Background
Biliary atresia is a rare paediatric biliary obliteration disease with unknown aetiology, and is the most common indication for paediatric liver transplantation (LT). However, no consensus ...for predicting Kasai portoenterostomy (KP) outcomes using liver histological findings exists. Ki67 is a popular biomarker for measuring and monitoring cellular proliferation.
Methods
Ki67 (clone, MIB‐1) liver parenchyma expression was measured by immunohistochemical staining of samples from living donors and patients with biliary atresia to assess its value in predicting outcomes after
KP.
Results
Of 35 children with biliary atresia, 13 were native liver survivors (NLS), 17 were non‐NLS, and five had primary LT. The median proportion of Ki67 immunostained areas in donors and patients with biliary atresia at KP was 0·06 and 0·99 per cent respectively. Univariable analysis identified a high proportion of Ki67 areas, high Ki67 cell numbers and high Ki67‐positive/leucocyte common antigen‐positive cell numbers at KP as significant predictors of poor native liver survival after KP (hazard ratio 9·29, 3·37 and 12·17 respectively). The proportion of Ki67 areas in the non‐NLS group was significantly higher than that in the NLS group (1·29 versus 0·72 per cent respectively; P = 0·001), and then decreased at LT (0·32 per cent versus 1·29 per cent at KP; P < 0·001).
Conclusion
This study has demonstrated the clinical data and time course of Ki67 expression in patients with biliary atresia. High Ki67 expression at KP may be an important predictor of native liver survival following the procedure.
Antecedentes
La atresia biliar (biliary atresia, BA) es una enfermedad pediátrica rara que consiste en una obstrucción biliar de etiología desconocida, y es la indicación pediátrica más frecuente de trasplante hepático (liver transplantation, LT). Sin embargo, no existe consenso para predecir los resultados de la portoenterostomía de Kasai (Kasai portoenterostomy, KP) en base a los hallazgos histológicos hepáticos. El Ki67 es un biomarcador conocido para medir y controlar la proliferación celular.
Métodos
Se midieron los niveles de expresión del parénquima hepático de Ki67 (clon, MIB‐1) por tinción inmunohistoquímica de las muestras de cinco donantes vivos y 35 pacientes con BA, para evaluar su valor predictivo de los resultados de la KP.
Resultados
Los pacientes con BA incluían 13 sobrevivientes con hígado nativo (native liver survivors, NLS), 17 no NLS y 5 pacientes que se sometieron inicialmente a LT. La proporción media de las áreas de expresión de Ki67 en donantes y pacientes con BA en KP fue de 0,06% y 0,99%, respectivamente. El análisis univariado identificó una alta proporción de áreas de Ki67, un alto número de células Ki67, un alto número de células Ki67 positivas (+)/leucocitos (LCA/CD45) + en KP como predictores significativos de una peor supervivencia del hígado nativo después de KP (cociente de riesgos instantáneos, hazard ratio, HR 9,29, 3,37 y 12,17, respectivamente). La proporción de las áreas Ki67 fueron significativamente superiores en los pacientes sin NLS que en los pacientes con NLS (P = 0,001). Entre los pacientes sin hígado nativo, los niveles de Ki67 disminuyeron posteriormente de acuerdo con la presencia de una lesión hepática irreparable, tales como son los hígados con BA en LT (en KP versus en LT = 1,29% versus 0.32%; P < 0,001).
Conclusión
Demostramos los datos clínicos y la evolución temporal de la expresión de Ki67 en los pacientes con BA. El alto nivel de expresión de Ki67 en KP puede ser un predictor importante para la supervivencia del hígado nativo después de KP.
No consensus exists for predicting outcomes after Kasai portoenterostomy (KP) using liver histological findings. Ki67 (clone, MIB‐1) expression in liver parenchyma was measured by means of immunohistochemical staining of samples from five living donors and 35 patients with biliary atresia to assess its value in predicting KP outcomes. Univariable analysis identified high expression of Ki67 at the time of KP as a significant predictor of poor native liver survival after the procedure.
