Tobacco use following liver transplantation for alcoholic liver disease: an underestimated problem.

Alcohol and tobacco use commonly co-occur, with at least 90% of those with an alcohol problem also using tobacco. Thus, 3 years ago when we discovered higher rate of late deaths due to lung and oropharyngeal cancer in patients who had received a transplant for alcoholic liver disease (ALD), we hypothesized that these patients were continuing to expose themselves to tobacco after liver transplantation (post-LTX) and that this behavior was increasing their risk for cancer. We subsequently began a prospective investigation of post-LTX tobacco use in patients having undergone LTX for ALD (n = 172). For 33 recipients we had data starting from our first assessment at 3 months post-LTX and for this subgroup we report on the details of the timing of tobacco use resumption and the redevelopment of nicotine addiction. We found that on average more than 40% are smoking across all time periods. ALD recipients resume smoking early post-LTX, increase their consumption over time, and quickly become tobacco dependent. These data highlight an underrecognized serious health risk for these patients and demonstrate our need for more stringent clinical monitoring and intervention for tobacco use in the pre- and post-LTX periods.     

Alcohol consumption patterns and predictors of use following liver transplantation for alcoholic liver disease.

For patients who receive a liver transplant (LTX) for alcoholic liver disease (ALD), investigators are focusing beyond survival to determine specific alcohol use outcomes. Studies suggest the use of alcohol ranges from 8 to 22% for the first post-transplant year with cumulative rates reaching 30 to 40% by 5 years following transplantation. Yet while investigators are interested in determining specific rates of alcohol use and predictors of use, only three studies since 1990 have been prospective. In 1998, we began a prospective study of post-LTX alcohol consumption in ALD recipients using multiple repeated measures of alcohol use. After 5 years of follow-up, we found that 22% had used any alcohol by the first year and 42% had a drink by 5 years. By 5 years, 26% drank at a heavier use (binge) pattern and 20% drank in a frequent pattern. In a univariate model, predictors of alcohol use included pre-transplant length of sobriety, a diagnosis of alcohol dependence, a history of other substance use, and prior alcohol rehabilitation.     

Early Trajectories of Depressive Symptoms after Liver Transplantation for Alcoholic Liver Disease Predicts Long‐Term Survival

Although it is well known that depression is associated with poorer medical outcomes, the association between depression‐ and liver transplant (LTX)‐specific outcomes has not been investigated. We identified three trajectories of depressive symptoms evolving within the first post‐LTX year in a cohort of 167 patients transplanted for alcoholic cirrhosis: a group with consistently low depression levels at all time points (group 1, n = 95), a group with initially low depression levels that rose over time (group 2, n = 41), and a group with consistently high depression levels (group 3, n = 31). Controlling for medical factors associated with poorer survival, recipients with increasing depression or persisting depression were more than twice as likely to die (all cause mortality) within the subsequent years. At 10 years post‐LTX the survival rate was 66% for the low depression group, but only 46% and 43%, respectively, for the increasing depression and high depression groups. Except for a paradoxically higher percentage of malignancies in the low depression group, the causes of death and other specific LTX outcomes were not different between groups. Whether treatment of depression will improve survival rates is an area for research.     

Are preoperative patterns of alcohol consumption predictive of relapse after liver transplantation for alcoholic liver disease?

Predictive factors for alcoholic relapse after liver transplantation (LT) performed for alcoholic liver disease (ALD) have been assessed in numerous studies, often with contradictory results. The aim of the study was to assess pretransplantation alcohol consumption characteristics on alcoholic relapse after LT. Patients transplanted for ALD for at least 6 months were included. An anonymous questionnaire assessed socio-demographic characteristics, medical history, and alcohol consumption before and after LT. Relapse was defined as any alcohol use after LT. Severe relapse was defined by heavy drinking: more than 21 units/week for males and 14 units/week for females. A total of 61 patients were studied. The mean follow up after LT was 49 +/- 34 months. Alcoholic relapse occurred in 32 of 61 patients (52%) and severe relapse in eight of 61 patients (13%). Risk factors for severe relapse were: length of abstinence before LT (P = 0.0001), more than one alcohol withdrawal before LT (P = 0.001), alcohol dependence (P = 0.05), alcohol abuse in first relatives (P = 0.05), and younger age (P = 0.05). Information on previous alcohol consumption (dependence, number of withdrawals, family history) helps to predict severe relapse after LT in patients with ALD, allowing early awareness and specific postoperative care.     

