Michał Wasilewicz

Plasmapheresis exerts a long‐lasting antipruritic effect in severe cholestatic itch

The amelioration of refractory cholestatic pruritus after plasmapheresis has been reported in single patients. Here, we analyse the efficacy of plasmapheresis in a cohort of patients with primary biliary cholangitis (PBC).

The relevance of intestinal dysbiosis in liver transplant candidates

The gut microbial ecosystem plays an important role in the pathogenesis of liver diseases. However, the association of microbial community structure with the severity of liver dysfunction is not completely understood.

TRAF1 gene polymorphism correlates with the titre of Gp210 antibody in patients with primary biliary cirrhosis.

Background. Polymorphisms of TRAF1 (Tumor necrosis factor receptor-associated factor 1) are associated with rheumatoid arthritis (RA). Whether TRAF1 polymorphisms confer increased risk for primary biliary cirrhosis (PBC), an autoimmune liver disease which can co-exist with RA, is unknown. Aim of the Study. To assess the frequency of the RA-conferring susceptibility TRAF1 polymorphisms rs3761847 and rs2900180 in a cohort of PBC patients. The association of TRAF1 polymorphisms with clinical features and autoantibody markers was also analyzed. Methods. We studied 179 PBC patients and 300 controls. Samples were genotyped for TRAF1 gene polymorphisms by real-time PCR. Autoantibodies were tested by ELISA. Results. The frequency of rs3761847 and rs2900180 polymorphisms did not differ between patients and controls. Laboratory or clinical features were not associated with specific polymorphisms. Gp210 autoantibody titres were conspicuously higher among GG homozygotes of rs3761847 as compared with AA homozygotes (P = 0.02). In contrast, antichromatin titers were higher in AA compared to GG rs3761847 homozygotes (P = 0.04). Rheumatoid factor IgG titres were significantly higher in rs2900180 TT homozygotes than CC homozygotes (P = 0.02). Conclusions. TRAF1 polymorphisms occur with the similar frequency in PBC patients and in the general population, but their presence is probably involved in the regulation of specific PBC-related autoantibodies.

Evolution Of The Results Of 1500 Liver Transplantations Performed In The Department Of General, Transplant And Liver Surgery Medical University Of Warsaw.

UNLABELLED Liver transplantation is a well-established treatment of patients with end-stage liver disease and selected liver tumors. Remarkable progress has been made over the last years concerning nearly all of its aspects. The aim of this study was to evaluate the evolution of long-term outcomes after liver transplantations performed in the Department of General, Transplant and Liver Surgery (Medical University of Warsaw). MATERIAL AND METHODS Data of 1500 liver transplantations performed between 1989 and 2014 were retrospectively analyzed. Transplantations were divided into 3 groups: group 1 including first 500 operations, group 2 including subsequent 500, and group 3 comprising the most recent 500. Five year overall and graft survival were set as outcome measures. RESULTS Increased number of transplantations performed at the site was associated with increased age of the recipients (p<0.001) and donors (p<0.001), increased rate of male recipients (p<0.001), and increased rate of piggyback operations (p<0.001), and decreased MELD (p<0.001), as well as decreased blood (p=0.006) and plasma (p<0.001) transfusions. Overall survival was 71.6% at 5 years in group 1, 74.5% at 5 years in group 2, and 85% at 2.9 years in group 3 (p=0.008). Improvement of overall survival was particularly observed for primary transplantations (p=0.004). Increased graft survival rates did not reach the level of significance (p=0.136). CONCLUSIONS Long-term outcomes after liver transplantations performed in the Department of General, Transplant and Liver Surgery are comparable to those achieved in the largest transplant centers worldwide and are continuously improving despite increasing recipient age and wider utilization of organs procured from older donors.

Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation

Microvascular invasion (MVI) is well known to negatively influence outcomes following surgical treatment of hepatocellular cancer (HCC) patients. The aim of this study was to evaluate the rationale for prediction of MVI before liver transplantation (LT). Data of 200 HCC patients after LT were subject to retrospective analysis. MVI was present in 57 patients (28.5%). Tumor number (p = 0.001) and size (p = 0.009), and alpha-fetoprotein (p = 0.049) were independent predictors of MVI used to create a prediction model, defined as: 0.293x(tumor number) + 0.283x(tumor size in cm) + 0.164xloge(alpha-fetoprotein in ng/ml) (c statistic  =  0.743). The established cut-off (≥2.24) was associated with sensitivity and specificity of 72%. MVI was not an independent risk factor for recurrence (p = 0.307), in contrast to tumor number (p = 0.047) and size (p < 0.001), alpha-fetoprotein (p < 0.001) and poor differentiation (p = 0.039). Recurrence-free survival at 5 years for patients without MVI was 85.9% as compared to 83.3% (p = 0.546) and 55.3% (p = 0.001) for patients with false negative and true positive prediction of MVI, respectively. The use of both morphological and biological tumor features enables effective pre-transplant prediction of high-risk MVI. Provided that these parameters are combined in selection of HCC patients for LT, pre-transplant identification of all patients with MVI does not appear necessary.

A novel approach to genome-wide association analysis identifies genetic associations with primary biliary cholangitis and primary sclerosing cholangitis in Polish patients

BackgroundPrimary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are forms of hepatic autoimmunity, and risk for both diseases has a strong genetic component. This study aimed to define the genetic architecture of PBC and PSC within the Polish population.MethodsSubjects were 443 women with PBC, 120 patients with PSC, and 934 healthy controls recruited from Gastroenterology Departments in various Polish hospitals. Allelotyping employed a pooled-DNA sample-based genome-wide association study (GWAS) approach, using Illumina Human Omni2.5-Exome BeadChips and the following novel selection criteria for risk loci: blocks of at least 10 single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium, where the distance between each adjacent SNP pair in the block was less than 30 kb, and each SNP was associated with disease at a significance level of P < 0.005. A selected index SNP from each block was validated using TaqMan SNP genotyping assays.ResultsNineteen and twenty-one SNPs were verified as associated with PBC and PSC, respectively, by individual genotyping; 19 (10/9, PBC/PSC) SNPs reached a stringent (corrected) significance threshold and a further 21 (9/12, PBC/PSC) reached a nominal level of significance (P < 0.05 with odds ratio (OR) > 1.2 or < 0.83), providing suggestive evidence of association. The SNPs mapped to seven (1p31.3, 3q13, 6p21, 7q32.1, 11q23.3, 17q12, 19q13.33) and one (6p21) chromosome region previously associated with PBC and PSC, respectively. The SNP, rs35730843, mapping to the POLR2G gene promoter (P = 1.2 × 10-5, OR = 0.39) demonstrated the highest effect size, and was protective for PBC, whereas for PSC respective SNPs were: rs13191240 in the intron of ADGRB3 gene (P = 0.0095, OR = 0.2) and rs3822659 (P = 0.0051, OR = 0.236) along with rs9686714 (P = 0.00077, OR = 0.2), both located in the WWC1 gene.ConclusionsOur cost-effective GWAS approach followed by individual genotyping confirmed several previously identified associations and discovered new susceptibility loci associated with PBC and/or PSC in Polish patients. However, further functional studies are warranted to understand the roles of these newly identified variants in the development of the two disorders.

NOD2/CARD15 mutations in Polish and Bosnian populations with and without Crohn's disease: prevalence and genotype-phenotype analysis

