Nonalcoholic fatty liver disease (NAFLD) accounts for nearly 75% of chronic liver diseases in the United States1 and is closely linked with features of metabolic syndrome, particularly insulin resistance.2,3 NAFLD exists in predominantly 2 main histological subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH).4 NAFL is characterized by presence of greater than 5% hepatic steatosis in the absence of cytological ballooning, and significant inflammation or fibrosis. In contrast, presence of cytological ballooning and lobular inflammation along with hepatic steatosis is the minimum histological criteria necessary to diagnose NASH.
NAFLD affects nearly 30% of the U.S. population, and its prevalence is higher in patients with diabetes and obesity.5 Although a rare cause of cirrhosis in the 1990s, NASH is now the fastest-growing listing indication for liver transplantation (LT) among new waitlist registrants.6 Additionally, the number of patients receiving LT for NASH continues to increase and NASH is the only indication for LT that appears to be rising.7 Despite the increase in frequency in LT for NASH, there is paucity of data regarding recurrence of NAFLD post-LT and factors associated with disease progression.8 The only study to systematically evaluate NAFLD post-LT reported universal recurrence of NAFLD after LT.9 In the largest study published on patients transplanted for cryptogenic or NASH-related cirrhosis, only 7% of the cohort consisted of patients who had LT for NASH.10 The published literature is thus limited by inconsistent definition of patients with NASH cirrhosis, detailed histological description on postliver transplant biopsies, lack of long-term follow-up, and selection bias.10-14 No study have systematically evaluated disease recurrence and fibrosis progression in patients transplanted for NASH cirrhosis. Furthermore, there is a paucity of data describing the causes of long-term mortality and their correlation with recurrent disease in patients who transplanted for NASH cirrhosis.7,15 To address these gaps in knowledge, the current study was conducted to evaluate the long-term fibrosis assessment and clinical outcomes in patients who received a LT for NASH cirrhosis.
MATERIALS AND METHODS
Patient Population
Patients were identified retrospectively by reviewing the liver transplant registry at the authors’ institution. Patients transplanted for NASH cirrhosis and those with cryptogenic cirrhosis thought to be secondary to NASH were included in the analysis. NASH cirrhosis was suspected in patients with cryptogenic cirrhosis with negative serological work up in the absence of significant alcohol use (as determined by social worker, psychologist, and hepatologist) with either steatohepatitis on explant, history of liver biopsy showing NAFLD, or those with components of metabolic syndrome even if the explant did not show features of NASH. Patients who had a LT between 1995 and 2013 were included in the analysis. The medical records of all patients who received a LT for NASH were reviewed for medical history, biochemical data, histology, and radiological reports.
Follow-Up Evaluation
All patients were followed up in liver transplantation clinic at least every 6 months after their LT. At each visit, a complete medical history and physical examination were performed including routine laboratory blood work and appropriate immunosuppressant levels. Patients with significant alcohol consumption after LT (>20 g/d in women and 30 g/d in men) were excluded. All alive patients underwent a transient elastography (TE) to assess for hepatic steatosis (controlled attenuation parameter [CAP]) and fibrosis (liver stiffness measurement [LSM]). A liver biopsy was recommended in patients in whom a TE could not be performed successfully. Medical records of deceased subjects were carefully reviewed and cause of mortality recorded. Deceased subjects were considered to have recurrent NAFLD if they had a liver biopsy post-LT showing histological findings consistent with NAFLD. The Social Security Death Index was queried for all patients who had not been seen in LT clinic for more than a year to identify deceased patients. Attempts were made to elucidate the cause of death by obtaining medical records. The cause of death was deemed unknown if patient’s medical records were not available or if no contact could be made with patient’s next of kin. Patients lost to follow up and not in the Social Security Death Index were contacted and offered repeat follow up. Patients who were still alive were considered lost to follow up if they refused to return to clinic or they could not be contacted. All the clinical and laboratory data presented in the study were collected at the their fibrosis assessment (TE or biopsy) or at the time of last follow up in deceased patients. Finally, because there is a time-dependent risk of developing NAFLD, TE was only performed in subjects at least 1 year after LT so as to minimize potential confounders that have been reported with TE.9,16
TE
All patients undergoing TE were required to fast for at least 6 hours before examination. Measurements were performed on the right hepatic lobe of the liver through the intercostal spaces with the patient in dorsal decubitus with the right arm in maximal abduction. All TE examinations were initially attempted with M probe, and XL probe was only used when adequate measurements could not be made with the M probe due to body habitus and skin to capsule distance. In all patients, at least 10 successful acquisitions were required using M or XL probes in order to be considered evaluable. The CAP has been designed to measure liver ultrasonic attenuation.17 CAP and LSM were obtained simultaneously and in the same volume of liver parenchyma. The final CAP value was the median of the individual values and expressed as dB/m. Failed LSM was defined as failure to obtain any valid measurements from a patient. LSM was considered reliable only if 10 valid acquisitions were obtained, the success rate was greater than 60% (successful attempts/total attempts), and the interquartile range-to-median ratio (IQR/M) of the measurement were below 0.3.16 A TE examination was considered technically successful if all 3 of the aforementioned criteria were met.
