Donor-specific anti-HLA antibodies are not associated with nonanastomotic biliary strictures but both are independent risk factors for graft loss after liver transplantation.

Donor-specific alloantibodies (DSA) have been associated with rejection and shorter graft survival after orthotopic liver transplantation (OLT). We examined the role of DSA in nonanastomotic biliary strictures (NAS) after OLT. Patients receiving first OLT who developed NAS (n = 68) and a control group without NAS (n = 83), with pre-OLT and 12 months post-OLT serum samples, were included. DSA were specified using the Luminex single antigen test. Risk factors for NAS and graft survival were analyzed. The presence of preformed DSA was not significantly different between patients with NAS and controls (P = .89). After 12 months, 26.5% of NAS patients and 16.9% of controls had generated de novo DSA (P = .15). Neither de novo class I DSA nor de novo class II DSA were associated with NAS. De novo DSA generally developed after the diagnosis of NAS. Time-dependent regression analysis identified both NAS (aHR 8.05, CI 3.28 - 19.77, P < .01) and de novo class II DSA (aHR 2.84, CI 1.38 - 5.82, P < .01) as independent risk factors for graft loss. Preformed or de novo DSA were not associated with the development of NAS. However, NAS as well as de novo class II DSA were independent risk factors for graft loss after OLT.

Prediction of biliary anastomotic stricture after deceased donor liver transplantation: the impact of platelet counts - a retrospective study.

Biliary stricture is a common cause of morbidity after liver transplantation (LT). This study aimed to determine the risk factors for post-transplant biliary anastomotic strictures (BAS), focusing on perioperative platelet counts. We enrolled 771 consecutive recipients who underwent ABO-identical/compatible deceased donor LT with duct-to-duct biliary reconstruction from January 2000 to June 2012. BAS was identified in 142 cases. The median time for stricture development was 176 days. Preoperative and postoperative platelet counts within 5 days after LT were significantly lower in patients with BAS than those without BAS. Using cutoff values acquired by the receiver operating characteristic curve analysis, persistent postoperative thrombocytopenia was defined as platelet counts <41 × 1000/µl and <53 × 1000/µl on postoperative day (POD) 3 and POD 5, respectively. Multivariate analysis indicated persistent postoperative thrombocytopenia (OR = 2.38) was the only independent risk factor for BAS. No significant associations were observed in terms of donor and surgical factors. Multivariate analysis demonstrated estimated blood loss (OR = 1.01, per 100 ml) was an independent contributing factor for persistent postoperative thrombocytopenia. We demonstrated low platelet count was associated with progression of post-transplant BAS. Minimizing intraoperative blood loss potentially contributes to maintain post-transplant platelet count, which may reduce incidence of BAS.

Antithrombin III and D-dimer levels as indicators of disease severity in patients with hyperlipidaemic or biliary acute pancreatitis.

Objective To assess changes in anticoagulation and fibrinolytic systems between biliary and hyperlipidaemic acute pancreatitis (AP). Methods Patients with biliary or hyperlipidaemic AP were enrolled. Demographic and clinical data were collected, and antithrombin III (ATIII), protein C, protein S, and D-dimer levels were investigated. Results A total of 45 patients with biliary AP and 50 patients with hyperlipidaemic AP were included (68 with mild AP and 27 with moderately-severe AP). ATIII and protein C levels in the mild AP group were significantly higher, but prothrombin time and D-dimer were significantly lower, versus the moderately-severe AP group. ATIII and D-dimer were found to be risk factors for moderately-severe AP. ATIII could predict AP severity, particularly in patients with biliary AP. D-dimer was a sensitive and specific predictor for disease severity in patients with AP, particularly in patients with hyperlipidaemic AP. Conclusion ATIII and protein C levels decreased as severity of AP increased, particularly in cases of biliary AP. D-dimer levels increased with severity of AP, particularly in hyperlipidaemic AP. ATIII and D-dimer may be useful biomarkers for assessing AP severity in patients with biliary and hyperlipidaemic AP, respectively.

