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1.
Endoscopy ; 52(2): 107-114, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31858509

RESUMO

BACKGROUND: Single-operator peroral cholangioscopy (sPOCS) is considered a valuable diagnostic modality for indeterminate biliary strictures. Nevertheless, studies show large variation in its characteristics and measures of diagnostic accuracy. Our aim was to estimate the diagnostic accuracy of sPOCS visual assessment and targeted biopsies for indeterminate biliary strictures. Additional aims were: estimation of the clinical impact of sPOCS and comparison of diagnostic accuracy with brush cytology. METHODS: A retrospective single-center study of adult patients who underwent sPOCS for indeterminate biliary strictures was performed. Diagnostic accuracy was defined as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The clinical impact of sPOCS was assessed by review of medical records, and classified according to its influence on patient management. RESULTS: 80 patients were included, with 40 % having primary sclerosing cholangitis (PSC). Prior ERCP was performed in 88 %, with removal of a biliary stent prior to sPOCS in 55 %. The sensitivity, specificity, PPV, and NPV for sPOCS visual impression and targeted biopsies were 64 %, 62 %, 41 %, and 84 %, and 15 %, 65 %, 75 %, and 69 %, respectively. The clinical impact of sPOCS was limited; outcome changed management in 17 % of patients. Sequential brush cytology sensitivity, specificity, PPV, and NPV were 47 %, 95 %, 80 %, and 83 %. CONCLUSIONS: The diagnostic accuracy of sPOCS for indeterminate biliary strictures was found to be inferior to brush cytology, with a low impact on patient management. These findings are obtained from a select patient population with a high prevalence of PSC and plastic stents in situ prior to sPOCS.

2.
Liver Int ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31758650

RESUMO

BACKGROUND & AIMS: Bu Gu Zhi (BGZ) is a Chinese herb consumed mainly for osteoporosis treatment. Only small case series of BGZ-induced liver injury (BGZILI) have been reported. We describe the clinicopathological features and clinical course of BGZILI. METHODS: Patients diagnosed with drug-induced liver injury (DILI) at Beijing Friendship Hospital from 2005 to 2017 were reviewed. Clinical and follow-up data were analysed. RESULTS: Of the 547 DILI patients, 40 cases (7.3%) were attributed to BGZILI. About 34/40 (85.0%) patients were females with a median age of 63 (range, 54-70) years. The median latency period was 45 (range, 29-90) days. Patients commonly presented with loss of appetite (57.5%), dark urine (57.5%) and fatigue (55.0%). The median level of alanine aminotransferase and aspartate aminotransferase at BGZILI onset was 673.5 and 423.0 U/L respectively. Total bilirubin (TB) and direct bilirubin (DB) were 59.0 and 39.4 µmol/L respectively. The biochemical liver injury pattern was hepatocellular (92.5%), cholestatic (5.0%) and mixed (2.5%). They were categorized into 'mild' (N = 23, 57.5%), 'moderate' (6, 15.0%) or 'severe' (11, 27.5%) according to severity assessment by DILI network. The main histological injury pattern in 9/40 patients with liver biopsy was acute hepatitis with/without cholestasis. Median duration of follow-up was 26.3 months with recovery in 37 patients within 6 months. No patients died or required transplantation. CONCLUSIONS: BGZ-induced liver injury manifested more often as a hepatocellular injury pattern with mild to moderate hepatocellular damage. Most patients recovered after cessation of BGZ within 6 months, and none developed end-stage liver disease or died.

