Management of alcohol use disorder in patients with cirrhosis in the setting of liver transplantation.

The prevalence of alcohol use disorder (AUD) has been steadily increasing over the past decade. In parallel, alcohol-associated liver disease (ALD) has been increasing at an alarming rate, especially among young patients. Data suggest that most patients with ALD do not receive AUD therapy. Although liver transplantation is the only curative therapy for end-stage ALD, transplant candidacy is often a matter of debate given concerns about patients being under-treated for AUD and fears of post-transplantation relapse affecting the allograft. In this Review, we discuss diagnosis, predictors and effects of relapse, behavioural therapies and pharmacotherapies, and we also propose an integrative, multidisciplinary and multimodality approach for treating AUD in patients with cirrhosis, especially in the setting of liver transplantation. Notably, this approach takes into account the utility of AUD pharmacotherapy in patients on immunosuppressive medications and those with renal impairment after liver transplantation. We also propose a comprehensive and objective definition of relapse utilizing contemporary biomarkers to guide future clinical trials. Future research using the proposed approach and definition is warranted with the goal of optimizing AUD treatment in patients with cirrhosis, the transplant selection process and post-transplantation care of patients with AUD.

Post-transplantation outcome in non-alcoholic steatohepatitis cirrhosis: Comparison with alcoholic cirrhosis.

INTRODUCTION AND OBJECTIVES: Non-alcoholic steatohepatitis (NASH) indication of liver transplant (LT) has increased recently, whereas alcoholic cirrhosis remains a major indication for LT. To characterize NASH-related cases and to compare the post-transplant outcome of these two conditions represents our major objective. MATERIAL AND METHODS: Patients undergoing LT for NASH between 1997 and 2016 were retrieved. Those transplanted between 1997 and 2006 were compared to an "age and LT date" matched group of patients transplanted for alcoholic cirrhosis (ratio 1:2). Baseline features and medium-term outcome measures were compared. RESULTS: Of 1986 LT performed between 1997 and 2016, 40 (2%) were labeled as NASH-related indications. NASH-related cases increased initially (from 0.8% in 1997-2001 to 2.7% in 2002-2006) but remained stable in subsequent years (2.3%). Hepatocellular carcinoma (HCC) prevalence was greater in NASH-vs alcohol-related cirrhosis (40% vs 3%, p=0.001). The incidence of overweight, obesity, arterial hypertension, dyslipidemia, diabetes, hyperuricemia, renal insufficiency and cardiovascular (CV) disease was similar in both groups at 5 years post-LT. Five-year survival was higher in NASH but without reaching statistical significance (83% vs 72%, p=0.21). The main cause of mortality in NASH-LT patients was HCC recurrence. CONCLUSION: Most previously considered cryptogenic cases are actually NASH-cirrhosis. While the incidence of this indication is increasing in many countries, it has remained relatively stable in our Unit, the largest LT center in Spain. HCC is common in these patients and represents a main cause of post-transplant mortality. Metabolic complications, CV-related disease and 5-yr survival do not differ in patients transplanted for NASH vs alcohol.

Polymorphism in the Promoter Region of NFE2L2 Gene Is a Genetic Marker of Susceptibility to Cirrhosis Associated with Alcohol Abuse.

Alcoholic liver disease (ALD) is a highly prevalent spectrum of pathologies caused by alcohol overconsumption. Morbidity and mortality related to ALD are increasing worldwide, thereby demanding strategies for early diagnosis and detection of ALD predisposition. A potential candidate as a marker for ALD susceptibility is the transcription factor nuclear factor erythroid-related factor 2 (Nrf2), codified by the nuclear factor erythroid 2-related factor 2 gene (NFE2L2). Nrf2 regulates expression of proteins that protect against oxidative stress and inflammation caused by alcohol overconsumption. Here, we assessed genetic variants of NFE2L2 for association with ALD. Specimens from patients diagnosed with cirrhosis caused by ALD were genotyped for three NFE2L2 single nucleotide polymorphisms (SNP) (SNPs: rs35652124, rs4893819, and rs6721961). Hematoxylin & eosin and immunohistochemistry were performed to determine the inflammatory score and Nrf2 expression, respectively. SNPs rs4893819 and rs6721961 were not specifically associated with ALD, but analysis of SNP rs35652124 suggested that this polymorphism predisposes to ALD. Furthermore, SNP rs35652124 was associated with a lower level of Nrf2 expression. Moreover, liver samples from ALD patients with this polymorphism displayed more severe inflammatory activity. Together, these findings provide evidence that the SNP rs35652124 variation in the Nrf2-encoding gene NFE2L2 is a potential genetic marker for susceptibility to ALD.