The cutoff value of CAP for detecting steatosis stages have been previously determined to be 236 dB/m for ≥ S1, 270 dB/m for ≥ S2, and 302 dB/m for ≥ S3.18 The optimal cutoff values for LSM differ based on whether M or XL probe was used.19 Using the M-probe, LSM of patients with F1, F2, F3, and F4 were 7.3 kPa or greater, 8.7 kPa or greater, 11.2 kPa or greater, and 21.2 kPa or greater, respectively.19,20 Corresponding values by XL probes were 6.1 kPa or greater, 8.8 kPa or greater, 9.5 kPa or greater, and 20.8 kPa or greater, respectively.
Liver Biopsy
Historical liver biopsies were included in the current analysis, which were done at the discretion of the transplant hepatologist or surgeon. In patients who failed TE, a liver biopsy was recommended. All liver biopsies were reviewed by a dedicated hepatopathologist and scored according to NASH-Clinical Research Network criteria or presence of bridging fibrosis.4 The presence of at least 5% steatosis was considered to be the minimal diagnostic criterion for NAFLD.4 The histopathologist determined the diagnosis of NASH.
Statistical Analysis
Categorical variables are expressed as numbers (percentages) and continuous variables are presented as means ± SD or as medians with interquartile range if not normally distributed. Categorical variables were compared using χ2 test or Fisher exact test as appropriate. An unpaired t test was used for comparison of continuous variables between groups for normally distributed data and Mann-Whitney U test was used for skewed data.
The cumulative overall mortality and mortality in patients with NAFL compared with NASH were calculated using Kaplan-Meier analysis and compared by log-rank test. To determine clinical and biochemical features associated with development of advanced fibrosis, binary logistic regression models were constructed. Variables independently associated with advanced fibrosis were analyzed by stepwise forward selection procedure using a threshold of P value < 0.1. Similarly, to determine factors associated with mortality post-LT, clinical, and biochemical parameters were evaluated using binary logistic regression analysis. Analysis was performed using IBM SPSS Statistics version 22.0 software (IBM Corporation, Armonk, NY).
RESULTS
Subject Characteristics
Of the 103 patients who met entry criteria, 47.5% (N = 48) had NASH as the waitlist listing diagnosis, while 52.5% (N = 53) had cryptogenic cirrhosis as the listing diagnosis. The mean age and body mass index (BMI) at LT was 55.9 ± 8.3 years and 31.4 ± 5.8 kg/m2, respectively. The majority of the cohort consisted of men (N = 60) and whites (N = 88). Follow-up data were available on 95 (92.2%) patients, whereas the remaining 8 (7.8%) patients were lost to follow up (Figure S1, SDC,https://links.lww.com/TP/B418).
