SARS­CoV­2 vaccination in liver transplant recipients: factors affecting immune response and refusal to vaccine.

INTRODUCTION: The effectiveness of SARS­CoV­2 vaccination in liver transplant (LT) recipients varies between reports. OBJECTIVES: In this study, we analyzed the immune response to the SARS­CoV­2 vaccine, factors affecting the response, and reasons for the vaccine refusal. PATIENTS AND METHODS: Among 300 consecutive LT recipients, 75% were vaccinated. The humoralresponse was assessed by the quantitative determination of antitrimeric spike protein­specific IgG antibodies to SARS­CoV­2. Thirty­four vaccinated patients with prior SARS­CoV­2 infection were analyzed separately. RESULTS: Among 192 LT recipients vaccinated without past natural infection, 69% developed the immune response (median time of 125 days after the second dose). Older age, worse kidney function, and dual immunosuppression negatively affected the humoral response. Mycophenolate mofetil increased the risk of nonresponse (odds ratio [OR], 2.99; 95% CI, 1.45-6.19). The antibody concentration was higher in the first 90 days from the second dose and stable as compared with 90-150 days and over 150 days. LT recipients with prior COVID­19 presented with a robust immune response (100%). The female sex, living in a rural area, lower body mass index, and younger age (all P <0.05) were associated with the refusal of the vaccine. CONCLUSIONS: The lower immune response in the vaccinated LT recipients than in the general population justifies administering the third dose of the vaccine. However, more data are needed to recommend any therapy modification before the vaccination.

Fatigue in chronic liver disease patients: prevalence, pathophysiology, and management.

Fatigue is the most commonly encountered symptom in patients with chronic liver disease (CLD). The resulting decrease in quality of life contributes markedly to the societal costs of fatigue. Moreover, fatigue is associated with social dysfunction, increased daytime somnolence, impaired working ability, and increased risk of mortality. Fatigue is not related to the severity of the underlying liver fibrosis or dysfunction. In CLD patients, fatigue manifests with both central symptoms, characterised by cognitive impairment, sleep disturbance, apathy, and autonomic dysfunction, and peripheral symptoms, characterised by decreased exercise tolerance and reduced physical activity levels. The pathogenesis of fatigue in CLD is multifactorial and involves changes in the brain-liver axis resulting from changes in inflammatory cytokines or the gut microbiome. Numerous interventions have attempted to alleviate fatigue in CLD by improving its central and peripheral manifestations or the underlying liver disease. Currently, however, there are no widely accepted or effective treatments for fatigue in CLD patients. In this review, we highlight the problem of fatigue in CLD, the current theories regarding its pathogenesis, and current approaches to its treatment.

Spontaneous rupture of a mucinous cystic neoplasm of the liver resulting in a huge biloma in a pregnant woman: A case report.

BACKGROUND: Mucinous cystic neoplasm of the liver (MCN-L) and intraductal papillary neoplasm of the bile duct (IPN-B) are two different types of mucin-producing bile duct tumour that may complicate the course of pregnancy. To the best of our knowledge, we describe herein the first case of MCN-L with spontaneous rupture during pregnancy necessitating complex surgical treatment. CASE SUMMARY: A 24-year-old woman was initially admitted to another hospital in October 2018 with signs of jaundice (serum bilirubin level 12 mg/dL) and upper abdominal pain radiating to the left shoulder. Initial magnetic resonance imaging (MRI) of the abdominal cavity revealed a multilocular cystic tumour of the liver hilum (37 mm × 40 mm in diameter) located between segments 3 and 4 of the left liver lobe. Six weeks later (December 2018), the patient was found to be 12 wk pregnant and was referred to our institution for further diagnostics and treatment. At admission, a soft, palpable, and tender mass in the left upper abdomen was found. It was determined via MRI (with no intravenous contrast in view of the first-trimester pregnancy) to be a large collection of fluid (19 cm × 17 cm × 10 cm) located close to the liver hilum and below the left liver lobe. The patient did not undergo any diagnostic or therapeutic procedures nor did they have any abdominal trauma in the preceding weeks. The fluid collection proved to be of biliary origin following percutaneous drainage. Therefore, we concluded this was a spontaneous rupture of an MCN-L with the formation of a biloma. The MRI study also revealed the previously found cystic tumour of the liver hilum communicating with the left hepatic duct, which, together with left hepatic duct dilatation, suggested the diagnosis of IPN-B. The follow-up MRI with intravenous gadolinium contrast performed in the second trimester of pregnancy (week 14) showed, in turn, some features of MCN-L, including enhancement of the internal septations within the cystic liver mass. A precise preoperative differential diagnosis between IPN-B and MCN-L was therefore not possible. The patient was submitted to surgery in the second trimester of pregnancy (week 18). Surgery included a cholecystectomy, left hepatectomy, and concomitant resection of the extrahepatic bile ducts followed by anastomosis of the right hepatic duct with the Roux limb of the jejunum. The post-operative period was uneventful and the patient was discharged 8 days after surgery. The histopathological examination of the resected specimen revealed a final diagnosis of MCN-L with low-grade dysplasia and epithelium surrounded by ovarian-type stromal tissue. The patient delivered a healthy baby girl and both remain well at present, after 2 years of follow-up since surgery. CONCLUSION: The differential diagnosis and management of MCN-L and IPN-B may be very challenging, particularly in the setting of pregnancy. When indications for surgery are obvious, the final diagnosis is based on histopathological examination, with ovarian-type stroma being pathognomonic for MCN-L. We believe that the growth of this subepithelial stroma secondary to the high levels of sex hormones produced during pregnancy might have been the main causative factor leading to the tumour rupture with the formation of a biloma in our patient.