The Munich-LTX-Score: predictor for survival after lung transplantation

Huppmann P, Neurohr C, Leuschner S, Leuchte H, Baumgartner R, Zimmermann G, Meis T, von Wulffen W, Überfuhr P, Hatz R, Frey L, Behr J for the Munich Lung Transplant Group (MLTG). The Munich‐LTX‐Score: predictor for survival after lung transplantation.
Clin Transplant 2012: 26: 173–183.
© 2011 John Wiley & Sons A/S. Abstract: Background: The purpose of this study was to create a prognostic score calculated one yr after LTX based on post‐transplant factors inclusive of donor and recipient characteristics that could be used to predict long‐term survival in patients after lung transplantation (LTX). Methods: Uni‐ and multivariate analysis in 206 consecutive LTX patients identified independent risk factors for post‐transplant mortality and onset of bronchiolitis obliterans syndrome. Munich‐LTX‐Score is devised by summing up each identified risk factor. Results: Multivariate analyses revealed acute rejection, lymphocytic bronchiolitis, donor age ≥55 yr, and HLA‐A ≥ 2‐/DR ≥ 2 mismatch and single LTX to be independent negative predictors for long‐term survival (p < 0.05). Munich‐LTX‐Score identified three discrete groups: low‐, moderate‐, and high risk. The actuarial five‐yr survival after score calculation one yr after LTX of the entire cohort was 58%, compared with 91% in low‐, 54% in moderate‐, and 0% in the high‐risk group (p < 0.001). Conclusion: Within our cohort of patients calculation of the Munich‐LTX‐Score, consisting of donor‐, recipient‐, and post‐transplant characteristics, one yr after LTX allowed to predict long‐term survival of lung transplant recipients. After prospective validation, this score could identify patients who may benefit from intensified surveillance after LTX.     

An ‘alcohol contract’ has no significant effect on return to drinking after liver transplantation for alcoholic liver disease

Return to drinking after liver transplantation for alcoholic liver disease (ALD) remains a source of unease with varying reported rates of return to drinking and impact this has on graft function. In 2005, the UK Transplant liver advisory group recommended an ‘alcohol contract’ in which ALD patients listed for transplantation confirmed in writing their commitment to abstinence. We aimed to measure the rates and consequences of return to drinking alcohol in a UK transplant programme and assess the effect of the ‘alcohol contract’. Consecutive patients transplanted for ALD during 1996–2011 were included. Every patient listed after Feb 2007 signed up to the ‘alcohol contract’. We compared rates and pattern of return to drinking and survival before and after the introduction of the contract. Overall, 52 (37%) patients returned to drinking alcohol; 37 (39%) before and 15 (34%) after the contract. There was no significant difference in the rate of return or pattern of drinking. Median survival was 176 months (145–207 95% CI). There was no significant difference in survival, mortality rates, or in the causes of death in either group. We report high rates of return to drinking alcohol in a UK liver transplant programme. Despite this, the impact on patient and graft survival is low. There is no evidence that an ‘alcohol contract’ has had any effect on alcohol consumption.     

Long‐term medical and psycho‐social evaluation of patients undergoing orthotopic liver transplantation for alcoholic liver disease

Abstract The major concern in transplanting patients with alcoholic liver disease (ALD) is the high rate of alcohol recidivism. Our aim was to assess the long‐term outcome of liver transplantation (OLT) in a group of ALD patients in terms of post‐OLT alcohol recidivism and its relationship with pre‐OLT psychosocial variables and medical follow up. Fifty‐one ALD patients underwent strict medical and psychosocial evaluation before and after OLT. Alcohol abuse was recorded in 60% and alcohol dependence in 40% of patients before OLT. The 5‐year survival was similar to the one observed in non‐ALD transplanted patients (64 vs 56%). Alcohol recidivism was observed in 33 % of transplanted patients, 64 % of whom were occasional and 36 % were heavy drinkers. The admission of alcoholism by the patient and his/her family prior to OLT significantly predicted abstinence after OLT. A multidisciplinary approach evaluating medical and psycho‐social variables before OLT and a close follow up after OLT are mandatory for ALD patients.     