Myelopathy due to human T-cell leukemia virus type-1 from the donor after ABO-incompatible liver transplantation.

We report the case of a 53-year-old-man who developed human T-cell leukemia virus type-1-associated myelopathy (HAM) after ABO-incompatible liver transplantation for alcoholic liver cirrhosis. The living donor was seropositive for human T-cell leukemia virus type-1 (HTLV-1) and the recipient was seronegative for HTLV-1 before transplantation. After transplantation, the recipient developed steroid-resistant acute cellular rejection, which was successfully treated using anti-thymocyte globulin, and he was eventually discharged. He underwent spinal surgery twice after the transplantation for the treatment of cervical spondylosis that had been present for a period of 9 months before the transplantation. The surgery improved his gait impairment temporarily. However, his gait impairment progressed, and magnetic resonance imaging revealed multiple sites of myelopathy. He was diagnosed with HAM 16 months after the transplantation. Pulse steroid therapy (1000mg) was administered over a period of 3 days, and his limb paresis improved. Presently, steroid therapy is being continued, with a plan to eventually taper the dose, and he is being carefully followed up at our institution. Our case suggests that liver transplantation involving an HTLV-1-positive living donor carries the risk of virus transmission and short-term development of HAM after transplantation.

Clinical Significance of Serum Adiponectin and Resistin Levels in Liver Cirrhosis.

INTRODUCTION: Adiponectin and resistin levels are increased in patients with cirrhosis, but it prognostic significance is unknown. We sought to investigate the factors associated with adiponectin and resistin levels and its clinical significance in patients with cirrhosis. MATERIALS AND METHODS: This was a prospective cohort study that included 122 subjects with cirrhosis who attended an outpatient clinic and were initially evaluated in 2012. Serum adiponectin and resistin levels were measured in samples collected in 2012 (adiponectin and resistin) and 2014 (adiponectin). Thirty healthy subjects served as a control group. RESULTS: Higher adiponectin (21.59 µ g/mL vs. 12.52 µg/mL, P < 0.001) and resistin levels (3.83 ng/mL vs. 2.66 ng/mL, P < 0.001) were observed among patients with cirrhosis compared to controls. Patients classified as Child-Pugh B/C had higher adiponectin levels in relation to Child-Pugh A patients. At second measurement, adiponectin levels increased significantly in non-transplant patients and decreased in liver transplant recipients. Univariate Cox analysis showed that among patients with alcoholic liver disease, adiponectin levels were associated with lower transplant-free survival (HR = 1.034, 95% CI 1.006 - 1.062, P = 0.016). The transplant-free survival was significantly lower among patients with alcoholic liver disease and adiponectin ≥ 17 µg/mL (26.55 months, 95% CI 21.40-31.70) as compared to those with levels < 17 µg/mL (33.76 months, 95% CI 30.70-36.82) (P = 0.045). No relationship was found between the levels of resistin and survival. CONCLUSION: Adiponectin but not resistin levels were associated with intensity of liver dysfunction and worse prognosis in patients with alcoholic liver disease, suggesting a potential as a prognostic biomarker.

Robotic left lateral sectionectomy as stepwise approach for cirrhotic liver.