Dehydroepiandrosterone sulfate indicates decreased sulfation capacity and impaired quality of life in patients with primary sclerosing cholangitis.

INTRODUCTION: Impaired elimination of toxic compounds via inadequate sulfation may contribute to the pathogenesis of primary sclerosing cholangitis (PSC). Dehydroepiandrosterone (DHEA), which is metabolized into its sulfated form (DHEA-S) in the liver, has been linked with health-related quality of life (HRQoL) in various conditions. OBJECTIVES: We aimed to assess the sulfation capacity of the liver in PSC using DHEA-S as a surrogate marker. PATIENTS AND METHODS: We assessed serum levels of DHEA-S in 233 patients with PSC and in 201 patients with other liver conditions serving as controls. We also evaluated the effect of low levels of DHEA-S on the course of PSC and HRQoL assessed using the 36-Item Short Form Health Survey (SF-36) and the PBC-40. RESULTS: The proportion of patients with low DHEA-S in the PSC group was 7-fold higher than in the control group (21% vs 3%; P <⁠0.001). Patients with decreased levels of DHEA-S were younger at the time of PSC diagnosis (median age, 23 vs 29 years; P = 0.007) and presented with lower HRQoL scores, particularly regarding the physical domains of the SF-36. Patients with low DHEA-S also complained of more severe fatigue (31 vs 23; P = 0.006) assessed with the PBC-40. CONCLUSIONS: Our findings support the role of impaired liver sulfation capacity in the development of PSC. Low levels of DHEA-S are associated with increased fatigue, a devastating symptom significantly affecting HRQoL. Thus, the effects of DHEA administration on chronic fatigue and other measures of HRQoL in patients with PSC warrant further attention.

Role of miR-506 in ulcerative colitis associated with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is commonly accompanied by ulcerative colitis (UC). MicroRNA-506 modulates expression of genes which are essential for sphingosine-mediated signaling pathway and intestinal mucosa protection. We investigated whether miR-506 and its target genes are involved in phenotypic presentations of colonic inflammation and/or neoplasia. We analyzed serum and colon tissue samples collected from patients with PSC, PSC with concurrent UC (PSC + UC), UC alone, and healthy controls (n = 10 each). MiR-506 was substantially upregulated in ascending colons of PSC and PSC + UC patients, in contrast to sigmoid colons of PSC and UC patients. Upregulation of miR-506 was associated with inhibition of SPHK1, AE2, InsP3R3, and p53. Colonic suppression of miR-506 presented in UC was accompanied by substantially increased DNMT1, SPHK1, and S1P lyase expressions. A functional in vitro analysis in Caco-2 cells showed that the induction of miR-506 activity by miR-506 mimic or GDCDA bile acid suppressed, whereas inhibition of miR-506 by miR-506 inhibitor or lipopolysaccharide (LPS) upregulated the expression of the examined target genes. A different phenotypic presentation of colitis may be related to miR-506 expression. In ascending colons with PSC + UC, upregulation of miR-506 may result in failure of bicarbonate secretion and inhibition of p53, which predisposes to pro-tumorigenic transformation. In contrast, downregulation of miR-506 enhances S1P production, leading to pro-inflammatory signaling.

