Aim: To determine the incidence of de novo NAFLD as diagnosed by magnetic resonance imaging (MRI) spectroscopy (MRS). Methods: Prospective data analysis of consecutive patients (pts) after LTx. The study interval was from January 2015 to December 2019. We included pts transplanted for cirrhosis of non-NAFLD aetiology, excluded pts after LTx for NAFLD, severe complications < 2 months after LTx, who died < 3 months after LTx. We recorded demographic and anthropometric characteristics, laboratory panel (FLI – fatty liver index) and MRS at months 3, 6, 12, 24 after LTx. NAFLD was defined as FLI ≥ 60; MRS fat content ≥ 5%. Results: During the study interval we performed 164 LTx in 153 pts, excluded 6 pts (4%) with NAFLD and 52 pts (34%) for pre-defined criteria. We included 95 pts (62%), aged 50.4 years (18–70), 38% women, MELD (model for end-stage liver disease) 15.7 points, Child-Pugh score 8.9 points. Etiology: Alcohol-associated liver disease 44 pts (46%), primary sclerosing cholangitis 16 (17%), autoimmune diseases 12 (13%), miscellaneous 8 (9%), hepatocellular carcinoma 7 (7%), viral hepatitis 3 (3%), secondary biliary cholangitis 3 (3%), Wilson’s disease 2 (2%). Body mass index (BMI) (kg/m2, at baseline, months 3, 6, 12): 25.76; 24.6; 24.95; 26.5 (P < 0.01); FLI (months 3, 6, 12, 24): 48.663 ± 5.878; 51.628 ± 6.166; 50.901 ± 7.075; 55.211 ± 13.832, MRS (> 5% fat, months 6, 12, 24): 26.5; 32.1; 42.9 (P = 0.368), MRS (% fat, median, months 6, 12, 24): 3.45; 4 (P = 0.045), 5 (P = 0.08). MRI elastography (≥ 2.88 kPa, months 6, 12, 24): 26.8; 29.6 (P = 0.07); 46.2 (P = 0.1). Conclusion: We identified rising liver fat content and BMI over time after LTx. Six months after LTx, MRS detected liver fat > 5% in 1/4 of the pts. Six and 12 months after LTx, fibrosis was present in 26 and 29% of the pts, resp. The clinical impact is not known.
Key words: liver transplantation – FLI – MRI spectroscopy – MRI elastography – de novo-NAFLD
Keywordsliver transplantation, FLI, MRI spectroscopy, MRI elastography, de novo-NAFLD
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing in parallel with the epidemics of global obesity and diabetes in so far as, with an estimated prevalence of 10–40%, NAFLD is currently one of the most common causes of chronic liver disease [1,2]. Its more progressive form – NASH (non-alcoholic steatohepatitis) – can lead to advanced chronic liver disease (ACLD) and hepatocellular carcinoma (HCC), which are the most sharply increasing indications for liver transplantation (LTx) [1,3–5]. Additionally, NAFLD may arise after LTx preformed for another indication when we talk about de novo NAFLD.
Recurrence of NAFLD after LTX
Following LTx, the use of immunosuppressant drugs such as corticosteroids, calcineurin inhibitors and mammalian target of rapamycin inhibitors is known to significantly impact the metabolic balance and is associated with the development of insulin resistance, diabetes, hypertension, obesity and hyperlipidaemia [6–8]. Many post-transplant patients (pts) fulfill the criteria for the metabolic syndrome with NAFLD recurrence after LTx . The recurrence rates for hepatic steatosis and steatohepatitis 5 years after the LTx are reported as ranging from 10 to 100% and from 4 to 28%, resp. [10–12]. NAFLD was identified in 30–60% of the pts between 1–5 years after LTx in the study by Yalamanchili et al. , but the Contos study reported up to 100% of NAFLD recurrence 5 years after LTx . In IKEM, the Czech transplant centre, NAFLD was detected by liver biopsy in 30% of the pts 1 year and in 48% of the pts 10 years, resp. after LTx . One risk involved in NAFLD recurrence is the development of liver fibrosis. According to literature, significant fibrosis ≥ F2 by METAVIR occurs in 0–33% of patients with NAFLD recurrence within one year [12,14].