Negative outcomes after liver transplantation in patients with alcoholic liver disease beyond the fifth post‐transplant year

Although up to 50% of patients with alcoholic liver disease (ALD) resume alcohol consumption after liver transplantation (LT), numerous studies indicate that long‐term results are not compromised. This study focused on evaluating the impact of ALD on outcomes up to and beyond the fifth year after LT. Among the 432 primary LT recipients included in this study, 97 underwent transplantation for ALD. Alcohol relapse rate at 10 yr was 33.5%, with younger recipient age being the only independent predictor (p = 0.019). Survival of patients with ALD (77.0%) was similar to those without (79.0%) up to the fifth post‐transplant year (p = 0.655) but worse during the five subsequent years among the five‐yr survivors (70.6% vs. 92.9%; p = 0.002). ALD was an independent risk factor for poorer survival beyond the fifth post‐transplant year (p = 0.049), but not earlier (p = 0.717). Conversely, alcohol relapse increased the risk of death only during the first five post‐transplant years (p = 0.039). There were no significant differences regarding graft failure incidence between ALD and non‐ALD recipients up to the fifth post‐transplant year (7.3% vs. 11.6%; p = 0.255) and beyond (12.9% vs. 5.0%; p = 0.126). In conclusion, pre‐transplant diagnosis of ALD yields negative effects on post‐transplant outcomes beyond the fifth post‐transplant year, not attributable to recidivism.     

Pulmonary thromboembolism as a complication of lung transplantation

Post‐transplantation mortality after lung transplantation (LTX) is higher than for other solid organ transplantations. Thoracic surgery is associated with increased risk of thromboembolic complications, and as LTX recipients lack the collateral bronchial circulation, pulmonary thromboembolism (PTE) may represent a pertinent yet largely underdiagnosed cause of post‐transplantation respiratory failure. In this systematic review, we sought to elucidate the occurrence and predilection site of PTE after LTX, and its potential impact on LTX‐associated mortality. Based on twelve original articles identified by a systematic search strategy in PubMed, we found that PTE was reported in 4% of LTX recipients, and 38% of these events occurred within the first 30 days after the LTX procedure. In single‐lung transplantation (SLTX) recipients, 12% were diagnosed with PTE, with 92% of these affecting the allograft. Of LTX patients diagnosed with PTE, 11% died within 1 year after LTX and 75% of these deaths occurred within the first 30 days. Our findings suggest that PTE is a potentially underdiagnosed cause of early post‐LTX respiratory failure. This should be confirmed in larger studies with systematic follow‐up diagnostic imaging.     

Good outcome after liver transplantation for ALD without a 6 months abstinence rule prior to transplantation including post‐transplant CDT monitoring for alcohol relapse assessment – a retrospective study

Alcoholic liver disease (ALD) is the second most common indication for liver transplantation (LT). The utility of fixed intervals of abstinence prior to listing is still a matter of discussion. Furthermore, post‐LT long‐term observation is challenging, and biomarkers as carbohydrate‐deficient transferrin (CDT) may help to identify alcohol relapse. We retrospectively analyzed data from patients receiving LT for ALD from 1996 to 2012. A defined period of alcohol abstinence prior to listing was not a precondition, and abstinence was evaluated using structured psychological interviews. A total of 382 patients received LT for ALD as main (n = 290) or secondary (n = 92) indication; median follow‐up was 73 months (0–213). One‐ and five‐year patient survival and graft survival rates were 82% and 69%, and 80% and 67%, respectively. A total of 62 patients (16%) experienced alcohol relapse. Alcohol relapse did not have a statistically significant effect on patient survival (P = 0.10). Post‐transplant CDT measurements showed a sensitivity and specificity of 84% and 85%, respectively. In conclusion, this large single‐center analysis showed good post‐transplant long‐term results in patients with ALD when applying structured psychological interviews before listing. Relapse rates were lower than those reported in the literature despite using a strict definition of alcohol relapse. Furthermore, post‐LT CDT measurement proved to be a useful supplementary tool for detecting alcohol relapse.     

