Objectives: With limited data on the morbidity profile of liver transplant as therapy for alcoholic hepatitis, we compared 30-day and 1-year morbidity in liver transplant recipients with alcoholic hepatitis versus alcoholic cirrhosis.

Materials and Methods: We retrospectively reviewed 38 perioperative variables in patients with alcoholic hepatitis (n = 15) and with alcoholic cirrhosis (n = 46). Multivariable analysis was performed to identify factors independently associated with outcomes.

Results: Patients with alcoholic hepatitis were younger (43 vs 58 years; P = .001), with higher pretransplant Model for End-Stage Liver Disease scores (36 vs 29; P = .009) and worse Karnofsky scores (20 vs 50; P < .001). All patients with alcoholic hepatitis received standard criteria deceased donor grafts; however, in the alcoholic cirrhosis group, 64% received standard criteria deceased, 11% living, 11% after cardiac death, 9% extended criteria, and 2% split graft donor organ donations (P > .05). The alcoholic hepatitis group had higher degree of steatosis on explant (P < .005), and the alcoholic cirrhosis group had higher 30-day reoperation rate (P = .001); however, 1-year interventions, vascular and biliary complications, graft and patient survival, and all other variables were similar (P > .05). Rates of alcohol relapse, 1-year infection, and 1-year rejection were higher but not significant (P > .05) in the alcoholic hepatitis group. Thirty-day reoperation (odds ratio of 82.63; 95% CI, 8.02-3338.96; P = .002) and Karnofsky scores (odds ratio of 1.18; 95% CI, 1.08-1.36; P = .006) remained significant on multivariate analysis.

Conclusions: Our results showed significant differences between our patient groups, including worse functional status in the alcoholic hepatitis group but significantly higher 30-day reoperation rates and more variable grafts in the alcoholic cirrhosis group, although both groups had similar overall 1-year complication and survival rates. Although not significant, patients with alcoholic hepatitis had higher alcohol relapse and 1-year infection and rejection rates. A larger cohort is necessary to confirm the strength of these findings.

Key words : Alcoholic liver disease, Functional status, Surgical morbidity

Introduction

Acute alcoholic hepatitis (AH) is defined by rapid onset of jaundice due to chronic, excessive alcohol intake. Liver transplant (LT) for AH without the conventional threshold of 6 months abstinence has been shown to be lifesaving compared with traditional medical treatment.¹ There has been a major increase in the number of transplants performed for this indication, given the survival difference compared with nonoperative management.^2-6 However, there are less robust data regarding perioperative features and medical and surgical complication rates. We investigated the perioperative morbidity of AH patients after LT and compared the morbidity profile with that of patients with alcoholic cirrhosis (AC).

Materials and Methods

We retrospectively reviewed all acute AH patients who underwent LT at Montefiore Medical Center between 2015 and 2019 (case group). All patients received deceased donor grafts, and subtypes of deceased donors are explained in the Results section, below. We also collected data on AC patients who underwent LT between 2010 and 2019 (control group). We compared 38 perioperative variables between AC and AH groups, as summarized in Table 1.

Variables included the following preoperative, intraoperative, and postoperative details. Preoperative features were age, Model for End-Stage Liver Disease (MELD) score, preoperative intensive care unit (ICU) status, Karnofsky score, and infection prior to transplant (based on cultures or empiric antibiotic treatment up to 1 month pretransplant). Intraoperative features were measurements of blood products, intraoperative continuous venovenous hemofiltration (CVVH), donor type (standard criteria deceased donor [SCD], donation after cardiac death [DCD], extended criteria donor [ECD], living donor [LD; living donors were related first- or second-degree relatives in this cohort]), and biliary and vascular anastomoses types. Postoperative features included ICU length of stay [LOS], total LOS, 30-day and 1-year reoperation (take back to surgery) rates, 30-day and 1-year all intervention rates (percutaneous or endoscopic procedures), proven 1-year vascular and biliary complication rates (patients who had intervention or reoperation or with clinical documentation for these complications), 1-year infection rates (based on cultures or empiric antibiotic treatment), 1-year rejection rates (biopsy proven), any alcohol relapse (based on clinical documentation), alcohol relapse type (incidental testing, confession of drinking, graft damage evidenced by liver function deterioration, or graft loss due to alcohol based on biopsy results), relapse rate causing graft damage, steatosis on explant (minimal [reported as none, focal, or < 33%], moderate [> 33%], or heavy [> 66% steatosis or diffuse]), incidental hepatocellular carcinoma on explant, graft loss, retransplant, and death.