3.
Mod Pathol ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570768

RESUMO

The molecular classification of hepatocellular adenomas highlights a distinctive genotype-phenotype correlation. Malignant transformation is an exceptionally rare complication of hepatocyte nuclear factor 1α (HNF1A)-inactivated hepatocellular adenomas. This subtype is characterized by loss of liver fatty acid binding protein immunoexpression. In this study, we characterized the histopathologic spectrum of 13 liver fatty acid binding protein-deficient hepatocellular adenoma cases showing malignant transformation from multiple centers. Clinicopathologic characteristics of these patients were evaluated. Stains for reticulin, liver fatty acid binding protein, beta-catenin and glutamine synthetase were applied to these lesions. Moreover, the findings were compared to patients with ß-catenin mutated hepatocellular adenoma. Liver fatty acid binding protein-deficient hepatocellular adenomas with borderline features/carcinoma were seen predominantly in females (77%) with an average age of 46 ± 18 years and multiple lesions (77%; five patients with adenomatosis). Meanwhile, ß-catenin mutated hepatocellular adenoma patients with malignant transformation were predominantly male (67%, p = 0.018) with single lesion (86%, p = 0.0009). The largest liver fatty acid binding protein-deficient hepatocellular adenoma nodule in each patient ranged from 4 to 15.5 cm. Loss of liver fatty acid binding protein by immunohistochemistry was noted in all adenoma and borderline/carcinoma components. Features of malignant transformation were pseudoglandular architecture (85%), cytologic atypia (85%), architectural atypia (100%) and lack of steatosis (100%). Other findings included myxoid change (39%), peliosis (46%) and sinusoidal dilatation (46%). Molecular studies confirmed somatic inactivation of HNF1A in 3 cases and absence of TERT promotor and exon 3 CTNNB1 mutations in five cases. To summarize, liver fatty acid binding protein-deficient hepatocellular adenoma with malignant transformation is most frequently seen in female patients with multiple lesions. Most of these lesions demonstrate pseudoglandular architecture, cytologic and architectural atypia, with lack of steatosis. The natural history of these lesions is relatively benign with the exception of disease recurrence in 1 patient.

4.
Hepatol Int ; 13(6): 766-776, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31559605

RESUMO

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) commonly affects subjects with obesity, yet non-obese NAFLD is increasingly being recognized. We aimed to investigate the clinicopathological and genetic characteristics of non-obese NAFLD patients. METHODS: The clinical, histological and genetic data of 84 NAFLD patients with biopsy for abnormal liver function test were reviewed. Both NAS-CRN and SAF scoring systems were applied for histopathological evaluation. PNPLA3 and TMS6F2 genotyping were also performed. RESULTS: All of the 84 patients were histologically diagnosed with non-alcoholic steatohepatitis (NASH), with 36 of them (42.9%) being non-obese (BMI < 25 kg/m2). Compared with the obese group, non-obese group were predominantly females (88.9% vs 52.1%, p < 0.001), tended to have higher prevalence of diabetes (p = 0.068). More importantly non-obese patients had a significant higher prevalence of advanced fibrosis (F ≥ 3) (58.3% vs 29.2%, p = 0.013), and a trend of higher degree of ballooning (p = 0.061). In addition, values of liver stiffness measurement were also significantly higher in non-obese group (12.1 kPa vs 8.1 kPa, p = 0.032). There was also a trend of higher prevalence of TM6SF2 T allele in non-obese group (p = 0.085), while the prevalence of PNPLA3 risk allele did not differ between two groups. Multivariate analysis showed that higher fasting glucose (p = 0.038) and lower serum platelets (p = 0.040) were two independent predictors for advanced fibrosis in non-obese patients. CONCLUSIONS: Non-obese NASH patients have a female predominance and more advanced fibrosis. Liver biopsy is crucial to evaluate the severity of disease in non-obese patients especially those with abnormal liver biochemistry. CLINICAL TRIAL NUMBER: NCT03386890.