Laparoscopy is considered the gold standard approach to perform left lateral sectionectomy (LLS). Furthermore, laparoscopy for cirrhotic patients can reduce intraoperative bleeding and postoperative morbidity when compared to open surgery. Although robotic surgery is feasible for both minor and major liver resections, it remains a work in progress and only few series reported this approach for cirrhotic patients. We reported two cases of 62-year-old men, both with hepatitis C virus and alcoholic cirrhosis, but with compensated liver functions (MELD 9-10 and Child-Pugh A5-A6). The patients were diagnosed with a single lesion in the left lobe. Robotic LLS was performed using intraoperative ultrasound to confirm findings of pre-operative image, and linear staplers were used to control left lobe inflow and outflow. The specimens were removed through Pfannenstiel incision in both patients. Both procedures followed the same standardization. The total operative time was 250 and 151 min with estimated blood loss of 100 and 70 ml, respectively, for cases 1 and 2. The procedures were made without Pringle maneuver and postoperative course was uneventful with hospital discharge at third and fourth postoperative day, respectively. The pathology examination confirmed a 2.5- and 4.5-cm hepatocellular carcinoma, respectively; both presented negative margins and cirrhosis. Robotic LLS seems to be as feasible as conventional laparoscopic approach as a stepwise procedure in a robotic learning curve for liver resection. Its benefits can also be offered to selected cirrhotic patients.

Same policy, different impact: Center-level effects of share 35 liver allocation.

Early studies of national data suggest that the Share 35 allocation policy increased liver transplants without compromising posttransplant outcomes. Changes in center-specific volumes and practice patterns in response to the national policy change are not well characterized. Understanding center-level responses to Share 35 is crucial for optimizing the policy and constructing effective future policy revisions. Data from the United Network for Organ Sharing were analyzed to compare center-level volumes of allocation-Model for End-Stage Liver Disease (aMELD) ≥ 35 transplants before and after policy implementation. There was significant center-level variation in the number and proportion of aMELD ≥ 35 transplants performed from the pre- to post-Share 35 period; 8 centers accounted for 33.7% of the total national increase in aMELD ≥ 35 transplants performed in the 2.5-year post-Share 35 period, whereas 25 centers accounted for 65.0% of the national increase. This trend correlated with increased listing at these centers of patients with Model for End-Stage Liver Disease (MELD) ≥ 35 at the time of initial listing. These centers did not overrepresent the total national volume of liver transplants. Comparison of post-Share 35 aMELD to calculated time-of-transplant (TOT) laboratory MELD scores showed that only 69.6% of patients transplanted with aMELD ≥ 35 maintained a calculated laboratory MELD ≥ 35 at the TOT. In conclusion, Share 35 increased transplantation of aMELD ≥ 35 recipients on a national level, but the policy asymmetrically impacted practice patterns and volumes of a subset of centers. Longer-term data are necessary to assess outcomes at centers with markedly increased volumes of high-MELD transplants after Share 35. Liver Transplantation 23 741-750 2017 AASLD.

Diagnostic Accuracy of Transient Elastography for Detecting Liver Fibrosis After Liver Trannsplantation: A Specific Cut-Off Value Is Really Needed?

INTRODUCTION: Liver transplant recipients often perform liver biopsy (LB), specially in the context of potentially recurring diseases, such as hepatitis C infection. However, the LB has risks of complications, despite being the gold standard. Transient elastography (TE) is a noninvasive method comparable to the LB to evaluate liver fibrosis in various settings, but its accuracy among transplant recipients is not fully understood. OBJECTIVE: To determine the accuracy of TE in liver transplant recipients compared with LB to successfully predict liver fibrosis. PATIENTS AND METHODS: Patients who underwent liver transplantation at Hospital Israelita Albert Einstein from 2010 to 2012 and presented with LB indication were also subjected to TE at the time of LB. The medium value of ten successful measurements was kept as a representative of the liver stiffness. The definition of cut-off points was made to ensure specificity of ≥90 % for all fibrosis stages (F0-F4). RESULTS: LB was performed in 267 patients. TE was not analyzed in only 8 (3 %) due to an elevated body mass index. The optimal liver stiffness cut-off value and diagnostic performance were 8.1 kPa for F ≥ 1, 12.3 kPa for F ≥ 2, 15.1 for F ≥ 3, and 16.7 for F = 4 for all patients and were 8.1 kPa for F ≥ 1, 12.3 kPa for F ≥ 2, 16.5 for F ≥ 3, and 17.6 for F = 4 for patients with hepatitis C. CONCLUSIONS: TE demonstrated good performance in defining cut-off points for fibrosis on liver histology observed in transplant recipients. The TE can be considered an alternative to LB in post-liver transplantation.