Kidney Function After Liver Transplantation in a Single Center.

BACKGROUND Renal dysfunction in the peri-transplant period appears to complicate both short- and long-term outcome of liver transplantation (LT). The aim of this study was to analyze the impact of selected clinical features in the peri-liver transplant period, as well calcineurin inhibitor, particularly tacrolimus given after LT, on kidney function in a single liver transplant center's experience. MATERIAL AND METHODS A total 125 consecutive liver-grafted individuals (82 M, 43 F), mean age 50±13 y (with alcohol-related liver disease in 48 (38%) patients) were included into the study. Their clinical data were collected in the database until 46 months of follow-up, and the Python packages Pandas (version 0.22.0) and scikit-learn (version 0.21.3) were used for data analysis. RESULTS More advanced liver disease as judged by Child-Pugh class and MELD score differed significantly patients with preserved (serum creatinine SCr <1.5 mg/dL) and impaired (SCr ≥1.5 mg/dL) kidney function before LT. Older age and higher SCr pre-LT were associated with higher levels of SCr after LT in 2 time-points. SCr before LT was correlated with delta SCr for the highest and last recorded value (P<0.0001). Higher amounts of transfused colloids during surgery were associated with increased delta SCr for the highest value (P=0.019) after grafting in logistic regression analysis. There were no associations between SCr after LT and duration of anhepatic phase, urine output ≤100 mL/h, or post-reperfusion syndrome during transplantation (all P>0.05). There were no associations between SCr after LT and tacrolimus trough levels in analyses of correlations and linear regression analyses (all P>0.05). CONCLUSIONS We found that pretransplant serum creatinine was the only factor affecting kidney function after LT in our liver transplant center. The restricted fluid policy was safe and effective in terms of long-term renal function. The role of kidney-saving immunosuppressive protocols in preserving renal function long-term after LT was also confirmed.

Chronic Fatigue Persists in a Significant Proportion of Female Patients After Transplantation for Primary Sclerosing Cholangitis.

Chronic fatigue and an impairment of general health-related quality of life (HRQoL) are frequently reported by patients with primary sclerosing cholangitis (PSC). Studies on patients with primary biliary cholangitis (PBC) suggest that, unlike pruritus, fatigue may not be ameliorated by liver transplantation (LT). However, there are few data regarding the assessment of fatigue before and after transplantation in PSC. To investigate the effect of LT on fatigue and HRQoL in patients with PSC, 81 patients with PSC (median age 33 years; 69% men) were prospectively enrolled in this study. The PBC-40 and Short Form 36 (SF-36) questionnaires were used for assessment before and twice after LT. A total of 26 patients who received a transplant for PBC were included as controls. The potential impact of the clinical and laboratory parameters was evaluated by univariate and multivariate analyses. Although in addition to other well-being indexes the median fatigue score improved after LT (P < 0.001), a detailed analysis demonstrated that fatigue persists in one-third of patients. A significant fatigue reduction was seen in men (P < 0.001) but not women (P = 0.25). Posttransplant fatigue did not depend on concomitant inflammatory bowel disease, laboratory indexes of cholestasis, or disease recurrence. In the multivariate regression model, female sex was the only independent covariate associated with persistent fatigue. In terms of other measures of HRQoL, LT caused a substantial improvement in the majority of SF-36 and PBC-40 domains. Recurrent PSC and unemployment negatively affected the well-being of patients. Patients who received a transplant for PSC had significantly better HRQoL than those patients with PBC. LT improves various measures of HRQoL, but it does not ameliorate fatigue in female patients with PSC.

Difficult iatrogenic bile duct injuries following different types of upper abdominal surgery: report of three cases and review of literature.