Irradiation before and donor splenocyte infusion immediately after transplantation induce tolerance to lung,but not heart allografts in miniature swine

Solid organs may differ in their potential to induce and maintain a state of donor‐specific tolerance. Previously, we induced stable immunological tolerance in a lung transplantation model in miniature swine. Here, we wished to transfer this established protocol into a heart transplantation model in miniature swine. Heterotopic heart transplantation (HTX) was performed in four and left‐sided lung transplantation (LTX) in seven minipigs from gender‐ and SLA‐mismatched donors. All recipients received nonmyeloablative irradiation, donor splenocyte infusion and intravenous pharmacologic immunosuppression for 28 postoperative days. All transplanted hearts were rejected within 95 days. In contrast, four animals of the LTX group developed stable tolerance surviving beyond 500 days, and three further animals rejected 119, 239 and 360 days post‐transplantation. In both groups, peripheral blood donor leucocyte chimerism peaked 1 h after reperfusion of the allograft. Importantly, the early chimerism level in the LTX group was significantly higher compared to the HTX group and remained detectable throughout the entire observation period. In conclusion, lungs and hearts vary in their potential to induce a state of tolerance after transplantation in a protocol with pre‐operative recipient irradiation and donor splenocyte co‐transplantation. This could be due to differential early levels of passenger leucocyte chimerism.     

Early Treatment of Depressive Symptoms and Long‐Term Survival After Liver Transplantation

While depression after liver transplantation (LTX) is associated with decreased survival, the effects of treating depression remain unknown. We assessed a previously described, prospective cohort of 167 patients transplanted for alcohol‐related liver disease from 1998 to 2003. Depressive symptoms were measured with the Beck Depression Inventory serially throughout the first posttransplant year. Adequacy of antidepressant treatment was measured with the Antidepressant Treatment History Form. Using Cox‐proportional Hazards modeling, survival times were assessed for recipients with no depression versus depression with adequate medications versus depression with inadequate medications. Seventy‐two recipients had depressive symptoms in the first posttransplant year. Of these, 43% (n = 31) received adequate pharmacotherapy and 57% (n = 41) received inadequate (n = 7) or no pharmacotherapy (n = 34). After a median follow‐up time of 9.5 years, 32% of the inadequately treated depressed group survived versus 52% of the adequately treated group and 56% of the nondepressed group (p = 0.006). Compared to the nondepressed group, those with adequately treated depression had no significant difference in survival. However, recipients with depression and inadequate pharmacotherapy had decreased survival times compared to nondepressed recipients (HR for death = 2.44, 95% CI = 1.45, 4.11), controlling for other known confounders. The factor most strongly linked to long‐term mortality after liver transplantation in this cohort was untreated depression.     

Donor and recipient HLA/KIR genotypes do not predict liver transplantation outcome

Whether or not Natural Killer (NK) cells affect the immune response to solid organ allografts is still controversial. Main determinants of NK‐cell activation are specific HLA/killer‐cell immunoglobulin‐like receptors (KIR) interactions that, in transplantation, may induce NK‐cell alloreactivity. So far, in liver transplantation (LTX) donor‐versus‐recipient alloreactivity has not been investigated; in addition, studies of predicted recipient‐versus‐donor NK‐cell alloreactivity have led to contradicting results. We typed a cohort of LTX donors and recipients for HLA‐C/Bw4 and KIRs. We estimated the effect of NK‐cell alloreactivity, as predicted by classically used models, in the donor‐versus‐recipient direction. The results indicate that HLA/KIR mismatches in the donor‐versus‐recipient direction do not predict graft rejection nor graft or patient survival, suggesting that donor‐derived NK cells do not play a major role in LTX outcome. In addition, when considering predicted NK‐cell alloreactivity in the reverse direction (recipient‐versus‐donor), we first confirmed that donor HLA‐C genotype was not associated with acute rejection, graft or patient survival and secondly we found that none of the models describing NK‐cell alloreactivity could predict LTX outcome. Overall our observations suggest that, in contrast to what is shown in haematopoietic stem cell transplantation, donor‐derived NK cells may not contribute in preventing liver graft rejection, and that recipient‐versus‐donor NK‐cell alloreactivity does not predict LTX outcome.     