Vanishing bile duct syndrome in Hodgkin's lymphoma: A case report and literature review.

Vanishing bile duct syndrome (VBDS) has been described in different pathologic conditions including infection, ischemia, adverse drug reactions, autoimmune diseases, allograft rejection, and humoral factors associated with malignancy. It is an acquired condition characterized by progressive destruction and loss of the intra-hepatic bile ducts leading to cholestasis. Prognosis is variable and partially dependent upon the etiology of bile duct injury. Irreversible bile duct loss leads to significant ductopenia, biliary cirrhosis, liver failure, and death. If biliary epithelial regeneration occurs, clinical recovery may occur over a period of months to years. VBDS has been described in a number of cases of patients with Hodgkin's lymphoma (HL) where it is thought to be a paraneoplastic phenomenon. This case describes a 25-year-old man found on liver biopsy to have VBDS. Given poor response to medical treatment, the patient underwent transplant evaluation at that time and was found to have classical stage IIB HL. Early recognition of this underlying cause or association of VBDS, including laboratory screening, and physical exam for lymphadenopathy are paramount to identifying potential underlying VBDS-associated malignancy. Here we review the literature of HL-associated VBDS and report a case of diagnosed HL with biopsy proven VBDS.

Carcinoembryonic Antigen Level in Primary Sclerosing Cholangitis Is Not Influenced by Dominant Strictures or Bacterial Cholangitis.

BACKGROUND: Carcinoembryonic antigen (CEA) can be used to screen for biliary tract cancer in patients with primary sclerosing cholangitis (PSC). AIM: To study the influence of benign dominant strictures (DS), superimposed bacterial cholangitis (SBC), smoking status, and inflammatory bowel disease on CEA serum levels. METHODS: A retrospective analysis of CEA values in cancer-free PSC patients was performed. We included the maximal CEA value obtained during follow-up and information on the presence of DS and SBC at that time, and we analyzed the CEA values in the presence and absence of DS and SBC. Results are reported as medians with the interquartile range (IQR). RESULTS: The median maximal CEA level, which was 1.8 ng/mL (IQR 1.2-2.9) in the final 270 PSC patients included in the study, was not influenced by the presence of either DS or SBC (P = 0.320). Moreover, in 49 patients, the first CEA value available at the time of DS (1.5 ng/mL; IQR 1.2-2.1) and that at a time without DS (1.6 ng/mL; IQR 1.1-2.3) did not differ significantly (P = 0.397). Lastly, in 24 patients, the median CEA values at a time without SBC (1.8 ng/mL; IQR 1.2-2.5) and at the time of SBC (1.8 ng/mL; IQR 1.0-3.0) were comparable (P = 0.305). Smoking did not influence CEA-based cancer screening. CONCLUSIONS: Serum CEA level is not influenced by the presence of DS or SBC and might therefore serve as a favorable parameter for improving cancer screening in PSC patients.

Use of Serum MicroRNAs as Biomarker for Hepatobiliary Diseases in Dogs.