5.
Liver Int ; 39(11): 2042-2045, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31483937

RESUMO

Hepatocyte nuclear factor 1A (HNF1A) maturity-onset diabetes of the young (MODY) is a monogenetic, autosomal dominantly inherited form of diabetes. HNF1A-MODY is associated with HNF1A-inactivated hepatocellular adenoma (H-HCA) formation. Hepatocellular adenoma (HCA) are benign liver tumours and related complications are rare but serious: hepatic haemorrhage and malignant transformation. Guidelines recommend resection of all HCA in men and do not take any co-occurring metabolic disorders into account. We report a family with HCA preceding diabetes mellitus. Male index patient presented with numerous, irresectable HCA. After initial diagnostic and aetiologic uncertainty HNF1A germline mutation c.815G>A (p.Arg272His) was confirmed 8 years later. No HCA-related complications occurred. His diabetic mother was diagnosed with HCA after severe hepatic haemorrhage years before. HNF1A-MODY should be considered in (non-)diabetic (male) patients with H-HCA. We advocate liver biopsy and, if necessary, genetic analysis to precede any intervention for HCA in males and screening for HCA in HNF1A-MODY patients.

6.
Mod Pathol ; 32(12): 1795-1805, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300804

RESUMO

Histologically, drug-induced liver injury could be classified into acute hepatitis, chronic hepatitis, acute cholestasis, chronic cholestasis, and cholestatic hepatitis. The correlation between these histologic patterns and long-term clinical outcomes has not been well established. Therefore, we conducted a retrospective cohort study to investigate the association of histologic patterns and long-term clinical outcomes defined as biochemical normalization, persistent abnormal liver biochemistry or death at designated time points. In this study, biochemical classification was determined by R-values; histologic injury pattern was determined by morphological features. Predictive ability of clinical outcomes by these two classifications was assessed using Receiver Operating Characteristic Curves. Logistic regression was performed to identify histologic factors associated with outcomes. Totally, 88 patients with drug-induced liver injury were included for final analysis. Biochemical and histologic classification were consistent in 50 (57%) cases. 53 (60%) cases showed biochemical normalization within 6 months, and a further 11 (13%), 16 (18%), and 6 (7%) cases within 1, 2, and 3 years, respectively. Compared with biochemical classification, histologic injury pattern had better predictive ability for abnormal biochemistry at 6 months (Areas under Receiver Operating Characteristic Curves 0.92 versus 0.60, P < 0.001) and 1 year (Areas under Receiver Operating Characteristic Curves 0.94 versus 0.69, P < 0.001). Interlobular bile duct loss in >25% portal areas was independently associated with abnormal biochemistry at 6 months, 1 year, and 2 years. In conclusion, histologic injury pattern is better correlated with clinical outcome at 6 months and 1 year than biochemical classification. Moderate bile duct loss is an important histologic feature associated with persistent biochemical abnormality at 6 months, 1 year, and 2 years.

7.
Liver Int ; 39(5): 905-913, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30773766

RESUMO

BACKGROUND & AIMS: Hepatocellular adenomas (HCA) are rare, hormone-driven, benign liver tumours. HCA >50 mm are associated with haemorrhage and malignant transformation. Guidelines recommend cessation of oral contraceptive pills (OCP) for size reduction; however, it is currently unknown how HCA respond to cessation of OCP. We sought to investigate the effect of OCP cessation on HCA size. METHODS: A retrospective cohort study was performed including HCA patients who stopped OCP intake within 6 months of imaging between 2005 and 2018. Biometrics and hormonal medication use were evaluated with self-designed questionnaires. Response of the largest HCA was evaluated according to Response Evaluation Criteria in Solid Tumours (RECISTv1.1). Cox regression was performed for analysis of factors influencing HCA regression. RESULTS: Seventy-eight HCA patients were included, diagnosed at a median (interquartile range) age of 32 (26-41) years. Follow-up was 1.6 (0.4-2.9) years. HCA size at diagnosis ranged 10-167 mm. After a median time of 1.3 (0.6-2.6) years after OCP cessation, 37.2% of HCA showed ≥30% regression, 5.1% complete regression, 56.4% stability and 1.3% progression. No HCA-induced complications were observed during follow-up. Cox regression analysis demonstrated a significant association of HCA size with rate of regression; 50 ≤ HCA < 100 mm (HR 2.4, 95% CI 1.1-5.3; P < 0.05), HCA ≥ 100 mm (HR 8.3, 95% CI 3.3-21.6; P < 0.001). CONCLUSIONS: Ninety-eight per cent of HCA remained stable or regressed after OCP cessation. A longer wait-and-see period was associated with a larger proportion of regressing HCA, without HCA-related complications during follow-up.