De novo NAFLD after LTx
There are only a few studies characterising de novo NAFLD (NAFLD after LTx in pts who underwent transplantation for indications other than NASH) [15–17]. The risk factors for de novo NAFLD are inactivity, diet, obesity, dyslipidaemia, diabetes mellitus (DM), arterial hypertension, tacrolimus treatment, alcoholic cirrhosis as an indication for LTx, and donor graft steatosis [16–18]. The incidence of de novo NAFLD ranges from 9 to 48.3%, with the progression to fibrosis and cirrhosis in 20–40% of the pts [15–17]. In some patients, coexisting NAFLD/NASH could remain undiagnosed before LTx, thus their de novo NAFLD could actually be a recurrence. Even if NAFLD after LTx does not progress to ACLD, the patients are at an increased risk of cardiovascular and renal morbidity and mortality [14,19].
Diagnosis of NAFLD after LTx
Despite the clear need for non-invasive diagnostic tools, liver biopsy remains the gold standard for the diagnosis of NAFLD/NASH before and after LTx. The most frequently used and most accurate methods for non-invasive diagnosis of NAFLD are fatty liver index (FLI) and magnetic resonance spectroscopy (MRS) with sensitivity and specificity of web FLI calculator  from 92 to 100% [21–24]. In addition to its diagnostic accuracy, the advantage of MRS is the ability to perform magnetic resonance elastography (MRE) with sensitivity and specificity of almost 100% [25–28].
We aimed to determine the incidence of de novo NAFLD in pts after LTx at a single Transplant Centre (TC).
In this prospective study, we analysed the data of consecutive patients from the Hospital Information System „Care Center®“, and the Liver Transplant Database. We enrolled patients transplanted for cirrhosis of non-NAFLD aetiology during the interval from January 2015 to December 2019. We excluded those pts who had LTx performed for NASH, who died during the first 3 months after LTx, or who had severe complications up to 2 months after LTx. We recorded the demographics (age, sex), anthropometrics (height, weight, waist circumference, BMI (body mass index) in kg/m2, laboratory (gama-glutamyltransferase, triacylglycerides and calculated FLI, MELD, Child-Turcootte-Pugh score (CTPS)), and imaging variables (magnetic resonance imaging (MRI) – MRS and MRE) in the Jessenius Diagnostic Centre, Ltd., Nitra. The measurements were taken at months 3, 6, 12, 24 after LTx. FLI was interpreted as supportive of the diagnosis of NAFLD, if ≥ 60 . The interpretation of the MRS was supportive of NAFLD if it was ≥ 5%, and the MRE of significant fibrosis if it was ≥ 2.88 kPa. For statistical analysis, we used legally obtained Wizard software. We give the results of continuous variables as median and interquartile range results for the proportions as the numbers of cases and percentages. A comparison of the continuous variables was carried out using the Mann-Whitney test, and the chi-square test was used to compare the proportions. We defined the statistical significance by the probability of null-hypothesis inferior to 0.05. All the participants signed an informed consent before LTx and agreed with the data publication.
During the study interval of 59 months, 164 LTx were performed in 153 pts. We excluded 6 pts (4%) transplanted for NAFLD and 52 (34%) for other pre-defined criteria. We included 95 pts (62%) with a median age of 50.4 years (18–70), 38% women, the median MELD was 15.7 points (7–34), and CTPS 8.9 points (5–14), (Scheme). The etiologies of ACLD before LTx were alcohol-associated liver disease in 44 pts (46%), primary sclerosing cholangitis in 16 (17%), autoimmune hepatitis and primary biliary cholangitis in 12 (13%), miscellaneous in 8 (9%), HCC in 7 (7%), viral hepatitis in 3 (3%), secondary biliary cholangitis in 3 (3%), and Wilson’s Disease in 2 (2%) (Graph 1). Summary statistics and study group characteristics are displayed in Tab. 1. The evolution of BMI (as measured at baseline, and at months 3, 6 and 12) was as follows: 25.76 (kg/m2), 24.6, 24.95, 26.5 (P < 0.01) (Tab. 2 and Fig. 1).
The diagnosis of de novo NAFLD
The FLI, suggestive of de novo NAFLD (as calculated at months 3, 6, 12 and 24 after LTx) was found in 39%, 38%, 42% and 53% of the pts. The median FLI results in these time periods increased, but did not differ significantly (48.663 ± 5.878, 51.628 ± 6.166, 50.901 ± 7.075 and 55.211 ± 13.832 (P = NS) (Tab. 3 and Fig. 1).
De novo NAFLD, as diagnosed by MRS at months 6, 12 and 24, was present in: 26.5%, 32.1% and 42.9% of the pts (P = 0.368). We observed a significant rise in the liver fat content by MRS, measured at months 6, 12 and 24: 3.45, 4 and 5 (P = 0.045 and P = 0.08, resp.) (Tab. 4 and Fig. 3).