BACKGROUND: Current biochemical indicators cannot discriminate between parenchymal, biliary, vascular, and neoplastic hepatobiliary diseases. MicroRNAs are promising new biomarkers for hepatobiliary disease in humans and dogs. OBJECTIVE: To measure serum concentrations of an established group of microRNAs in dogs and to investigate their concentrations in various types of hepatobiliary diseases. ANIMALS: Forty-six client-owned dogs with an established diagnosis of hepatobiliary disease and stored serum samples and eleven client-owned healthy control Labrador Retrievers. METHODS: Retrospective study. Medical records of dogs with parenchymal, biliary, vascular, or neoplastic hepatobiliary diseases and control dogs were reviewed. Concentrations of miR-21, miR-122, miR-126, miR-148a, miR-200c, and miR-222 were quantified in serum by real-time polymerase chain reaction. RESULTS: No different microRNA concentrations were found in the adenoma and congenital portosystemic shunt groups. In all other diseases, miR-122 concentrations were elevated with the highest concentration in the mucocele group (267-fold, CI: 40-1,768, P < .001). In dogs with biliary diseases, miR-21 and miR-222 were only increased in dogs with mucoceles (26-fold, CI: 5-141, P = .005 and 13-fold, CI: 2-70, P = .025, respectively). Uniquely increased microRNAs were found in the hepatocellular carcinoma group (miR-200c, 35-fold increase, CI: 3-382, P = .035) and the chronic hepatitis group (miR-126, 22-fold increase, CI: 5-91, P = .002). CONCLUSIONS AND CLINICAL IMPORTANCE: A microRNA panel consisting of miR-21, miR-122, miR-126, miR-200c, and miR-222 can distinguish between parenchymal, biliary, and neoplastic hepatobiliary diseases. Serum microRNA profiling is a promising new tool that might be a valuable addition to conventional diagnostics to help diagnose various hepatobiliary diseases in dogs.

High peak alanine aminotransferase determines extra risk for nonanastomotic biliary strictures after liver transplantation with donation after circulatory death.

Orthotopic liver transplantation (OLT) with donation after circulatory death (DCD) often leads to a higher first week peak alanine aminotransferase (ALT) and a higher rate of biliary nonanastomotic strictures (NAS) as compared to donation after brain death (DBD). This retrospective study was to evaluate whether an association exists between peak ALT and the development of NAS in OLT with livers from DBD (n = 399) or DCD (n = 97) from two transplantation centers. Optimal cutoff value of peak ALT for risk of development of NAS post-DCD-OLT was 1300 IU/l. The 4-year cumulative incidence of NAS after DCD-OLT was 49.5% in patients with a high ALT peak post-OLT, compared with 11.3% in patients with a low ALT peak. (P < 0.001). No relation between peak ALT and NAS was observed after DBD-OLT. Multivariate analysis revealed peak ALT ≥1300 IU/l [adjusted hazard ratio (aHR) = 3.71, confidence interval (CI) (1.26-10.91)] and donor age [aHR = 1.04, CI 1.00-1.07] to be independently associated with development of NAS post-DCD-OLT. A peak ALT of <1300 IU/l carries a risk for NAS similar to DBD-OLT. Thus, in DCD-OLT, but not in DBD-OLT, peak ALT discriminates patients at high or low risk for NAS.

Routine coagulation screening is an unnecessary step prior to ERCP in patients without biochemical evidence of jaundice: a cross-centre study.

INTRODUCTION: Guidelines suggest that all patients with choledocholithiasis should have a coagulation screen prior to endoscopic retrograde cholangiopancreatography (ERCP). This study aims to establish the incidence of deranged coagulation in such patients and its relationship with bleeding complications. METHODS: Analysis of consecutive patients undergoing ERCP procedures at two NHS sites was undertaken. Exclusion criteria were anti-coagulation use, bleeding disorders or incomplete data. Demographic data, pre-procedure bilirubin and prothrombin time (PT), ERCP procedural information, and bleeding complications were recorded for each. The cohort was divided into jaundice and non-jaundiced groups. Statistical analysis was performed using the student's t-test, Chi-squared test and Fisher's exact test. RESULTS: 793 patients (419 jaundiced; 374 non-jaundiced) were included. PT was significantly higher in the jaundiced group (greater by 2 (1.35-2.64) seconds; p < 0.001). PT was prolonged in 26.7 per cent of the jaundiced group; 28 patients (6.7 per cent) had a PT of >16.8 s 5.9 per cent of the non-jaundiced group had prolonged PT, with 1 patient having a PT >16.8 s. There were 5 major, and 32 minor bleeding complications with no differences between groups. In those with abnormal coagulation, only 1 minor bleeding complication occurred in a jaundiced patient. DISCUSSION: Normal pre-ERCP bilirubin was 99.7% (98.5-100) sensitive to predict a PT <16.8 s. Cost savings of £14,350 could have been achieved with judicial use of coagulation screening. CONCLUSION: Pre-ERCP coagulation screening should only be indicated in patients with a raised bilirubin or individuals on anticoagulation therapy or with a history of bleeding diathesis.