Characteristics of liver transplant candidates delisted following recompensation and predictors of such delisting in alcohol‐related liver disease: a case–control study

Whether and when recovery beyond the need for transplant may occur in patients listed for decompensation remains unclear. This study aimed to investigate the characteristics of patients delisted following recompensation. Seventy‐seven patients who were listed between 2005 and 2015 for decompensation, but later delisted following recompensation were included. Alcohol‐related liver disease (ALD) was the underlying etiology in the majority (n = 47, 61%). Listing characteristics of these patients were compared with those of decompensated ALD patients who either underwent deceased donor liver transplantation or died on the waiting list. The model for end‐stage liver disease (MELD) score <20 and serum albumin ≥32 g/l at listing were the only independent predictors of recompensation/delisting in ALD. The probability of recompensation was 70% when both factors were present at listing. Interestingly, about a tenth of decompensated ALD patients who died on the waiting list (median duration on waiting list 11 months) and a quarter of decompensated ALD patients who underwent living donor liver transplantation (median duration on waiting list 2 months) also had both factors at listing. In conclusion, ALD seems to be the most favorable etiology for recompensation beyond the need for transplantation. Both MELD and serum albumin at listing independently predict recompensation/delisting in ALD. It seems advisable to implement a period of observation for ALD patients with both favorable factors, before embarking on living donor liver transplantation.     

Potentially modifiable risk factors for atrial fibrillation following lung resection surgery: a retrospective cohort study

Atrial fibrillation is the most frequent arrhythmia after thoracic surgery and is associated with increased hospital costs, morbidity and mortality. In this study, we aimed to identify potentially modifiable risk factors for postoperative atrial fibrillation following lung resection surgery and to suggest possible measures to reduce risk. We retrospectively reviewed the medical records of 4731 patients who underwent lobectomy or more major lung resection over a 6‐year period. Patients who developed atrial fibrillation postoperatively and required treatment were included in the postoperative atrial fibrillation group, while the remaining patients were assigned to the non‐postoperative atrial fibrillation group. Risk factors for postoperative atrial fibrillation were analysed by multivariate analysis and propensity score matching. Overall, 12% of patients developed postoperative atrial fibrillation. Potentially modifiable risk factors for postoperative atrial fibrillation were excessive alcohol consumption (odds ratio (OR) = 1.48, 95% CI 1.08–2.02, p = 0.0140), red cell transfusion (2.70(2.13–3.43), p < 0.0001), use of inotropes (1.81(1.42–2.31), p < 0.0001) and open (vs. thoracoscopic) surgery (1.59(1.23–2.05), p < 0.0001). Compared with inotrope use, vasopressor administration was not related to postoperative atrial fibrillation. Use of steroids or thoracic epidural anaesthesia did not reduce the incidence of postoperative atrial fibrillation. We conclude that high alcohol consumption, red cell transfusion, use of inotropes and open surgery are potentially modifiable risk factors for postoperative atrial fibrillation. Pre‐operative alcohol consumption needs to be addressed. Avoiding red cell transfusion and performing lung resection via video‐assisted thoracoscopic surgery may reduce the incidence of postoperative atrial fibrillation and the administration of vasopressors rather than inotropes is preferred.     

Impact of the 2011 Great East Japan Earthquake on the Resumption of Alcohol Consumption After Living-Donor Liver Transplantation for Alcoholic Cirrhosis: A Report of Two Cases

Alcoholic liver disease (ALD) is a leading indication for liver transplantation (LT) in Western countries. The rate of resumption of alcohol abuse is 7% to 95% after LT for ALD. A high prevalence of alcohol abuse has been observed in disaster-exposed populations; however, little is known about the association between resumption of alcohol abuse after LT and disasters. Between June 2007 and March 2011, 3 patients with alcoholic cirrhosis (2 men and 1 woman) underwent living-donor LT (LDLT) at Tohoku University Hospital, Sendai, Japan. The female patient died of graft failure 6 months after LDLT. The other patients (ages 55 and 56 years), who survived to discharge, resumed alcohol abuse after the 2011 Great East Japan Earthquake. Before transplantation, both patients had been abusing alcohol for >35 years, with a daily ethanol intake of 110 g and 140 g, respectively. The period of abstinence from alcohol consumption ranged from 4 to 6 months. After transplantation, patients showed good compliance with treatment and seemed at low risk of relapse until the earthquake. One patient was living in the nuclear evacuation zone at Fukushima, and resumed alcohol consumption after the evacuation. Another patient resumed alcohol consumption while temporarily living apart from his family during restoration work after the disaster. Extreme stress and changes in living arrangements after the Great East Japan Earthquake seemed to trigger the desire to drink. This is the first report on patients who underwent LT for ALD and who resumed alcohol consumption after a disaster.     