NAFLD Recurrence Based on Biopsy
Thirty-four patients had a liver biopsy post-LT and the median time from LT to biopsy was 47 months (Table 1). NAFLD recurred in 88.2% (N = 30) of the cohort while NASH was noted in 41.2% of patients (Figure 1A). Most patients had grade 1 steatosis (50.0%), whereas a smaller minority of patients had grade 2 and grade 3 (20.6% and 17.6%, respectively) (Figure 1B). Lobular inflammation was uncommon in these patients, as most had none (44.1%) or grade I (55.9%) lobular inflammation. Cytological ballooning was noted in 13 subjects, with 7 (20.6%) having few ballooned cells, whereas 6 (17.6%) had more than few. Although most patients had none to mild fibrosis, 20.6% had bridging fibrosis. One of the patients with histologically evident bridging fibrosis on liver biopsy went on to develop clinically significant portal hypertension and decompensated cirrhosis (Figure 1C).
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TABLE 1: Distribution of clinical characteristics in liver transplantation recipients by either histology or TE
FIGURE 1: Disease recurrence as defined by histology in patients transplanted for NASH (N = 34). A, Recurrence of NAFLD and NASH post-LT in all subjects who had a liver biopsy. B, Distribution of steatosis grade in liver transplant recipients (LTR) undergoing a liver biopsy. C, Distribution of fibrosis grade in LTR undergoing a liver biopsy. D, Serum ALT in patients with post-LT NAFLD. E, Serum ALT across steatosis grade in patients with post-LT NAFLD. F, Serum ALT across fibrosis stage in patients with post-LT NAFLD.
Although the prevalence of diabetes was similar between patients who had recurrence of NAFLD compared to those who did not (91% vs 82%), the fasting serum glucose concentrations in NAFLD were significantly higher compared with those without disease recurrence (169 ± 81 mg/dL vs 98 ± 3 mg/dL; P < 0.01). Serum triglyceride levels of 256 ± 172 mg/dL in patients with recurrent NAFLD were significantly higher compared with 148 ± 32 mg/dL observed in patients without recurrence. Similarly, patients with recurrent NASH had higher serum glucose (199 ± 99 mg/dL vs 98 ± 3 mg/dL, P < 0.01) and triglycerides (258 ± 72 mg/dL vs 148 ± 32 mg/dL) compared with those without recurrent NAFLD. Interestingly, NAFLD recurred in all female patents transplanted for NASH, whereas only 75% recurred in male patients transplanted for NASH (P = 0.03). No difference in biometric and biochemical parameters was noted in patients with NAFL versus NASH. Finally, there were no significant differences in serum aminotransferases between patients with NAFLD recurrence, NASH, steatosis grade, or fibrosis stage (Figures 1D-F).
NAFLD Recurrence Based on TE
Fifty-six subjects successfully underwent TE post-LT after a median time of 75 months after LT (Table 1). Using a cutoff of 236 dB/m, 49 (87.5%) subjects had subjects had presence of hepatic steatosis. Forty (71.4%) subjects had a CAP score greater than 270 dB/m, whereas 28 (50%) had a CAP score of greater than 302 dB/m (Figure 2A and Table S1, SDC,https://links.lww.com/TP/B418). An inverse relationship was observed between serum high density lipoprotein (HDL) and presence of hepatic steatosis on TE with an odds ratio (OR) of 0.96 (95% confidence interval [CI], 0.926-1.000, P = 0.05). No fibrosis was noted in 24 (42.9%) patients who underwent TE (Figure 2B). Any fibrosis was noted in 32 (57.1%) subjects, whereas 17 (30.4%) had unadvanced fibrosis (F1-F2). Advanced fibrosis (>F3) was noted in 15 (26.8%) subjects and cirrhosis in 3 (5.4%) subjects. Using logistic regression models, the presence of advanced fibrosis was associated with BMI (OR, 1.14; 95% CI, 1.003-1.287; P = 0.04), serum triglycerides (OR, 1.008; 95% CI, 1.001-1.014; P = 0.02), and use of oral hypoglycemic agents (OR, 4.57; 95% CI, 1.276-16.38; P = 0.02). In multivariate regression, BMI (OR, 1.193; 95% CI, 1.011-1.409; P = 0.03), triglyceride levels (OR, 1.008; 95% CI, 1.001-1.015; P = 0.028), and use of oral hypoglycemic agents (OR, 7.97; 95% CI, 1.368-46.443; P = 0.02) remained significantly associated with advanced fibrosis.