BACKGROUND: Iatrogenic bile duct injuries (BDIs) are mostly associated with laparoscopic cholecystectomy but may also occur following gastroduodenal surgery or liver resection. Delayed diagnosis of type of injury with an ongoing biliary leak as well as the management in a non-specialized general surgical units are still the main factors affecting the outcome. CASE PRESENTATION: Herein we present three types of BDIs (Bismuth type I, IV and V) following three different types of upper abdominal surgery, ie. Billroth II gastric resection, laparoscopic cholecystectomy and left hepatectomy. All of them were complex injuries with complete bile duct transections necessitating surgical treatment. All were also very difficult to treat mainly because of a delayed diagnosis of type of injury, associated biliary leak and as a consequence severe inflammatory changes within the liver hilum. The treatment was carried out in our specialist hepatobiliary unit and first focused on infection and inflammation control with adequate biliary drainage. This was followed by a delayed surgical repair with the technique which had to be tailored to the type of injury in each case. CONCLUSION: We emphasize that staged and individualized treatment strategy is often necessary in case of a delayed diagnosis of complex BDIs presenting with a biliary leak, inflammatory intraabdominal changes and infection. Referral of such patients to expert hepatobiliary centres is crucial for the outcome.

Renaissance of Modified Charlson Comorbidity Index in Prediction of Short- and Long-Term Survival After Liver Transplantation?

BACKGROUND Orthotopic liver transplantation (OLT) is the standard of care for end-stage liver disease. The Charlson Comorbidity Index (CCI) was originally created to assess the survival rate of patients with chronic diseases, although it was modified and adopted in OLT recipients as CCI-OLT. MATERIAL AND METHODS In total of 248 consecutive liver transplant recipients with viral cirrhosis in 98 (39.5%) patients were included. CCI-OLT was calculated assigning a weight of 3 to chronic obstructive pulmonary disease; weight of 2 to coronary artery disease, connective tissue disease, and renal insufficiency; and a weight of 1 to diabetes mellitus. RESULTS CCI-OLT was significantly correlated with recipient age (p<0.001; R=0.333) and was a significant risk factor for early post-transplant mortality (p=0.004). The presence of diabetes mellitus significantly increased the odds of early mortality (p=0.010). The optimal cut-off for CCI-OLT in prediction of mortality during the first 90 days after transplantation was ≥1, with an AUROC of 0.780 (95% CI: 0.670-0.891; p<0.001). Increasing CCI-OLT was a significant risk factor for worse 5-year post-transplant survival (p=0.001), along with coronary artery disease (p=0.008) and diabetes mellitus (p=0.021). The optimal cut-off for prediction of 5-year mortality for CCI-OLT was ≥1, with the AUROC of 0.638 (95% CI: 0.544-0.733; p=0.004). CONCLUSIONS CCI-OLT is a useful tool for measuring the effect of pretransplant comorbidities and to stratify the effect of risk on both short- and long-term outcomes after OLT. Recipient age and diabetes strongly affected short-term survival after OLT, and metabolic and vascular complications were the leading causes of death at 5 years after OLT.

Acute liver injury, acute liver failure and acute on chronic liver failure: A clinical spectrum of poisoning due to Gyromitra esculenta.

Gyromitra esculenta, also known as "false morel" is one of the most poisonous mushrooms. This species is found all over the world, growing in coniferous forest in early spring time. Common manifestation of poisoning includes gastrointestinal symptoms which include varied degrees of liver impairment. We describe three cases: acute liver injury, acute liver failure and acute-on-chronic liver failure due to G. esculenta poisoning. At admission patients presented with encephalopathy and features of liver failure. Two of them recovered completely following supportive management while the remaining patient who also had preexisting liver disease developed multiorgan failure and subsequently died. Although a rare occurrence, G. esculenta poisoning should be considered in the differential diagnosis of acute liver failure.

Excessively Long Duodenum of the Pancreatic Graft Segment as a Rare Cause of Hyperammonemia After Simultaneous Pancreas-Kidney Transplant.