A laboratory diagnostic approach to hepatobiliary disease in small animals.

Routine biochemical tests generally include serum enzymes, proteins, and other markers useful for identifying hepatobiliary disease in dogs and cats. Obtaining results outside the reference intervals can occur with direct hepatocellular injury, enzyme induction by hepatocytes or biliary epithelium, or decreased hepatic function. However, detection of biochemical abnormalities does not necessarily indicate clinically significant disease. For a comprehensive approach to detection and treatment of hepatobiliary disease, the laboratory results must be correlated with the history and physical examination findings, diagnostic imaging results, and other assays.

Prevalence of vitamin K and vitamin D deficiency in patients with hepatobiliary and pancreatic disorders.

Little is known about the role of fat-soluble vitamins K and D in liver function and bone metabolism in biliary and pancreatic diseases associated with cholestasis and/or fat malabsorption. The aim of this study was to determine vitamin K of bone, vitamin D and parathyroid hormone status in patients with biliary and pancreatic disorders. In 90 consecutive patients (mean +/- SD age, 65.5 +/- 17.7 years; 45 females) undergoing endoscopic retrograde cholangiopancreatography (68 with choledocholithiasis, 14 with other benign condition, and 8 with cholangiopancreatic cancers) fasting concentrations of carboxylated (cOC) and undercarboxylated osteocalcin (ucOC), 25-hydroxyvitamin D, calcium, phosphorus, magnesium, prothrombin time, liver function tests, lipase, and creatinine were measured. Vitamin D deficiency (25-hydroxyvitamin D <50 nmol/L) was found in 45.6% of patients and elevated parathyroid hormone levels in 27.8%. The ratio ucOC/cOC (index of vitamin K deficiency) was above 20% in 50.6% of patients, above 30% in 31%, and above 50% in 18.4%. Hyperbilirubinemia was a significant independent predictor of low cOC (odds ratio [OR], 11.6; 95% confidence interval [CI], 1.9-59.4; P = .07). The ratio ucOC/cOC positively correlated with alanine aminotransferase levels (r = 0.410; P < .001). Elevated gamma-glutamyltransferase (>180 U/L) and international normalized ratio (>1.1) levels were significant independent predictors of ucOC/cOC greater than 30% after adjustment for other covariants (OR, 5.5; 95% CI, 1.2-25.2; P = .027, and OR, 3.1; 95% CI, 1.1-8.8; P = .036, respectively). This study demonstrates that vitamin K and vitamin D deficiencies are common in patients undergoing endoscopic retrograde cholangiopancreatography. Liver dysfunction is associated with and predictive of vitamin K deficiency of bone and decreased production of osteocalcin, indicating the need for appropriate supplementation.

Elevation of carbohydrate antigen 19.9 in benign hepatobiliary conditions and its correlation with serum bilirubin concentration.

BACKGROUND: Carbohydrate antigen 19.9 (CA19.9), a tumor marker for malignancies of the hepatobiliary tract and pancreas, has frequently been shown to be deranged in a number of non-malignant conditions that are associated with jaundice. This study aims to demonstrate the correlation between CA19.9 and serum bilirubin concentration in patients with benign conditions and to determine the frequency of a false-positive increase in CA19.9 in patients being investigated for potential HPB malignancies. METHODS: This is a retrospective review of 83 consecutive patients presenting with an abnormal CA19.9 and radiological or clinical features suggestive of HPB malignancy subsequently shown to have benign disease. All patients were thoroughly investigated and followed up until the diagnosis of malignancy could be safely excluded. RESULTS: Serum bilirubin, sodium, lymphocyte count, neutrophil:lymphocyte ratio (NLR), beta-human chorionic gonadotrophin (HCG), and age were found to correlate with CA19.9 by Pearson's correlation (P = 0.001, P = 0.006, P = 0.006, P < 0.001, P = 0.012, and P = 0.049, respectively). In multivariate regression analysis, bilirubin was identified as an independent variable that may predict CA19.9 level (P = 0.028). CONCLUSION: CA19.9 level is significantly influenced by serum bilirubin and elevated levels have been observed in patients with non-malignant HPB conditions. Adjusting CA19.9 according to bilirubin levels is likely to improve the specificity of this antigen in the differential diagnosis of benign and malignant HPB diseases and its reliability in the monitoring of disease response to chemotherapy.