Transplant candidacy of patients was determined by transplant surgeons, a hepatologist, a psychologist, a social worker, and financial specialists at the multidisciplinary team discussion. All patients received standard immunosuppression that included (basiliximab for induction and tacrolimus, mycophenolate, and prednisone as maintenance therapy. Initiation time of tacrolimus and all dose adjustments were determined at multidisciplinary daily discussions depending on each patient’s postoperative course.

Overall findings were summarized as median and minimum-maximum values or proportions. Compa­risons between groups were made with the Mann-Whitney U test, the Pearson chi-square test, or the Fisher exact test as appropriate. Multivariable analysis was performed with logistic regression to identify factors independently associated with outcomes. Results at P ≤ .05 were considered significant.

Results

We evaluated a total of 54 acute AH patients during the defined time period evaluated for LT. Of these, 15 patients were deemed eligible for transplant by the multidisciplinary team (case group). We identified 38 predetermined perioperative variables and compared these variables with 46 AC patients (control group) who had complete electronic medical records available for the study (Table 1). Patients with AH were younger (43 vs 58 years; P = .001), with higher pretransplant MELD scores (36 vs 29;P = .009) and worse Karnofsky scores (20 vs 50; P < .001) compared with the control group. Preoperative infection status was similar. Patients with AH were more commonly in the ICU at the time of transplant compared with patients with AC (47% vs 13%, P > .05). All of the AH patients received SCD grafts, whereas, in the AC group, 67% of patients received SCD grafts (n = 33), 10.8% received living donor grafts (n = 5), 10.8% received DCD grafts (n = 5), 8.6% received ECD donor grafts (n = 2), and 2.1% received split liver grafts (n = 1) (P > .05).

Other intraoperative features, including vascular reconstruction rates, biliary anastomosis types, and blood product measurements, were similar (P > .05). The need for intraoperative CVVH was higher in the case group without statistical significance (27% vs 5%, P > .05). The 30-day take back rate was significantly higher in the AC group compared with that shown in the AH group (76% vs 13%, P = .001; odds ratio of 19.45; 95% CI, 3.61-203.24); however, when we combined all procedures (any intervention) including percutaneous and endoscopic interventions, there was no significant difference at 30 days or 1 year between the case and control group (P > .05).

Vascular and biliary complication rates were similar in AH and AC patients (7% vs 11%; [P > .05] and 20% vs 26% [P > .05], respectively). The AH group had a higher moderate-to-severe steatosis on explant (40% vs 4%; P = .0047; odds ratio of 0.03; 95% CI, 0.002-0.31). Rates of incidental cancer on explant (7% vs 7%; P > .05), graft loss (13% vs 9%; P > .05), and mortality (0% vs 9%; P > .05) during the observation time were also similar between groups (Table 1). Although AH patients had higher rates of any alcohol relapse (40% vs 17%), higher 1-year infection rates (87% vs 62%), and higher 1-year rejection rates (40% vs 22%), none of these reached statistical significance (P > .05). Similarly, alcohol relapse associated with graft damage was higher in the AH group compared with the control group (27% vs 9%); however, this was not statistically significant (P > .05). When we performed multivariate analysis, only take back to surgery at 30 days (odds ratio of 82.63; 95% CI, 8.02-3338.96; P = .002) and Karnofsky score (odds ratio of 1.18; 95% CI, 1.08-1.36; P = .006) remained significantly different between the case and control groups (Table 2).

Discussion

Since the first publication by Mathurin and colleagues, there has been mounting evidence on the survival benefit of early LT for AH patients.^1-6 However, less robust data are available on the morbidity profile after LT for AH. Herein, we reported our extensive analysis of perioperative features following LT for AH. We found that AH patients were younger, with higher MELD scores and worse functional status. Despite the higher risk profile according to the preoperative features in this group, AC patients had significantly higher reoperation rate at 30 days; however, when all interventions (operative, percutaneous, or endoscopic) at 1 year were combined together or when we looked at biliary or vascular complications at 1 year, there was no difference between the groups. Therefore, we conclude that AH and AC patients have similar surgical morbidity profiles after LT. Blood product requirements and ICU LOS or total hospital LOS were also similar.