FIGURE 2: Disease recurrence as defined by TE in patients transplanted for NASH. A, Distribution of CAP scores in patients transplanted for NASH. B, Distribution of LSM in patients transplanted for NASH. C, Serum ALT across CAP scores in patients transplanted for NASH. D, Serum ALT across LSM in patients transplanted for NASH.
The technical success rate of TE was 94.7% (56/59); 3 subjects (5.3%) failed LSM, which was not associated with any clinical parameters. In 22 (40.7%) subjects, TE was performed using the M probe, whereas an XL-probe was required in 32 (59.3%) subjects. Subject BMI was the only significant factor associated with the need to upgrade from M probe to XL probe with an OR of 1.47 (95% CI, 1.165-1.749; P < 0.01).
There were no differences seen between gender, BMI, age, and time from transplant in patients who had at least S1 steatosis compared to those who had none. The distribution of components of metabolic syndrome including hypertension (NAFLD 95% vs non-NAFLD 100%) and hyperlipidemia (NAFLD 96% vs non-NAFLD 79%) were similar between the 2 groups. The prevalence of diabetes was higher in patients with recurrent NAFLD (81% vs 51%; P = 0.08). When compared with those without NAFLD recurrence, serum HDL levels were significantly lower in patients with NAFLD recurrence (36.5 ± 11.9 mg/dL vs 55.2 ± 33.6 mg/dL, respectively; P = 0.006). Furthermore, serum triglycerides were higher in patients with NAFLD compared with patients without recurrent NAFLD (221 ± 115 mg/dL vs 147 ± 54 mg/dL; P = 0.05). Serum alanine aminotransferase and aspartate aminotransferase did not correlate with NAFLD recurrence, and CAP and LSM values as measured on TE (Figures 2C-D).
The recurrence of NAFLD after LT was similar based on liver biopsy (88.2%) and TE (87.5%) as determined by elevated CAP value. Using LSM, advanced fibrosis (F ≥ 3) was present in 26.8% of subjects who had a TE. These numbers are similar to biopsy data in which 20.6% had histologically documented bridging fibrosis (F = 3).
Clinical Outcomes
The prevalence of diabetes, hypertension, obesity, and dyslipidemia was high in patients transplanted for suspected NASH (Table 1). The greatest increase in prevalence of diabetes, obesity, and hypertension occurred within the first 3 years after LT, after which the increase in prevalence of these metabolic comorbidities was incremental. All patients were on calcineurin inhibitor-based regimens as the primary immunosuppressant. A majority of patients were managed on tacrolimus-based regimens (73.7%) with a mean tacrolimus level of 5.8 ± 2.5 ng/mL, whereas 27.3% received cyclosporine with a mean level of 150 ± 90 ng/mL. Sirolimus was used in 15.8% of the cohort with mean level of 5.7 ± 1.2 ng/mL at follow up while prednisone use was relatively uncommon (N = 15; 15.8%) at the time of follow-up with a mean daily dose of 5.3 ± 1.7 mg/day. Eleven of these patients also had a kidney transplant and were on prednisone by protocol. No association between maintenance immunosuppression, NAFLD recurrence or fibrosis progression was noted.
Acute cellular rejection (ACR) occurred in 13 (12.6%) patients after a median follow up of 20 weeks; 3 (2.9%) patients had an episode of ACR 1 year or longer post-LT. The mean BANFF ACR score was 4.8 ± 2.0, and no patients had evidence of chronic rejection on biopsies. Having ACR after LT had no impact on disease recurrence or fibrosis progression.