Simultaneous pancreas-kidney transplant is currently standard therapy to achieve long-term insulin-free euglycemia in patients with type 1 diabetes mellitus and concomitant end-stage kidney failure. A patient with symptoms of encephalopathy caused by hyperammonemia and with new-onset iron deficiency anemia was admitted to our institution 20 months after a simultaneous pancreas-kidney transplant. Detailed screening did not reveal any specific cause for the hyperammonemia, and despite standard treatment, hyperammonemia did not resolve. An abdominal computed tomographic scan was performed, which showed a distended duodenal segment of the pancreas graft. This was confirmed during exploratory laparotomy when the anastomosis between duodenum and ileum was dismantled and found not to be stenotic. The excessively long stumps of the duodenum were then dissected and shortened, and a new anastomosis between graft-duodenum and recipient-ileum was created. The operation was followed by an uncomplicated postoperative course in which the serum ammonia normalized on the first postoperative day and remained normal afterwards. An excessively long segment of the duodenum of the pancreatic graft may lead to encephalopathy with hyperammonemia after a simultaneous pancreas-kidney transplant. This emphasizes the need for meticulous preparation of the graft to avoid this complication.

Leisure time physical activity and health-related behaviours after liver transplantation: a prospective, single-centre study.

INTRODUCTION: Leisure time physical activity is of proven significance in surveys of fitness levels in various patient groups. Low physical functioning may affect recovery after liver transplantation (LTx). AIM: To assess patients' leisure time activity and health-related habits after transplantation. MATERIAL AND METHODS: One hundred and seven patients after LTx were included. They were divided into groups depending on aetiology of liver problem and the period after LTx. Minnesota Leisure Time Physical Activity Questionnaire (MILTPAQ) and Health Behaviour Inventory (HBI) were applied. RESULTS: Neither the primary indication for the procedure nor the period after surgery had a significant relationship with physical activity assessed with MILTPAQ; however, activity was lower in females than males (1804.3 ±1848.9 vs. 2619.9 ±2067; p = 0.03). Age at survey/surgery was inversely associated with higher activity (p = 0.02 and p = 0.03, respectively). Health Behaviour Inventory analysis showed a correlation between all four of its domains and age at transplantation/survey (p < 0.001 for both). There was a negative correlation between positive mental attitude and body mass index (BMI). CONCLUSIONS: The primary indications for grafting and, surprisingly, the period after surgery did not seem to be related to the patients' physical activity in leisure time. Younger and leaner patients appeared to understand the standards of healthy behaviour better and implement them in their daily activities. As higher BMI are associated with a negative mental attitude in patients after LTx, a particular emphasis should be placed on proper counselling in this subgroup of patients.

Female Sex But Not Original Indication Affects Physical Activity After Liver Transplant: A Prospective, Single Center Study.

OBJECTIVES: Physical activity has an effect on long-term recovery after major surgical operations including liver transplant. Seven-Day Physical Activity Recall Questionnaire is a semistructured survey that assesses an individual's time spent in physical activity, strength, and flexibility activities during the 7 days prior to the interview. In this study we applied the Seven-Day Physical Activity Recall Questionnaire in patients who underwent liver transplant in our center. MATERIALS AND METHODS: We surveyed 107 consecutive patients (62 male and 45 female), who were ≥ 6 months after liver transplant. Patients were divided into 3 groups, depending on time after liver transplant: group A (n = 21), 6 to 12 months posttransplant; group B (n = 48), 13 to 36 months posttransplant; and group C (n = 38), > 37 months posttransplant. Relations were analyzed between physical activity and various factors including sex, age at procedure and survey, time after grafting, original diagnosis, and body mass index. RESULTS: Female patients were significantly less active in daily and weekly measurements (981 ± 212 kcal vs 1267 ± 229 kcal; P < .0001) (6864 ± 1484 kcal vs 8866 ± 1607 kcal; P < .0001). There was a negative correlation between physical activity and age at transplant (P = .02) and survey (P = .02). Neither the time after liver transplant nor the original diagnosis before grafting affected physical activity. CONCLUSIONS: Female patients, when assessed with Seven-Day Physical Activity Recall Questionnaire, were significantly less physically active than male subjects after liver transplant. Younger patients were more active, but primary diagnosis had no significant effect on physical activity after grafting.

Factors affecting health-related quality of life and physical activity after liver transplantation for autoimmune and nonautoimmune liver diseases: a prospective, single centre study.