Bile duct complications of hepatic arterial infusion chemotherapy evaluated by helical CT.

AIM: To describe the imaging findings of bile duct complications of hepatic arterial infusion chemotherapy (HAIC) using helical CT, to set diagnostic criteria, to develop a CT grading system, and to correlate these with clinical findings and laboratory data. METHODS: Follow-up helical CT of the abdomen was performed every 3 months for 60 patients receiving HAIC. Three radiologists reviewed all CT studies before and after treatment, using either the picture archiving and communication system or hard copies. The findings of bile duct abnormalities were correlated with findings from other imaging techniques, clinical symptoms and laboratory data. RESULTS: Bile duct abnormalities developed in 34 (57%) of cases either during HAIC or 1 to 12 months after treatment. In 14 (41%) of these 34 patients, enhancement of the hepatic parenchyma along the dilated bile duct or in the segmental or lobar distribution was observed. In 43 cases (72%), normal or abnormal alkaline phosphatase levels were consistent with normal or abnormal CT findings, respectively. Increasing alkaline phosphatase and bilirubin levels were related to CT grade. CONCLUSION: Imaging findings of bile duct complications of HAIC are similar to those of primary sclerosing cholangitis, and correlate well with abnormal clinical and laboratory data. In the presence of such clinical abnormalities, thin-section helical CT with careful review of the imaging studies helps to determine the correct diagnosis, monitor the changes and guide appropriate treatment.

Clinical significance of serum levels of vascular endothelial growth factor and its receptor in biliary disease and carcinoma.

AIM: To investigate the clinical significance of serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor-1 (VEGFR1/Flt-1) (sVEGFR1) levels in biliary diseases. METHODS: We analyzed the serum levels of these proteins in patients with acute cholangitis (group 1), biliary malignancies (group 2), and primary biliary cirrhosis or primary sclerosing cholangitis (group 3), and in healthy donors (group 4). The influence of inflammation was also analyzed. Serum VEGF levels were expressed as VEGF per platelet (VEGF/PLT, pg/10(6)) in order to exclude the influence of platelet counts. RESULTS: sVEGFR1 levels were significantly higher in groups 1 and 2 than in the control group, but did not correlate with inflammatory markers. VEGF/PLT levels were generally higher in patients with active inflammation than in those with carcinoma. C-reactive protein strongly correlated with the levels of serum VEGF independently of platelet and leukocyte counts, even in cancer patients. In cancer patients, VEGF/PLT and sVEGFR1 levels might be indicators for evaluating the effect of medical treatment or the disease progression. CONCLUSION: Serum VEGF and VEGFR1 might be useful markers for gauging the clinical effect of various treatments on patients.

Dominant strictures in patients with primary sclerosing cholangitis.

BACKGROUND: Repeat endoscopic dilatations of dominant strictures (DS) have been reported to be of benefit in patients with primary sclerosing cholangitis (PSC). We aimed to determine the prevalence of DS in patients with PSC and the spontaneous course of ALP and bilirubin, up to a year from diagnosis in patients with and without DS. METHOD: Cholangiographies from 125 patients with PSC were reevaluated. DS was defined as a stenosis < or =1.5 mm in diameter of the common bile duct (CBD) and/or < or = 1.0 mm of right (RHD) or left hepatic duct (LHD). RESULTS: A dominant stricture in common bile duct and/or right hepatic duct or left hepatic duct was present in 56 out of 125 (45%) patients. Mean values for alkaline phosphatase were 16 and 15.2 microkat/L and bilirubin values were 42 and 35 micromol/L before cholangiography in patients with and without DS, respectively (NS). The change in ALP and bilirubin observed from the precholangiographic value up to 2 and 12 months afterward was not significantly different in those with and without DS. CONCLUSIONS: Cholestasis in patients with PSC does not seem to be related to the presence of DS. Endoscopic therapy of DS should not be routinely undertaken and randomized studies are needed to clarify its potential benefits.