Mortality
The overall unadjusted mortality rate during the study period was 31%(N = 32), and 5, 10, and 15 years posttransplant survival rates were 86%, 71%, and 51%, respectively (Figure 3A). No differences in survival were noted in patients with recurrent NAFL versus NASH as determined by biopsy (P = 0.64) (Figure 3B). The leading cause of long-term mortality in these patients was malignancy (recurrent hepatocellular carcinoma as well as nonliver malignancy, 25%), infectious complications (25%), and cardiovascular complications (21.9%) (Table 2 and Figure 3C). Three patients (9.4% of total deaths) died from complications related to recurrent graft cirrhosis after a mean follow up of 73 months from LT (Table 2). Among pretransplant factors, pretransplant obesity (BMI > 30 kg/m2) and age of 60 years at the time of transplant predicted post-LT death with an OR 2.921 (95% CI, 1.216-7.854, P = 0.01) and 4.005 (95% CI, 1.534-10.457; P = 0.005), respectively. In survival analysis, both BMI and age older than 60 years at transplant remained statistically significant with OR of 3.242 (95% CI, 1.097-9.583; P = 0.03) for obesity and OR of 4.382 (95% CI, 1.599-12.012; P = 0.005) for those older than 60 years. Posttransplant factors associated with mortality included serum low density lipoprotein cholesterol (OR, 1.025; 95% CI, 1.005-1.045; P = 0.01), triglycerides (OR, 1.005; 95% CI, 1.000-1.009; P = 0.03), and total cholesterol (OR, 1.014; 95% CI, 1.004-1.025; P < 0.01). In contrast, use of statin (OR, 0.342; 95% CI, 0.127-0.924; P = 0.03), fish oil (OR, 0.096; 95% CI, 0.012-0.769; P = 0.03), and antihypertensive medications (OR, 0.231; 95% CI, 0.069-0.779; P = 0.01) were associated with improved survival.
FIGURE 3: Mortality in patients transplanted for NASH. A, Overall survival in patients transplanted for NASH. B, Survival in patients with recurrent NAFL and NASH post-LT as documented on liver biopsy (n = 34). C, Causes of mortality in patients transplanted for NASH.
TABLE 2: Causes of mortality in patients transplanted for suspected NASH
DISCUSSION
NASH cirrhosis is poised to become the leading indication for LT.7 However, relatively little is known about disease recurrence, fibrosis progression, and clinical course in these patients after LT. There are 2 notable studies that have attempted to evaluate posttransplant course in patients transplanted for NASH or suspected NASH.9,10 The first study is limited by relatively small sample size, length of follow up and scarcity of data regarding clinical course.9 In contrast, the second study consisted of much larger cohort (N = 257), however, the only comprised 7% of the cohort had a LT for NASH cirrhosis, and it is not clear what proportion of patients transplanted for cryptogenic cirrhosis had underlying NASH.10 Finally, the study was limited by lack of granular histological assessment in those with a liver biopsy post-LT. Thus, the current study aimed to bridge this gap in knowledge by systematically providing long-term follow-up in all patients who underwent LT at the authors' institution. We clearly defined patients with cryptogenic cirrhosis who likely had underlying NASH as the etiology of cirrhosis to avoid confounding the results of the study. Finally, we provide assessment of hepatic steatosis and fibrosis in nearly 92% of the patients transplanted for NASH cirrhosis. Although 8% of subjects were lost to follow up, we believe that remaining 92% of the cohort is representative as the rate of recurrence of NAFLD and NASH are similar to what have been reported previously.9
In patients transplanted for suspected NASH nearly 90% developed recurrent disease whether it was evaluated histologically or TE. A potential limitation of the current study is that not all patients had protocol liver biopsies. Because there is no approved treatment for NAFLD, protocol biopsies do not alter medical management. As such, most institutions opt against protocol biopsies in patients transplanted for NASH. Additionally, patients may refuse liver biopsy or performing a biopsy may not be feasible (ie, need for chronic anticoagulation) which may further bias the results. TE is a FDA-approved and well-validated noninvasive method of evaluating hepatic fibrosis and steatosis.18,20-23 Although we are unable to distinguish between benign hepatic steatosis and NASH on TE, we can evaluate for presence of hepatic steatosis (CAP) and liver fibrosis (LSM), which have important prognostic implications, and have been linked to clinically relevant outcomes.24,25 Therefore, a noninvasive approach via TE improves patient participation without putting patients at unnecessary risks for procedural complications. TE has also been validated in liver transplant recipients.26-29 However, there is limited data with TE particularly when evaluating LTR with NAFLD. The cutoffs used for both LSM and CAP were developed in nontransplant population and the proposed optimal cutoffs for detecting steatosis and fibrosis via TE in NAFLD are highly variable.30 The LSM represent a spectrum rather than discrete stages, which explains heterogeneity in proposed optimal cutoff.25,30 However, TE becomes increasingly more accurate with higher cutoff values.25 Thus, by using higher published cutoffs for TE, we aimed to not overestimate the prevalence of steatosis or fibrosis.