Data on prevalence and phenotypic consequences of nucleotide-binding oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) variants in Crohns disease (CD) population in Poland and Bosnia and Herzegovina (B&H) are nonexistent. We aimed to determine the prevalence of NOD2/CARD15 mutations and their association with disease phenotype in Polish and Bosnian patients with CD and in healthy controls. We prospectively recruited 86 CD patients and 83 controls in Poland and 30 CD patients and 30 controls in B&H, 229 in total. We determined the prevalence of NOD2/CARD15 mutations and their association with the disease phenotype according to Montreal classification. Participants were genotyped for Leu1007fsinsC and Gly908Arg mutations. At least one CD-associated allele was found in 29/86 (33.7%) of Polish CD patients and in 9/83 (10.8%) of healthy controls (p<0.001). In both CD patients and controls in Bosnian sample, at least one NOD2 mutation was found in equal number of patients (3/30; 10%) with all of the NOD2 mutation positive CD patients being homozygous, while controls being heterozygous. In Polish sample, perianal disease was less frequent in CD patients with any NOD2 mutation (1/21; 4.8%) compared to those without (11/41; 26.8%; p=0.046). Higher percentage of patients with NOD2 mutations had history of CD related surgery when compared with those without mutations (66.7% vs. 43.3%; p=0.05). The risk for CD is increased in patients with NOD2 mutations (Poland) and especially in the presence of homozygous NOD2 mutations (Poland and Bosnia). The presence of variant NOD2 alleles is associated with increased need for surgery and reduced occurrence of perianal disease.

Ischemia-reperfusion injury and the risk of hepatocellular carcinoma recurrence after deceased donor liver transplantation

This study aimed to evaluate the effects of ischemia-reperfusion injury (IRI) on the risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation. Data of 195 patients were retrospectively analysed. Post-reperfusion aspartate (AST), alanine transaminase, and lactate dehydrogenase (LDH) levels were the primary measures of IRI. Tumour recurrence was the primary endpoint. Post-reperfusion AST was a continuous risk factor for tumour recurrence in patients within Milan criteria (p = 0.035), with an optimal cut-off of 1896 U/L. Recurrence-free survival of patients within Milan criteria and post-reperfusion AST of <1896 and ≥1896 U/L was 96.6% and 71.9% at 5 and 3.7 years, respectively (p = 0.006). Additionally, post-reperfusion AST and LDH exceeding the upper quartile significantly increased the risk of HCC recurrence in patients within Milan criteria (p = 0.039, hazard ratio [HR] = 5.99 and p = 0.040, HR = 6.08, respectively) and to a lesser extent, in patients within Up-to-7 criteria (p = 0.028, HR = 3.58 and p = 0.039, HR = 3.33, respectively). No other significant IRI effects were found in patients beyond the Up-to-7 criteria and in analyses stratified for independent risk factors for recurrence: tumour number and differentiation, alpha-fetoprotein, and microvascular invasion. Thus, IRI exerts major negative effects on the risk of HCC recurrence after liver transplantation in patients within standard and extended criteria.

Orthotopic liver transplantation (OLTx) in non-cirrhotic portal hypertension secondary to ADAMTS13 deficiency.