Post-cholecystectomy syndrome and magnesium deficiency.

BACKGROUND AND OBJECTIVE: In 20%-30% of cholecystectomised patients a biliary syndrome (called Post-Cholecystectomy Syndrome: PCES) reappears after some weeks or months. Its etiology, in certain cases, is an anatomic one: (choledochal lithiasis or stricture, obstructive papillitis, pancreatic duct stenosis), but there are many cases in which all organic causes are excluded. METHODS: The aim of this study was to analyze the correlation between these functional disturbances and magnesium (Mg) deficiency (MD). We analysed 52 patients with PCES and MD, in which organic lesions of the remaining bile ducts were excluded by imaging and endoscopic methods. RESULTS: MD was confirmed by serum and erythrocytic low Mg levels. 82% of patients were women. Supplemental therapy was provided with Tiomag (Mg gluconate and methionine), vitamin B6 and Ca lactate for 6 weeks or more. In 50 patients, PCES symptomatology disappeared after this treatment. In 14 cases some symptoms reappeared after a few weeks-months, but after repetition of the same therapy they completely disappeared. CONCLUSIONS: Our results demonstrate the dependence of PCES functional manifestations on MD, especially the recurrence of symptoms, which again subsided after Tiomag therapy was reinstituted.

Factors predicting concurrent cholangiocarcinomas associated with hepatolithiasis.

BACKGROUND/AIMS: Hepatolithiasis is a risk factor for cholangiocarcinoma. However, it is difficult to detect early cholangiocarcinoma that occurs as a complication of hepatolithiasis. To identify the factors, which can be used for predicting cholangiocarcinomas in patients with hepatolithiasis, we compared the clinical characteristics of patients who had cholangiocarcinoma associated with hepatolithiasis with those of patients with hepatolithiasis only. METHODOLOGY: Forty patients with cholangiocarcinoma associated with hepatolithiasis (group HC) and 73 patients with hepatolithiasis only (group H) were randomly selected for this study. Mean tumor size was 6.1 +/- 2.4 cm in diameter. RESULTS: Patients of group HC were older (56.7 +/- 8.9 yr) than those of group H (49.2 +/- 12.9 yr) (p < 0.001). Weight loss was more frequent in group HC (51.5%) than in group H (5.5%) (p < 0.001) and serum alkaline phosphatase levels were higher in group HC (181 +/- 184 IU/L) than in group H (426 +/- 385 IU/L) (p < 0.001). The proportion of the patients who had hepatolithiasis in the right or both lobes of the liver was higher in group HC (72.5%) than in group H (50.6%) (p = 0.024). The optimal cutoff value of serum CEA level for cholangiocarcinoma detection was set at 4.2 ng/mL using ROC cure to give a sensitivity of 67.6% and a specificity of 90.5%. Group HC differed from group H because of its lower rates of both abdominal pain and cholangitis, longer duration of stone history, and lower serum albumin level. Factors that did not predict cholangiocarcinoma included sex ratio, white blood cell count, serum bilirubin level, and hepatic atrophy. CONCLUSIONS: Cholangiocarcinoma should be suspected in patients with hepatolithiasis, especially when, the patient is over 40 years old, has a long history of hepatolithiasis with weight loss, a higher level of serum alkaline phosphatase, a lower level of serum albumin, a serum carcinoembryonic antigen level exceeding 4.2 ng/mL, and hepatolithiasis that is located either in the right or both lobes of the liver.