Ki67 a potential marker for liver survival after Kasai portoenterostomy
Background and aims: The pathogenesis of Crohn’s disease (CD), a chronic inflammatory bowel disease characterised by a Th1 immune response, remains unclear. Osteopontin (OPN) is a phosphoprotein ...known as an adhesive bone matrix protein. Recent studies have shown that OPN plays an important role in lymphocyte migration, granuloma formation, and interleukin 12 (IL-12) production. The present study investigated expression and the pathophysiological role of OPN in CD. Methods: Plasma OPN concentration was measured by enzyme linked immunosorbent assay. Expression of OPN in human intestinal mucosa was determined using reverse transcription-polymerase chain reaction and western blot, and localisation of OPN was examined by immunohistochemistry. Expression of integrin β3, an OPN receptor, on lamina propria mononuclear cells (LPMC) was assessed by flow cytometry. Functional activation of OPN in LPMC was investigated by measuring the production of cytokines. Results: Plasma OPN concentration was significantly higher in patients with CD compared with normal controls or patients with ulcerative colitis (UC). OPN was upregulated in intestinal mucosa from UC and CD patients. OPN producing cells were epithelial or IgG producing plasma cells, or partial macrophages. OPN was detected in areas surrounding granuloma from mucosa in CD. Integrin β3 expressing macrophages infiltrated inflamed mucosa in UC and CD; in contrast, there was no expression of integrin β3 on intestinal macrophages in normal mucosa. OPN induced production of IL-12 from LPMC in CD but not in normal controls or UC. Conclusions: Increased OPN expression facilitates cytokine production and is closely involved in the Th1 immune response associated with CD.
Our laboratory has suggested that loss of tolerance to pyruvate dehydrogenase (PDC-E2) leads to an anti-mitochondrial antibody response and autoimmune cholangitis, similar to human primary biliary ...cirrhosis (PBC). We have suggested that this loss of tolerance can be induced either via chemical xenobiotic immunization or exposure to select bacteria. Our work has also highlighted the importance of genetic susceptibility. Using the non-obese diabetic (NOD) congenic strain 1101 (hereafter referred to as NOD.1101 mice), which has chromosome 3 regions from B6 introgressed onto a NOD background, we exposed animals to 2-octynoic acid (2OA) coupled to bovine serum albumin (BSA). 2OA has been demonstrated previously by a quantitative structural activity relationship to react as well as or better than lipoic acid to anti-mitochondrial antibodies. We demonstrate herein that NOD.1101 mice immunized with 2OA-BSA, but not with BSA alone, develop high titre anti-mitochondrial antibodies and histological features, including portal infiltrates enriched in CD8⁺ cells and liver granulomas, similar to human PBC. We believe this model will allow the rigorous dissection of early immunogenetic cause of biliary damage.
Citrulline has been advocated as a marker for acute cellular rejection (ACR) in intestinal transplantation; however, its significance as a forewarning in the long‐term follow‐up remains unknown. This ...study aimed to investigate the association between citrulline levels and the grading of ACR to establish a cutoff point that accurately predicts ACR beyond 3 months posttransplant in the pediatric patient population. During a 16‐year period (1995–2011), a total of 13 499 citrulline samples were prospectively collected from 111 consecutive pediatric intestinal/multivisceral transplant recipients: 2155 were obtained concurrently with intestinal biopsies. There were 185 ACR episodes observed among 74/111 (67%) patients (median follow‐up: 4.4 years). Citrulline levels were inversely proportional to the severity of ACR. Negative predictive values for any type of ACR (cutoff, 20 μmol/L) and moderate/severe ACR (cutoff, 10 μmol/L) were 95% and 99%, respectively. When patients were divided according to graft size, diagnostic accuracy using the same cutoff was identical. Similarly, subgroup analysis by the timing of citrulline measurement prior to biopsy varying from 1 to 7 days demonstrated comparable results. Citrulline is a potent indicator as a danger signal for ACR, being an exclusionary, noninvasive biomarker with excellent negative predictive values in the long term after pediatric intestinal/multivisceral transplant.