Another noteworthy item is that all AH patients received SCD grafts, whereas the AC group had all types of grafts, including DCD, ECD, split, and living donor grafts. There could be several explanations for this. Patients with AC are at higher risk, as demonstrated in this study by higher MELD scores, worse Karnofsky scores, and higher preoperative ICU status. These patients also usually have a “short window” for transplant because of the acute deterioration of their baseline disease. Finally, AH patients may be less likely to have a living donor candidate because of time constraints specific to the acute hepatitis disease process,^7-9 as well as less favorable social and psychological factors; however, this remains to be investigated. Given all of the factors mentioned above, surgeons may be more likely to avoid the possibility of additional complications related to high-risk grafts such as DCD, split, or living donor. However, AC patients are more likely to be stable physiologically and more likely to have social and family support; therefore, they may be more suitable for high-risk graft options or living donor grafts. Although graft type comparison was not statistically significant between the groups in our report, this may change with a larger cohort.

In their comparison of 9 LT cases for AH compared with a control group of AH patients who did not qualify for transplant, Im and colleagues4 reported a posttransplant infection rate of 67% (6 of 9 cases), 4 reoperations for bleeding and wash out, and 7 perioperative hemodialysis procedures with ultimate renal recovery. They reported 1 death due to prolonged respiratory failure requiring tracheostomy and subsequent death due to septicemia 16 weeks after LT. They reported no rejection episodes, and patients were discharged from hospital at a median LOS of 16 days after LT.⁴ These findings were similar to our results. Our median LOS was 17 days for AH. Im and colleagues observed that, despite a high rate of complications, 8 of 9 early LT recipients remained alive with excellent graft function at a median of about 2 years.⁴

Weeks and colleagues reported 46 severe AH patients who underwent LT and compared these with 34 patients with AC who received LT.⁵ They reported that patients with severe AH and AC had similar posttransplant rejection rates (15% vs 18%; P > .05) and infection rates (52% vs 56%; P > .05).⁵ Any alcohol relapse or alcohol relapse with harmful patterns were also similar in both arms.⁵ Sundaram and colleagues reported outcomes of 10 AH patients after LT through a median follow-up of 261 days (range, 52-702 days).6 They reported 100% patient and graft survival during the study period, with 1 rejection (10%) and 1 alcohol relapse (10%); however, there were no other details regarding complications. They concluded that LT for AH was associated with significantly improved patient survival and low rates of relapse, with the limitation of having 10 patients.⁶ The only reported complication was rejection.⁶

Although we found higher 1-year infection rates (87% vs 62%) and higher 1-year rejection rates (40% vs 22%) in the AH case group compared with the AC control group, these did not reach statistical significance. This could be caused by the small sample size. It is also noteworthy that we did look at preoperative infection rates, and these were similar in both study groups. There could have been also a preoperative steroid effect on the posttransplant infection rates. Approximately one-half of the AH patients received pretransplant steroid treatment (data not shown). Higher rejection rates in the AH group could be a part of a compliance issue or younger median age profile in the AC group, or this could be evidence of an enhanced inflammatory immune response during AH. Further studies with a larger and more homogenous population and longer follow-up are necessary to evaluate each parameter independently.

Recidivism is a critical concern for LT in alcoholic patients, especially given the liberalized indications with AH. Data from the American Consortium of Early Liver Transplantation for Alcoholic Hepatitis (ACCELERATE-AH) included 12 centers in the United States from 8 United Network for Organ Sharing regions studying early LT for severe AH.² The primary outcomes were survival and alcohol use after LT, defined as slip or sustained. Of 432 AH cases, 147 underwent LT. Cumulative patient survival rates after LT were 94% at 1 year and 84% at 3 years. The cumulative incidence of any alcohol use was 25% at 1 year after LT (95% CI, 18%-34%) and 34% at 3 years (95% CI, 25%-44%). The cumulative incidence of sustained alcohol use was 10% at 1 year (95% CI, 6%-18%) and 17% at 3 years (95% CI, 10%-27%) after LT. Sustained alcohol use after LT was associated with increased risk of death, and only younger age was associated with alcohol use following LT. They concluded that most patients survive for 3 years (84%), similar to patients who receive LTs for other indica­tions. Sustained alcohol use after LT was infrequent but associated with increased mortality. The study recommended selective use of LT as treatment for severe AH.2 They did not report complication profiles of AH patients after LT. In our experience, the alcohol relapse rate was up to 40% when defined as any kind of alcohol use, although the harmful drinking rate was 27% in the AH group compared with 9% in the AC group. However, this was not statistically significant, likely because of the low number of patients.