Significant fibrosis by MRE at months 6, 12 and 24 was present in 26.8%, 29.6% and 46.2% of the pts, resp. (P = 0.07 and P = 0.1, resp.). MRE (mean ± SD kPa, months 6, 12, 24; P = 0.368): 2.672 ± 0.107; 2.656 ± 0.114 (P = 0.123); 2.876 ± 0.369 (P = 0.197) (Tab. 5 and Fig. 4).
The most important finding of this single-centre prospective study covering an almost 5-year span was that the presence of de novo NAFLD was high and increasing: in 26% of the pts 6 months and in 42.5% of the pts 2 years after LTx, resp. Since our centre does not use protocol-biopsies (performed each year, irrespective of clinical and laboratory findings), we diagnosed de novo NAFLD by MRS. In the current era of the search for non-invasive diagnostic tools for NAFLD, MRS has been described as the most promising instrument – with an accuracy similar, if not identical to liver histology [23–25]. The rate of de novo NAFLD in our study is comparable to 48% after 3 years, found in the study by Galvin et al.  and higher than in three other studies. Seo et al. reported 18% steatosis and 9% NASH in a similar cohort at a median of 28 months, Dumortier et al. reported NAFLD in 31.1% during a median of 40 months, and Kim et al. found de novo NAFLD incidence of 27% [15,16,29]. Our results add to the literature on the impact of de novo NAFLD, which could be more important than previously thought, since it may significantly affect the prognosis by promoting fibrosis and cirrhosis. We determined that almost 29% of the pts with de novo NAFLD one year after LTx had significant fibrosis (≥ 2.88 kPa on MRE). The above-mentioned study by Galvin et al. showed significant fibrosis in 40.0% of the biopsies of patients with de novo NAFLD 3 years after LTx . Morisaka et al. considered MRE to be a viable alternative to a liver biopsy for the staging of fibrosis . Not using liver biopsies for comparison with MRI can be considered a limitation of our study. However, we believe that, in the near future, MRI at the head of non-invasive modalities will play an increasing role in diagnosing NAFLD as well as the staging of the fibrosis .
There are other results in our study which add to the validity of the results in terms of increasing liver fat content over time after LTx – BMI, and FLI. The BMI increased significantly during the 1st year (P < 0.01). According to FLI measured at months 3, 6, 12 and 24, NAFLD was present in 39%, 39%, 42% and 53% of the patients, resp. These results are higher than those achieved by the MRS but still comparable to the prevalence in literature. Apart from the absence of systematic liver biopsies, there is another drawback to our study. We have not studied the main environmental, lifestyle, host and graft risk factors of de novo NAFLD. The most important factors cited in literature are a sedentary lifestyle, obesity by BMI or waist circumference, high blood pressure, DM type 2, high triglycerides, low HDL-cholesterol, donor graft steatosis, hepatic denervation and immunosuppression after LTx [17,30,31]. Immunosuppressive protocol in our TC includes a triple combination of intravenous methylprednisolone 500 mg in the anhepatic phase followed by a daily intravenous dose of 20 mg with a switch to oral dose at the resumption of oral intake, tapering over 3–6 months, tacrolimus 0.1 mg/kg/day, or ciclosporin 5–10 mg/kg/day and mycophenolate mofetil 2,000 mg/day. Tacrolimus increases hyperlipidaemia and incidence of obesity, DM (NODAT – new onset diabetes after transplantation) and arterial hypertension. Ciclosporin A has the same side effects, but has a more significant effect on hyperlipidaemia, while the incidence of NODAT is lower [17,31]. Glucocorticoids and weight gain also predispose the development of de novo NAFLD and NODAT following LTx [17,31]. Although we have studied some of these associations in another work, we were unable to link these risk factors to the occurrence of NAFLD in the current study . Furthermore, we have not studied the clinical impact of de novo NAFLD on the prognosis of our patients. Prior studies have shown that patients with recurrent NAFLD are at increased risk of cardiovascular events and renal impairment [14,17,19]. On the basis of the shared metabolic risk factors, post‐LT patients with de novo NAFLD are likely to be at increased risk of cardiovascular death, in addition to progression to liver cirrhosis and subsequent complications of portal hypertension . Early recognition and targeted therapy could potentially reduce the risk of the associated complications.
In conclusion, our study identified rising BMI, liver fat content by LFI, and MRI up to 2 years after LTx. As early as 6 months after LTx, one in four pts had MRS-detected NAFLD. As early as 1 year after LTx, one in three patients had MRE-detected fibrosis of the liver graft.
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