Association Between Dyspnea and Severity of Liver Disease in Patients in the Pre-transplantation Period-A Pilot Study.

BACKGROUND: Liver transplantation is indicated at the end stage of chronic liver failure, and severity of disease will determine the precocity of this happening. At this stage, the presence of chronic dyspnea is one of several manifestations of progression of the disease, which leads the patient to inactivity. A rehabilitation program can positively influence the evolution of liver transplant recipients. The objective of this study was to establish an association between the perception of dyspnea and the severity of liver disease in patients at a single center of a Brazilian liver pre-transplantation clinic. METHODS: Measurements were performed at a liver pre-transplantation clinic. The severity of liver disease was assessed with the use of the Model for End-Stage Liver Disease (MELD) score, and dyspnea was assessed with the use of a modified Medical Research Council scale of dyspnea (mMRC). RESULTS: Men had a higher prevalence of viral hepatitis. Dyspnea was reported only during intense exercise. Duration of disease and MELD score showed medians of 49 months and 20, respectively. CONCLUSIONS: We found no correlation between mMRC and the MELD score. In addition, no correlation was found between duration of disease and MELD score or mMRC.

Anxiety and Stress Levels on Liver Transplantation Candidates.

The objective of the present study was to determine the anxiety and stress levels of liver transplant candidates during the preoperative period. A cross-sectional, prospective study was conducted on 52 liver transplantation candidates seen at a specialized public hospital outpatient clinic in the interior of the state of São Paulo, Brazil. Data were collected from November 2014 to April 2015 using a self-applicable questionnaire for the assessment of anxiety (State-Trait Anxiety Inventory, short version) and stress (Perceived Stress Scale), in addition to sociodemographic and clinic characterization. The mean (±SD) anxiety level detected was 23.06 ± 5.51 points, with 1.92% of the subjects showing minimum levels (0 to 12 points), 59.62% a medium level (12 to 24 points), 36.54% a moderate level (24 to 36 points), and 1.92% a severe level (36 to 48 points) of anxiety. The mean level on the stress scale was 12.10 ± 5.62 points, with 7.69% of the subjects showing high stress levels. When individuals with good and poor stress levels were compared, a significant difference was observed between them (P = .0004). The Spearman correlation test showed that the higher the stress, the higher the levels of anxiety (r = 0.4258), P < .0001. The present study contributes to the analysis of the mental health of liver transplantation candidates in view of the need for interventions for the improvement of anxiety and stress levels since the waiting period for the organ generates emotional changes that can affect the quality of life of the patient and the success of this complex therapeutic modality.

Biliary Complications After Liver Transplantation: Incidence, Risk Factors and Impact on Patient and Graft Survival.

INTRODUCTION: Biliary complications (BC) are one of the most frequent surgical complications after liver transplantation. They include biliary stenosis, leaks, choledocolitiasis and sphincter of Oddi dysfunction. These complications can cause graft dysfunction, retrasplantation, or even death. The purpose of this study was to identify factors related to BC. MATERIALS AND METHODS: The medical records of all adult patients who underwent their first liver transplantation in our institution from 2005 to 2013 were reviewed, and any BC that required management was recorded. Cumulative incidence of BC was estimated using Kaplan-Meier. Patient and graft survival was compared using the log-rank test. The Cox regression model was used to establish associated factors. RESULTS: Of the 236 patients who underwent liver transplantation, 41 patients (17.8%) developed BC. Cumulative incidence was 12.9%, 17.2%, and 20%, after 1, 3 and 5 years of the transplantation, respectively. Twenty-six cases of biliary stenosis, 11 of leaks, and 4 of choledocolitiasis were identified. Most patients were managed endoscopically (82.9%). There were no differences in patient or graft survival. DISCUSSION: Biliary stenosis is the most frequent BC. Patients with higher risk of BC were of blood type AB (P < .001), had viral hepatitis (P = .049), or had alcoholic cirrhosis (P = .036). The success with the endoscopic treatment reduced the need for surgical interventions. CONCLUSIONS: The incidence of BC in our institution is comparable with the incidence reported in other institutions. Further prospective studies with larger series of patients are warranted to identify other factors associated with development of BC.