The lack of association between recurrent NAFLD or NASH and metabolic comorbidities described in nontransplant patients was lost in our cohort.3,31-33 This is likely is due to relatively low number of patients without recurrent disease and high prevalence of metabolic co-morbidities in this cohort. Furthermore, it is important to note that the prevalence of NASH post-LT was high and nearly a quarter of patients transplanted for NASH had advanced fibrosis within a short period of follow up. Additionally, liver enzymes in these patients did not correlate with disease recurrence or fibrosis progression, underscoring the need for alternative and more sensitive methods for assessing disease recurrence in this cohort. Although the prevalence of recurrent NAFLD was high in LTR, it was not universal as has been described previously.9 A possible explanation for this discrepancy may be related changes in immunosuppression as exposure to and dose of corticosteroids is now minimized. Additionally, with increasing awareness of medical comorbidities and cardiovascular disease (CVD) in LTR, early recognition and aggressive management of these risk factors may reduce disease recurrence and severity. Finally, TE was used to define disease recurrence in a subset of patients with NAFLD, which does have known limitations.16,34 There have been concerns regarding overestimation of fibrosis stage when significant amount of hepatic steatosis is present.34 However, to circumvent this potential limitation, the cutoffs used for both fibrosis and steatosis were higher and are more likely to underestimate these parameters. Additionally, the prevalence of hepatic steatosis and advanced fibrosis was similar between liver biopsy and TE cohorts thereby adding further validity to these findings. A major limitation of TE in patients with NAFLD is the high failure rate ranging from 3.8% to 50%.22,35-38 In the current study, the failure rate was relatively low at 5.3%, however XL-probe was necessary in nearly 60% of the cohort and was related patient BMI.
Metabolic syndrome and its components are common after LT and are poor prognostic indicators in LTR.39 In the current study, the prevalence of components of metabolic syndrome was higher than previously described in patients transplanted for non-NASH indication. This likely stems from the metabolic nature of the NASH as most patients undergoing LT for NASH have the metabolic milieu for developing these diseases. No association between metabolic syndrome or its components and disease progression, recurrence, or mortality was noted in the current study. This can be explained by the smaller sample size and the fact that most patients had metabolic syndrome.
Finally, we evaluated causes of long-term mortality, which was comparable to what has been reported in patients transplanted for NASH.7 There was no difference in mortality with regard to disease recurrence. Similarly, the degree or presence of advanced fibrosis did not impact mortality and is likely due to the fact that death related to recurrent graft cirrhosis only occurred in 2.9% of the cohort. However, it should be stressed that progression to decompensated graft cirrhosis followed an accelerated course in LTR when compared with nontransplant population.40 Expectedly, mortality related to metabolic complications (CVD) and chronic immunosuppressant use (malignancy and infections) were leading causes of death in patients transplanted for NASH. Lipid parameters were positive predictors of death, whereas use of medications (statin, fish oil and anti-hypertensive medications) aimed at better control of features of metabolic syndrome were associated with better survival. This expands on prior studies, which show significant subclinical atherosclerosis disease in patients with hepatic steatosis post-LT.41,42 Embedded within these findings is the importance of optimizing management of metabolic syndrome in patients transplanted for NASH cirrhosis. Although data regarding BMI and its impact on morbidity and mortality remain unclear, pretransplant BMI was associated with a shorter posttransplant survival43-45 and larger studies necessary to fully evaluate this association.
In conclusion, the recurrence of NAFLD and NASH is high post-LT and nearly quarter of patients will develop advanced fibrosis. Despite this, death related to graft cirrhosis is relatively uncommon cause of mortality. Instead death due to cancers, infectious complications and CVD is common post-LT. Because the risk of ACR is low, an approach that minimizes immunosuppression post-LT can potentially improve outcomes. However, well-designed prospective trials with larger cohort are needed to determine the best immunosuppressant approach in managing patients transplanted for NASH.
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