Non-cirrhotic intrahepatic portal hypertension (NCIPH), also called idiopathic or benign, may lead to life-threatening complications. It is a rare indication for orthotopic liver transplantation (OLTx), although it may remain underdiagnosed. Overt symptoms of portal hypertension, predominantly variceal bleedings, misleadingly suggest that these patients are cirrhotic. Non-cirrhotic intrahepatic portal hypertension can be related to obliteration of portal venous microcirculation as a consequence of ADAMTS13 deficiency, a metalloproteinase which cleaves the ultra-large molecular weight forms of von Willebrand factor (VWF). The physiological role of VWF, secreted from endothelium, is to facilitate platelet adhesion at sites of endothelial damage. Decreased ADAMTS13 activity and persistence of ultra-large VWF at the endothelial surface predisposes to platelet clumping, causing microvascular occlusion. We describe the first OLTx for ADAMTS13 deficiency-related NCIPH in Poland. A 20-year-old, previously healthy male student presented with upper gastrointestinal bleeding. Gastroduodenoscopy revealed active bleeding from oesophageal varices, which was successfully treated with endoscopic banding ligation. Physical examination showed splenomegaly, but was otherwise normal with no signs suggesting chronic liver disease. Laboratory investigations were all normal except thrombocytopenia of 40,000/ml. Viral, metabolic, and autoimmunological markers of liver disease as well as bone marrow examination were normal. Transjugular liver biopsy was performed and was essentially normal. However, the tissue sample size was rather slight and we were not able to measure hepatic venous pressure gradient (HVPG). Percutaneous liver biopsy performed later confirmed these findings. Contrast enhanced magnetic resonance imaging scan excluded portal vein thrombosis and Budd-Chiari syndrome. Laboratory investigations showed undetectable levels of ADAMTS13. The patient has been followed up over a period of 5 years, showing constant progression of his portal hypertension with continuous enlargement of his spleen (Figures 1 and ​and2)2) and frequent oesophageal/gastric variceal treatments. Follow-up liver biopsy showed progression to F2 fibrosis. He underwent OLTx with rapid recovery and remains extremely well 6 months after surgery. The histological changes in the explanted liver are shown in Figures 3 A–C. Figure 1 Magnetic resonance imaging of portal hypertension Figure 2 Computed tomography images of the liver hypotrophy and spleen enlargement Figure 3 Histopathology of the explanted liver: A – Liver fibrosis with inflammatory infiltrates. Neocholangioles, small venules, and lack of correct arterioles. Haematoxylin and eosin stain (H + E). Objective magnification 10×. B – Thick ... Non-cirrhotic intrahepatic portal hypertension secondary to ADAMTS13 deficiency is a progressive condition and in case of uncontrolled symptoms of portal hypertension may require liver transplantation. Non-cirrhotic intrahepatic portal hypertension is also called idiopathic or benign portal hypertension. The latter term is misleading as it was shown that more than half of these patients develop liver failure when observed over a median period of 88 months [1]. Thus NCIPH is considered a rare but clinically important cause of portal hypertension. The underlying problem is related to the obliteration of portal venous microcirculation, secondary to the deficiency of ADAMTS13, a metalloproteinase that cleaves the ultra-large molecular weight forms of VWF to smaller ones [2]. The physiological role of VWF, secreted from endothelium, is to facilitate platelet adhesion at sites of endothelial damage. Mutations of ADAMTS13 are seen in congenital TTP, while antibodies to ADAMTS13 are found in the majority of adult acquired cases. Decreased ADAMTS13 activity and persistence of ultra-large VWF at the endothelial surface is thought to predispose to platelet clumping, causing microvascular occlusion. The imbalance in VWF and ADAMTS13 levels in portal microcirculation, where hepatic arterial blood pressures are superimposed, with upstream relation to hepatic stellate cells, would provide a mechanism for obliteration of terminal portal venules, which is characteristic of NCIPH. In our patient plasma activity of ADAMTS13 was below 1%, and its inhibitor was within the normal ranges. He has been treated with β-blockers and remains clinically stable with appropriate endoscopic surveillance. However, in sequential MRI and computed tomography imagines, atrophy of the right lobe of the liver has been observed, with enlargement of the left lobe, periportal fibrosis, varices, and dilatation of the portal tract veins. Chronic NCIPH leads to hepatic atrophy, although the progression of the disease is usually slow. The disorder can be associated with celiac disease and ulcerative colitis, and sustained deficiency of ADAMTS13 appears characteristic of NCIPH despite preserved liver function [1]. Older age at first presentation, hepatic encephalopathy, and portal vein thrombosis were found to be significant predictors of reduced transplant-free survival with, as already mentioned, progression to decompensated liver disease and the need for liver transplantation in a significant proportion of patients [1].

A rare but life-threatening complication in liver transplant recipients

Graft versus host disease (GvHD) occurs in as little as 1–2% of cases after liver transplantation (LT), but is probably under-diagnosed and under-reported. Skin rash, diarrhoea, and/or fever are early symptoms of GvHD, and the most common causes of death are sepsis or gastrointestinal bleeding as a result of bone-marrow involvement. The delay in diagnosis as well as lack of standard treatment contributes to the high lethality of GvHD.