Predictive factors of abstinence in patients undergoing liver transplantation for alcoholic liver disease.

INTRODUCTION: Alcoholic cirrhosis is one of the most common indications for liver transplantation (LT) in western countries. A major concern about transplant patients due to alcoholic liver disease (ALD) is alcoholic recidivism. Data concerning psycho-social characteristics of patients with 6 months of abstinence at initial evaluation for LT is scarce. Objectives. The aims of this study were 1) To evaluate the psycho-social profile of a cohort of patients with alcoholic cirrhosis being evaluated for LT. 2) Determine factors associated with abstinence from alcohol at initial psycho-social evaluation for LT and 3) To evaluate the potential impact of alcohol-free beer consumption on 6-month abstinence. MATERIAL AND METHODS: Ninety patients referred to the Alcohol Unit of the Hospital Clínic of Barcelona (January 1995-December 1996) were included. Univariate and multivariate logistic regression analyses were used to identify the factors associated with cessation in alcohol consumption and with 6-month abstinence. RESULTS: Factors associated with cessation in alcohol consumption were awareness of alcohol toxicity (OR = 5.84, CI 1.31-26.11, p = 0.02) and family recognition (OR = 3.81, CI 1.27-11.41, p = 0.01). Cessation of alcohol consumption at knowledge of ALD (OR = 5.50, CI 1.52-19.81, p = 0.009), awareness of alcohol toxicity (OR = 2.99, CI 1.02-9.22, p = 0.05) and family recognition (OR = 5.21, CI 1.12-24.15, p = 0.03) were the independent factors associated with 6-month abstinence previous to psycho-social evaluation for LT. CONCLUSION: In conclusion awareness of alcohol toxicity and family recognition are the independent factors that influence cessation in alcohol consumption and 6-month abstinence in patients evaluated for LT. The use of alcohol-free beer was associated with a higher rate of abstinence in patients without alcohol cessation.

[Cytokines expression in peripheral blood cells of patients with orthotopic liver transplant: preliminary results]. / Expresión de citocinas en células de sangre periférica de pacientes con trasplante hepático ortotópico: resultados preliminares.

BACKGROUND: Cytokines are important in immune and inflammation response in liver transplantation. Determination of cytokine expression may lead to early detection of risk of rejection and infection in patients with this treatment. OBJECTIVE: To evaluate the expression of interleukin- 1beta (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL- 8), tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-ß) and granulocyte macrophage colony stimulating factor (GMCSF) in peripheral blood mononuclear cells in patients who received an orthotopic liver transplantation (OLT). METHODS: Fourteen patient who underwent OLT due to cirrhosis were analyzed before and after (at 24, 48, 72 hours, 7, 15 and 30 days) transplantation. Peripheral blood cells were tested for IL-1ß, IL-6, IL-8, TNF-α, TGF-ß and GM-CSF using semiquantitative reverse transcriptase-polymerase chain reaction (Roche Kit). RESULTS: No patient present acute rejection, and 11 of them had bacterial infections, 1 to 19 days after OTL. The cytokines IL-6 and TNF-α showed no expression in any phases studied and IL-1ß only in 21% in the first phase post-transplant. Sixty percent of patients who presented bacterial infections express GM-CSF. TGF-b was the most frequently expressed cytokine. CONCLUSIONS: Cytokines expression in the evaluated patients did not follow a defined pattern according to etiology. Increasing the size of the sample is deemed important to establish the implication of the diverse cytokines in liver transplantation.

Anxiety levels observed in candidates for liver transplantation.

