High frequency of the c.3207C>A (p.H1069Q) mutation in ATP7B gene of Lithuanian patients with hepatic presentation of Wilson's disease

AIM: To investigate the prevalence of the ATP7B gene mutation in patients with hepatic presentation of Wilson's disease (WD) in Lithuania. METHODS: Eleven unrelated Lithuanian families, including 13 WD patients were tested. Clinically WD diagnosis was established in accordance to the Leipzig scoring system. Genomic DNA was extracted fromwhole venous blood using a salt precipitation method. Firstly, the semi-nested polymerase chain reaction (PCR) technique was used to detect the c.3207C>A (p.H1069Q) mutation. Patients not homozygous for the c.3207C>A (p.H1069Q) mutation were further analyzed. The 21 exons of the WD gene were amplified in a thermal cycler (Biometra T3 Thermocycler, G?ttingen, Germany). Direct sequencing of the amplified PCR products was performed by cycle sequencing using fluorescent dye terminators in an automatic sequencer (Applied Biosystems, Darmstadt, Germany). RESULTS: Total of 13 WD patients (mean age 26.4 years; range 17-40; male/female 3/10) presented with hepatic disorders and 16 their first degree relatives (including 12 siblings) were studied. Some of WD patients, in addition to hepatic symptoms, have had extrahepatic disorders (hemolytic anemia 3; Fanconi syndrome 1; neurophsychiatric and behavioural disorder 2). Liver biopsy specimens were available in all of 13 WD patients (8 had cirrhosis; 1-chronic hepatitis; 3-acute liver failure, 1-liver steatosis). Twelve of 13 (92.3%) WD patients had the c.3207C>A (p.H1069Q) mutation, 6 of them in both chromosomes, 6 were presented as compound heterozygotes with additional c.3472-82delGGTTTAACCAT, c.3402delC, c.3121C>T (p.R1041W) or unknown mutations. For one patient with liver cirrhosis and psychiatric disorder (Leipzig score 6), no mutations were found. Out of 16 first degree WD relatives, 11 (68.7%) were heterozygous for the c.3207C>A (p.H1069Q) mutation. Two patients with fulminant WD died from acute liver failure and 11 are in full remission under penicillamine or zinc acetate treatment. Three women with WD successfully delivered healthy babies. CONCLUSION: The c.3207C>A (p.H1069Q) missense mutation is the most characteristic mutation for Lithuanian patients with WD. Even 92.3% of WD patients with hepatic presentation of the disease are homozygous or compound heterozygotes for the p.H1069Q mutation.

Risk of venous congestion in live donors of extended right liver graft

AIM: To investigate middle hepatic vein(MHV)management in adult living donor liver transplantation and safer remnant volumes(RV).METHODS: There were 59 grafts with and 12 grafts without MHV(including 4 with MHV-5/8 reconstructions).All donors underwent our five-step protocol evaluation containing a preoperative protocol liver biopsy Congestive vs non-congestive RV, remnantvolumebody-weight ratios(RVBWR) and postoperative outcomes were evaluated in 71 right graft living donors. Dominant vs non-dominant MHV anatomy in total liver volume(d-MHV/TLV vs nd-MHV/TLV) was constellated with large/small congestion volumes(CVindex).Small for size(SFS) and non-SFS remnant considerations were based on standard cut-off- RVBWR and RV/TLV. Non-congestive RVBWR was based on non-congestive RV.RESULTS: MHV and non-MHV remnants showed no significant differences in RV, RV/TLV, RVBWR, total bilirubin, or INR. SFS-remnants with RV/TLV < 30%and non-SFS-remnants with RV/TLV ≥ 30% showedno significant differences either. RV and RVBWR for non-MHV(n = 59) and MHV-containing(n = 12)remnants were 550 ± 95 ml and 0.79 ± 0.1 ml vs568 ± 97 ml and 0.79 ± 0.13, respectively(P = 0.423 and P = 0.919. Mean left RV/TLV was 35.8% ± 3.9%.Non-MHV(n = 59) and MHV-containing(n = 12)remnants(34.1% ± 3% vs 36% ± 4% respectively,P = 0.148. Eight SFS-remnants with RVBWR < 0.65 had a significantly smaller RV/TLV than 63 non-SFSremnants with RVBWR ≥ 0.65 [SFS: RV/TLV 32.4%(range: 28%-35.7%) vs non-SFS: RV/TLV 36.2%(range: 26.1%-45.5%), P < 0.009. Six SFS-remnants with RV/TLV < 30% had significantly smaller RVBWR than 65 non-SFS-remnants with RV/TLV ≥ 30%(0.65(range: 0.6-0.7) vs 0.8(range: 0.6-1.27), P < 0.01.Two(2.8%) donors developed reversible liver failure.RVBWR and RV/TLV were concordant in 25%-33%of SFS and in 92%-94% of non-SFS remnants. MHV management options including complete MHV vs MHV-4A selective retention were necessary in n = 12 vs n =2 remnants based on particularly risky congestive and non-congestive volume constellations.CONCLUSION: MHV procurement should consider individual remnant congestive- and non-congestive volume components and anatomy characteristics,RVBWR-RV/TLV constellation enables the identification of marginally small remnants.