Effect of chronic alcohol consumption on the development and progression of non-alcoholic fatty liver disease (NAFLD)

A number of epidemiologic studies show a protective effect of light to moderate daily alcohol consumption on the development of non-alcoholic fatty liver disease (NAFLD). Although these small amounts of ethanol may prevent fatty liver, they may also be a risk factor for other diseases such as breast and colon cancer. Those individuals who have underlying hepatic steatosis or non-alcoholic steatohepatitis (NASH) should not use ethanol chronically since the data available at present do not support a beneficial effect of alcohol in this situation. Especially overweight and obese individuals may be more susceptible towards alcohol even at moderate doses. Animal experiments show a negative effect of ethanol on liver histology in either dietary or genetic NASH models. In addition, patients with NASH reveal a significant increased risk for hepatocellular cancer (HCC) even with social alcohol consumption. Thus, subjects with underlying NASH should abstain from alcohol at any amounts.     

Significance of nodular regenerative hyperplasia occurring de novo following liver transplantation.

Nodular regenerative hyperplasia (NRH) of the liver usually occurs in patients with rheumatological and myelolymphoproliferative disorders; the occurrence post-liver transplantation (LT) has traditionally been ascribed to the use of azathioprine. We report the clinical, biochemical, and radiological features of 14 patients who developed NRH, unrelated to azathioprine in most cases, 3 months to 11 yr after orthotopic LT. A total of 10 patients developed NRH within 4 yr (early onset), and 4 other patients developed the condition beyond 4 yr of LT (late onset). A total of 7 symptomatic patients, all in the early group, had features of portal hypertension with vascular abnormalities on Doppler ultrasonography that were preceded by the diagnosis of NRH. All asymptomatic patients, including each of the 4 patients in the late group, had normal hepatic ultrasound (US) studies. Two symptomatic patients had normalization of histologic abnormalities after correction of vascular abnormalities. In conclusion, observation is appropriate for patients who develop NRH late following LT. Patients in whom NRH is detected on liver biopsy early after transplantation are likely to develop portal hypertension in the future. Intervention aimed at correcting the vascular abnormalities in these patients may result in clinical as well as hepatic histological improvement.     

Treatment of osteoporosis after liver transplantation with ibandronate

Osteoporosis is a major side‐effect after liver transplantation (LTX). Therefore, the objective of the study was to evaluate the efficacy of ibandronate to reduce fractures after LTX. Seventy‐four patients after LTX were included in the study and measurements of bone mineral density (BMD) of lumbar spine and proximal femur using dual energy X‐ray absorptiometry (DEXA) were performed prior to and 3, 6, 12 and 24 months after surgery. The study group (IBA) consisted of 34 patients who received calcium (1 g/day), vitamin D3 (800–1000 IE/day) and ibandronate 2 mg every 3 months intravenously for 1 year. The control group consisted of 40 patients (CON) who received calcium and vitamin D3 at the same dosages. Prevalence of new fractures was predefined as primary endpoint. Changes of BMD and biochemical markers of bone metabolism were also investigated. In all patients, we found a reduction of BMD in the first few months after LTX. In the lumbar spine and the proximal femur the maximum reduction occurred 3 and 6 months post‐LTX. One and 2 years after transplantation, the group receiving ibandronate demonstrated a better recovery from loss of BMD and a significantly lower prevalence of fractures (IBA 2 vs. CON 10 P < 0.04, χ²). Ibandronate with calcium and vitamin D3 reduces the BMD‐loss after LTX and decreases the rate of bone fractures significantly.