INTRODUCTION: Anxiety can be considered an emotional state that does not present itself at the same intensity in all patients, and can be classified into 3 levels: mild, moderate, and severe. The patient, upon entering the waiting list for transplantation, reflects on the decision taken, which leaves him constantly anxious about the idea of possible death. OBJECTIVE: This study had the aim of evaluating the degree of anxiety observed in orthotopic liver transplantation (OLT) candidates and whether there was a correlation between anxiety and etiologic diagnosis. METHODS: This study was a prospective study where the patients underwent psychological evaluation by Beck Anxiety Inventory (BAI). The anxiety level was minimal, mild, moderate, or severe. The Model for End-Stage Liver Disease (MELD) score and etiology were recorded. RESULTS: The level of anxiety found were as follows: 55% minimal, 27% mild, 12% moderate, and 7% severe. The correlation between level of anxiety and etiologic diagnosis showed that 71% of patients with alcoholic cirrhosis and 60% of those with liver cancer showed a minimal degree of anxiety and 27% of patients with autoimmune cirrhosis had severe anxiety. CONCLUSION: We found that in patients with autoimmune hepatitis, the degree of anxiety was more pronounced. It is believed that the absence of physical symptoms is an important factor when observing anxiety in OLT candidates.

Effects of TIPS on global end-diastolic volume and cardiac output and renal resistive index in ICU patients with advanced alcoholic cirrhosis.

The transjugular porto-systemic stent-shunt (TIPS) reduces portal pressure in cirrhotic patients and is used as a nonsurgical treatment for refractory ascites, recurrent variceal hemorrhage or hepatorenal syndrome. There are concerns regarding a negative impact on cirrhotic cardiomyopathy and deterioration of hyperkinetic circulatory dysfunction. We analyzed a prospectively maintained database containing hemodynamic data on cirrhotic ICU patients. Hemodynamic monitoring was performed using transpulmonary thermodilution (PiCCO, Pulsion Medical Systems, Munich, Germany). Renal perfusion was assessed by Doppler ultrasound during studies of portal and TIPS perfusion before and after the procedure. Complete data sets of 8 patients (4 male, 4 female, age 60 years (52-67), Child-Pugh-Turcotte score 10 (8-12)) were available. After TIPS, there was a substantial increase of GEDVI (646 ml/m2 (580-737) to 663 mL/m2 (643-792); p=0.036) that was even more pronounced at 24 hours (716 mL/m2 (663-821); P=0.012). CI increased from 3.3 L/min/m2 (3.1-4.2) to 3.9 L/min/m2 (3.6-5.3) (p=0.012) and 3.9 L/min/m2 (3.7-5.2) (p=0.017), respectively. There was a significant decrease of renal RI from 0.810 (0.781-0.864) to 0.746 (0.710-0.798) (p=0.028) and a transient increase of fractional excretion of sodium. SVRI (1737 dyn*s/cm5/m2 (1088 . 2115) vs. 1917 dyn*s/cm5/m2 (1368-2177) was not significantly altered immediately after TIPS but decreased to 1495 dyn*s/cm5/m2 (833- 1765) at 24 hours (p=0.036). There were no significant changes of mean arterial pressure (MAP). In conclusion, TIPS resulted in a pronounced increase of central blood volume. The observed hemodynamic effects are compatible with a preload driven increase of cardiac output and secondary decreases in SVRI and RI.

Unusual cause of gastrointestinal bleeding in a cirrhotic patient: hepatocellular carcinoma with gastric invasion.

BACKGROUND: Upper gastrointestinal (GI) bleeding is a common complication of portal hypertension in cirrhotic patients, and hepatocellular carcinoma (HCC) is the most common tumor in cirrhotic livers. Bleeding from tumor erosion into the GI tract is very rare. A patient with HCC and gastric tumor invasion was described and the previously reported cases were reviewed. METHOD: A patient with upper GI bleeding was treated in a tertiary hospital. RESULTS: A cirrhotic patient with a HCC invading the stomach leading to upper GI bleeding was treated by left lateral segmentectomy and sub-total gastrectomy. The bleeding was controlled and a good surgical outcome was achieved. CONCLUSIONS: HCC with gastric invasion should be differentially diagnosed from upper GI bleeding in cirrhotic patients. Bleeding can be controlled and symptomatic relief marked in selected cases.