Serum citrulline is an indicator of acute cellular rejection of the intestinal allograft beyond 3 months and has promise as an exclusionary biomarker with correlation to the severity of rejection.
Since the adoption of the Model for End‐Stage Liver Disease, simultaneous liver/kidney transplants (SLKT) have substantially increased. Recently, unfavorable outcomes have been reported yet ...contributing factors remain unclear. We retrospectively reviewed 74 consecutive adult SLKT performed at our center from 2000 to 2010 and compared with kidney transplant alone (KTA, N = 544). In SLKT, patient and death‐censored kidney graft survival rates were 64 ± 6% and 81 ± 5% at 5 years, respectively (median follow‐up, 47 months). Multivariable analyses revealed three independent risk factors affecting patient survival: hepatitis C virus positive (HCV+, hazard ratio HR 2.9, 95% confidence interval CI 1.1–7.9), panel reactive antibody (PRA) > 20% (HR 2.8, 95% CI 1.1–7.2) and female donor gender (HR 2.9, 95% CI 1.1–7.9). For death‐censored kidney graft survival, delayed graft function was the strongest negative predictor (HR 8.3, 95% CI 2.5–27.9), followed by HCV+ and PRA > 20%. The adjusted risk of death‐censored kidney graft loss in HCV+ SLKT patients was 5.8 (95% CI 1.6–21.6) compared with HCV+ KTA (p = 0.008). Recurrent HCV within 1 year after SLKT correlated with early kidney graft failure (p = 0.004). Careful donor/recipient selection and innovative approaches for HCV+ SLKT patients are critical to further improve long‐term outcomes.
In simultaneous liver–kidney transplant recipients, hepatitis C infection and pretransplant sensitization are significant negative predictors of patient and kidney graft survival, and early hepatitis C recurrence negatively impacts kidney graft survival. See editorial by Feng and Trotter on page 2869.
Abstract
Background
A paradigm shift in the treatment of inflammatory bowel disease (IBD) has emerged with recent medical advancements. Beyond clinical remission, endoscopic mucosal healing has ...become a major therapeutic goal of IBD and is associated with better long-term prognosis. Therefore, endoscopic evaluation is considered indispensable, however, frequent ileocolonoscopy (CS) may not be feasible due to its invasiveness. Transabdominal ultrasonography (TAUS) is a non-invasive imaging technique which enables to frequently monitor the disease and its utility has been previously reported. This study examined the usefulness of Doppler TAUS in assessing disease severity of IBD comparing with CS for each ileocolonic segment.
Methods
A retrospective chart review of 60 patients with IBD (ulcerative colitis (UC) 35, Crohn’s disease (CD) 25) who were examined both CS and Doppler TAUS from May 2017 to November 2018 within the interval of 1 month was conducted. The Mayo Endoscopic Subscore (MES) or the Simple Endoscopic Score for Crohn's disease (SES-CD) were used for CS and Limberg score was graded from Grade 0 to 4 for Doppler TAUS 2 . Endoscopic scoring indices (MES, SES-CD) and Limberg score were compared per-segment (ileum, ascending, transverse, descending, sigmoid and rectum) and per-patient. The sum of each score was calculated. Finally, the association of Limberg score with endoscopic indices was assessed by non-parametric Spearman rank correlation (rs) and receiver-operating characteristic analysis.