Lee and colleagues reported that, in explant examinations, 96% had cirrhosis, 59% had steatohepatitis, and the remainder had cirrhosis alone without concurrent steatohepatitis on explant.2 We did have moderate (> 33%) to severe (> 66%) steatosis in 40% of the AH group versus 4% in the AC group, and the difference was significant. On the other hand, one-half of the patients in the AH group had none, mild, or focal steatosis. Given the clinical and pathological overlap between severe AH and acute-on-chronic liver failure, the National Institute on Alcohol Abuse and Alcoholism Alcoholic Hepatitis Consortia recently recommended the following standard definition for AH10: onset of jaundice within the last 8 weeks, ongoing heavy alcohol consumption for at least 6 months with less than 60 days abstinence prior to jaundice, aspartate aminotransferase more than 50 IU, aspartate aminotransferase-to-alanine aminotrans­ferase ratio more than 1.5, and serum bilirubin more than 3.0 mg/dL.10 With confounding factors (eg, sepsis, shock, or possible drug-induced liver disease), liver biopsy is recommended.10 Histologic alcoholic steatohepatitis is defined as macrovesicular steatosis with at least 1 of the following: neutrophil infiltration, hepatocyte ballooning, or Mallory-Denk bodies.10 As the frequency of LT for severe AH grows, a standard definition for AH is timely and facilitates uniformity for LT selection and clinical studies.^3,9,10

Lee and colleagues also developed the following Sustained Alcohol Use Post-LT (SALT) scoring system11 (range, 0-11): > 10 drinks per day at initial hospitalization (+4 points), multiple prior reha­bilitation attempts (+4 points), prior alcohol-related legal issues (+2 points), and prior illicit substance abuse (+1 point), where > 5 points had 25% positive predictive value (95% CI, 10%-47%) and < 5 points had 95% negative predictive value (95% CI, 89%-98%) for sustained alcohol use posttransplant.¹¹ They concluded that 4 objective pretransplant variables identify candidates with AH for early LT who are at low risk for sustained alcohol use posttransplant.11 This tool may assist in the selection of patients with AH for early LT or in guiding risk-based interventions post-LT. We proceeded with our conventional multidisciplinary discussion and psychosocial evaluation; however, our findings revealed that more objective scoring systems with better predictive capacity are necessary to facilitate a careful patient selection process and reduce the risk of recidivism and related complications.

Limitations of our study are the retrospective nature of the design and small sample size. Small sample size could have been one the major reasons of statistical indifferences in many parameters. For instance, AH patients had higher rates of any alcohol relapse (40% vs 17%), higher 1-year infection rates (87% vs 62%), and higher 1-year rejection rates (40% vs 22%); however, there was no statistical difference. We do not know whether these could be significant in a larger cohort. Also, despite the conclusion that the P value was not significant, we do see a higher rate of recidivism, which shows that the current patient selection criteria are not perfect. Lastly, we were not able to report the exact psycho-social evaluation of these patients, which could have added more value in terms of selection criteria in alcohol use disorder patients.

Conclusions

We found that AH patients were younger, with higher MELD scores and worse functional status. Despite higher risk profiles based on preoperative features, in carefully selected AH patients, early LT provides excellent short-term survival and similar complication profile, similar 1-year intervention rates, similar surgical morbidity rates, and similar LOS compared with AC patients. Although we found higher alcohol relapse, higher 1-year infection rates, and higher 1-year rejection rates in AH patients, these did not reach statistical significance. Harmful patterns of relapse remain challenging in this population, emphasizing the need for validated models to predict alcohol relapse and the need for extreme caution during the selection of patients for this exceptional indication. Larger prospective studies and longer follow-up are necessary.

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