Digital single-operator video cholangioscopy improves endoscopic management in patients with primary sclerosing cholangitis-a retrospective observational study

BACKGROUND Patients with primary sclerosing cholangitis(PSC)are at a high risk of developing cholestatic liver disease and biliary cancer,and endoscopy is crucial for the complex management of these patients.AIM To clarify the utility of recently introduced digital single-operator video cholangioscopy(SOVC)for the endoscopic management of PSC patients.METHODS In this observational study,all patients with a history of PSC and in whom digital SOVC(using the SpyGlass DS System)was performed between 2015 and 2019 were included and retrospectively analysed.Examinations were performed at a tertiary referral centre in Germany.In total,46 SOVCs performed in 38 patients with a history of PSC were identified.The primary endpoint was the evaluation of dominant biliary strictures using digital SOVC,and the secondary endpoints were the performance of selective guidewire passage across biliary strictures and the diagnosis and treatment of biliary stone disease in PSC patients.RESULTS The 22 of 38 patients had a dominant biliary stricture(57.9%).In 4 of these 22 patients,a cholangiocellular carcinoma was diagnosed within the stricture(18.2%).Diagnostic evaluation of dominant biliary strictures using optical signs showed a sensitivity of 75%and a specificity of 94.4%to detect malignant strictures,whereas SOVC-guided biopsies to gain tissue for histopathological analysis showed a sensitivity of 50%and a specificity of 100%.In 13%of examinations,SOVC was helpful for guidewire passage across biliary strictures that could not be passed by conventional methods(technical success rate 100%).Biliary stone disease was observed in 17.4%of examinations;of these,in 37.5%of examinations,biliary stones could only be visualized by SOVC and not by standard fluoroscopy.Biliary stone treatment was successful in all cases(100%);25%required SOVC-assisted electrohydraulic lithotripsy.Complications,such as postinterventional cholangitis and pancreatitis,occurred in 13%of examinations;however,no procedure-associated mortality occurred.CONCLUSION Digital SOVC is effective and safe for the endoscopic management of PSC patients and may be regularly considered an additive tool for the complex endoscopic management of these patients.

NOD2/CARD15 gene polymorphism in patients with inflammatory bowel disease: Is Hungary different?

AIM: To analyse the impact of NOD2/CARD15 mutations on the clinical course of Crohn's disease patients from an eastern European country (Hungary).METHODS: We investigated the prevalence of the three common NOD2/CARD15 mutations (Arg702Trp, Gly908Arg,1007finsC) in 148 patients with Crohn's disease, 128patients with ulcerative colitis and 208 controls recruited from the University of Szeged, Hungary. In patients with Crohn's disease, the prevalence of NOD2/CARD15 mutations was correlated to the demographical and clinical parameters.RESULTS: In total, 32.4% of Crohn's disease patients carried at least one mutant allele within NOD2/CARD15compared to 13.2% of patients with ulcerative colitis (P = 0.0002) and to 11.5% of controls (P＜0.0001). In Crohn's disease patients, the allele frequencies for Arg702Trp,Gly908Arg and 1007finsC were 7.1%, 3.0% and 10.8%respectively. Interestingly, only the 1007finsC mutation was associated with a distinct clinical phenotype. The patients positive for the 1007finsC mutation suffered more frequently from stenotic disease behaviour (P = 0.008). Furthermore,51.9% of patients positive for the 1007finsC mutation underwent a surgical resection within the ileum compared to only 17.4% of patients without the 1007finsC mutation (P = 0.001). With respect to the other two mutations (Arg702Trp and Gly908Arg), no associations were found with all investigated clinical parameters.CONCLUSION: NOD2/CARD15 mutations are frequently found in Crohn's disease patients from Hungary. The 1007finsC mutation is associated with stenotic disease behaviour and frequent ileal resections.

Gastrointestinal side effects in children with Wilson's disease treated with zinc sulphate

AIM:To investigate the side effects of a zinc sulphate therapy in a cohort of Polish pediatric patients with Wilson's disease. METHODS:We retrospectively analyzed a cohort of 53 pediatric patients with Wilson's disease treated at the Children's Memorial Health Institute in Warsaw, Poland between the years 1996 and 2011 with zinc sulphate. Patients were diagnosed with Wilson's disease according to the scoring system of Ferenci, with 49 cases confirmed by mutation analysis. Data about the dosage scheme of zinc sulphate, side effects and efficacy and toxicity of the treatment were collected and recorded in the patient's medical chart at each visit to the hospital. RESULTS:Mean age of diagnosis for the entire cohort was 10 years (range, 2.5-17 years). Duration of treatment with zinc sulfate was 83.3 wk (range, 8-344 wk). Side effects, all of gastrointestinal origin, were observed in 21 patients (40% 9 males and 12 females), irrespective of the duration of therapy. Thirteen out of 21 patients were over the age of 10 years. The most common ATP7B mutation was p.H1069Q. Esophagogastroduodenoscopy, performed in 7 patients (33.3%) suffering from persistent and severe abdominal pain, revealed gastrointestinal ulcerations or erosions with negative Helicobacter pylori tests in all subjects investigated. The above mentioned 7 patients were treated with proton pump inhibitors. Three of those experienced resolution of symptoms, whereas proton-pump inhibitors failed to alleviate symptoms of the remaining four children and conversion of therapy to D-penicillamine was needed. CONCLUSION:Zinc sulphate appears to cause significant gastrointestinal side effects, which children on therapy for Wilson's disease should be closely monitored for.