Results
Limberg score was significantly associated with MES (rs = 0.68, p < 0.01) or SES-CD in per-patients analysis (rs = 0.53, p < 0.01). The sum of Limberg scores of five segments also well-correlated with the sum of MES (rs = 0.84, p < 0.01) and SES-CD (rs = 0.76, p < 0.01). Per-segment analysis (UC: 208 segments, CD: 149 segments) demonstrated a significant correlation between Limberg score and MES/SES-CD (rs = 0.84 and 0.67, respectively). Association was significant in ileum, ascending, transverse, descending, and sigmoid colon, whereas not significant in rectum (Table 1). Limberg score ≤1 had a sensitivity of 1.00 and a specificity of 0.75 for mucosal healing defined by MES ≤ 1 or SES-CD (ulcer score) = 0 with area under the receiver-operating characteristic curve values of 0.91.
Table 1. Correlation (rs, Spearman rank test) between ultrasonographic (Limberg score) and endoscopic score (MES/SES-CD) in per-ileocolonic segment analysis. *p < 0.01.
Total
Ileum
Ascending
Transverse
Descending
Sigmoid
Rectum
UC
r
s
0.84*
0.56*
0.88*
0.87*
0.81*
0.70*
0.30
CD
r
s
0.67*
0.69*
0.59*
0.42*
0.52*
0.52*
0.32
Conclusions
Doppler TAUS is a useful monitoring tool alternative to CS, however, is less accurate in the assessment of rectum.
References
1. Sturm A, Maaser C, Calabrese E, et al. ECCO-ESGAR guideline for diagnostic assessment in inflammatory bowel disease. J Crohns Colitis 2018. doi:10.1093/ecco-jcc/jjy114.
2. Limberg B. Diagnosis of chronic inflammatory bowel diseases by ultrasonography. Z Gastroenterol 1999;37:495–508.
Background Gastrointestinal tract is one of the most susceptible organ systems to ischaemia. Not only mucosal injury but also alterations of the intestinal motility and loss of interstitial cells of ...Cajal (ICC) have been reported in response to ischaemia and reperfusion (I/R). However, there are few reports on the changes in the gastric motility after gastric I/R. The present study was designed to investigate the alterations in gastric emptying, the ICC and enteric nerves that regulate smooth muscle function in response to gastric I/R.
Methods Seven‐week‐old male Wistar rats were exposed to gastric I/R, and the gastric emptying rates at 12 and 48 h after I/R were evaluated by the phenol red method. Expressions of gene product of c‐kit receptor tyrosine kinase (c‐Kit), a marker of ICC, and of neuronal proteins were also examined.
Key Results Gastric emptying was transiently delayed at 12 h after I/R, but returned to normal by 48 h. Expression of c‐Kit protein as assessed by Western blotting and immunofluorescent staining of the smooth muscle layer, as well as expression of the mRNA of stem cell factor, the ligand for c‐Kit, were reduced at both 12 and 48 h after I/R. The expression of neuronal nitric oxide synthase (nNOS) protein as assessed by Western blotting and immunofluorescent staining was also decreased at 12 h after I/R, but was restored to normal by 48 h.
Conclusions & Inferences Gastric I/R evokes transient gastroparesis with delayed gastric emptying, associated with disruption of the ICC network and nNOS‐positive neurons.
Previous studies have suggested that the human leukocyte antigen (HLA) is involved in the etiology of Crohn's disease (CD); however, few reports are available on the association between HLA class I ...antigens and CD in Japan. In this study, we performed association analysis of HLA class I antigens in CD using 208 Japanese patients and 384 healthy controls. We identified novel positive associations between CD and HLA-A*02:01 (odds ratio (OR)=1.64, P=0.016) and HLA-A*02:07 (OR=2.31, P=0.0067) and confirmed previously reported positive associations between CD and HLA-Cw*14:02 (OR=2.18, P=0.0021) and HLA-B*51:01 (OR=1.70, P=0.033). We also identified novel negative associations between CD and HLA-A*24:02 (OR=0.60, P=0.0047) and HLA-B*07:02 (OR=0.38, P=0.0041). Although the associations were not significant after full Bonferroni correction, we suggested that HLA class I genes have dual functions, susceptibility and resistance in controlling the development of CD.
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