BACKGROUND/AIM: With the improvement of the outcomes after liver transplantation (LTx), health-related quality of life (HRQoL) and physical activity are becoming significant outcome parameters. We prospectively assessed these parameters in patients with autoimmune and nonautoimmune liver disorders undergoing LTx. MATERIALS AND METHODS: Patients (n = 107) were subdivided into 3 groups depending on the time after LTx: group-A (n = 21): 6-12 months; group-B (n = 48): 13-36 months; and group-C (n = 38): >37 months. SF-36 and IPAQ were applied in HRQoL and physical activity assessment. RESULTS: Females had impaired HRQoL in most SF-36 domains. Younger patients showed higher scores at SF-36 physical functioning domain but IPAQ was not influenced by age. Group-B had higher general health and physical component summary than group-A (P = 0.037, P = 0.04, resp.) and total IPAQ than group-C (P = 0.047). The sitting time domain was longer in group-A than in group-B and group-C (P = 0.0157; P = 0.042, resp.). Employed patients had better HRQoL and higher physical activity than those not working. SF-36 and IPAQ were unrelated to the autoimmune etiology of liver disease. CONCLUSIONS: These findings show that female and unemployed patients have worse HRQoL, while gender and age at LTx time do not affect IPAQ's physical activity. The autoimmune etiology of liver disease does not influence HRQoL and physical activity after LTx.

Isolated right posterior bile duct injury following cholecystectomy: report of two cases.

Anatomic variations of the right biliary system are one of the most common risk factors for sectoral bile duct injury (BDI) during cholecystectomy. Isolated right posterior BDI may in particular be a challenge for both diagnosis and management. Herein we describe two cases of isolated right posterior sectoral BDI that took place during laparoscopic cholecystectomy. Despite effective external biliary drainage from the liver hilum in both cases, there was a persistent biliary leak observed which was not visible on endoscopic retrograde cholangiogram. Careful evaluation of images from both endoscopic and magnetic resonance cholangiograms revealed the diagnosis of an isolated right posterior sectoral BDI. These were treated with a delayed bisegmental (segments 6 and 7) liver resection and a Roux-en-Y hepaticojejunostomy respectively with good outcomes at 24 and 4 mo of follow-up. This paper discusses strategies for prevention of such injuries along with the diagnostic and therapeutic challenges it offers.

Mini-Mental State Examination in patients with hepatic encephalopathy and liver cirrhosis: a prospective, quantified electroencephalography study.

BACKGROUND: Mini-Mental State Examination (MMSE) is one of the most commonly used methods in the assessment of cognitive mental status. MMSE has been used in hepatology but its usefulness in the evaluation of hepatic encephalopathy (HE) has never been properly assessed. The aim of the study was to investigate the value of MMSE in detection of HE in patients with cirrhosis. METHODS: One hundred and one consecutive patients with liver cirrhosis underwent neurological examination, MMSE and electroencephalography (EEG). Spectral analysis of EEG was done with calculation of mean dominant frequency (MDF) and relative power of delta, theta, alpha and beta rhythms. Minimal HE was diagnosed in patients with normal neurological status and alterations in spectral EEG. Statistical analysis included Fisher's exact and Anova analysis. Categorical data were compared using Levene's test for equality of variances. Correlation-coefficient analysis was performed by the Pearson's r or Z-test, as needed. Tests performance was assessed by the calculating the area under the ROC curve (AUC) and evaluating its difference from reference area (AUC=0.5). A p value <0.05 was considered statistically significant. RESULTS: Overt HE was identified in 49 (48.5%) and minimal HE in 22 (21.8%) patients. Although there were significant correlations between both severity of liver disease (Child-Pugh classification), overt HE (West-Haven criteria) and various MMSE items, MDF showed no correlation with any of MMSE items as well as MMSE summary score. MMSE (score and items) did not discriminate patients without HE and minimal HE. The only significant differences between patients without HE and with overt HE were seen in respect of MMSE score (p<0.02), orientation to place (p<0.003), repetition (p<0.01) and complex commands-understanding (p<0.02). Test performance analysis has shown that MMSE has no value as a prediction method in determining minimal HE and in respect of overt HE has a sensitivity of 63% and specificity of 52% by a cut-off level at 27.5 points to diagnose overt HE. CONCLUSIONS: In conclusion, although MMSE score and single items are altered in patients with overt HE, MMSE has no value in the assessment of minimal HE. Because MMSE could be impaired in several cognitive dysfunctions, more specific test should be used for measuring HE.