8.
Transplantation ; 103(7): 1405-1413, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30395120

RESUMO

BACKGROUND: Ex situ normothermic machine perfusion (NMP) can be used to assess viability of suboptimal donor livers before implantation. Our aim was to assess the diagnostic accuracy of bile biochemistry for the assessment of bile duct injury (BDI). METHODS: In a preclinical study, 23 human donor livers underwent 6 hours of end-ischemic NMP to determine biomarkers of BDI. Livers were divided into groups with low or high BDI, based on a clinically relevant histological grading system. During NMP, bile was analyzed biochemically and potential biomarkers were correlated with the degree of BDI. Receiver operating characteristics curves were generated to determine optimal cutoff values. For clinical validation, identified biomarkers were subsequently included as viability criteria in a clinical trial (n = 6) to identify transplantable liver grafts with low BDI. RESULTS: Biliary bicarbonate and pH were significantly higher and biliary glucose was significantly lower in livers with low BDI, compared with high BDI. The following cutoff values were associated with low BDI: biliary bicarbonate greater than 18 mmol/L (P = 0.002), biliary pH greater than 7.48 (P = 0.019), biliary glucose less than 16 mmol/L (P = 0.013), and bile/perfusate glucose ratio less than 0.67 (P = 0.013). In the clinical trial, 4 of 6 livers met these criteria and were transplanted, and none developed clinical evidence of posttransplant cholangiopathy. CONCLUSIONS: Biliary bicarbonate, pH, and glucose during ex situ NMP of liver grafts are accurate biomarkers of BDI and can be easily determined point of care, making them suitable for the pretransplant assessment of bile duct viability. This may improve graft selection and decrease the risk of posttransplant cholangiopathy.

9.
Hepatology ; 69(4): 1719-1734, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30506902

RESUMO

Peribiliary glands (PBG) are a source of stem/progenitor cells organized in a cellular network encircling large bile ducts. Severe cholangiopathy with loss of luminal biliary epithelium has been proposed to activate PBG, resulting in cell proliferation and differentiation to restore biliary epithelial integrity. However, formal evidence for this concept in human livers is lacking. We therefore developed an ex vivo model using precision-cut slices of extrahepatic human bile ducts obtained from discarded donor livers, providing an intact anatomical organization of cell structures, to study spatiotemporal differentiation and migration of PBG cells after severe biliary injury. Postischemic bile duct slices were incubated in oxygenated culture medium for up to a week. At baseline, severe tissue injury was evident with loss of luminal epithelial lining and mural stroma necrosis. In contrast, PBG remained relatively well preserved and different reactions of PBG were noted, including PBG dilatation, cell proliferation, and maturation. Proliferation of PBG cells increased after 24 hours of oxygenated incubation, reaching a peak after 72 hours. Proliferation of PBG cells was paralleled by a reduction in PBG apoptosis and differentiation from a primitive and pluripotent (homeobox protein Nanog+/ sex-determining region Y-box 9+) to a mature (cystic fibrosis transmembrane conductance regulator+/secretin receptor+) and activated phenotype (increased expression of hypoxia-inducible factor 1 alpha, glucose transporter 1, and vascular endothelial growth factor A). Migration of proliferating PBG cells in our ex vivo model was unorganized, but resulted in generation of epithelial monolayers at stromal surfaces. Conclusion: Human PBG contain biliary progenitor cells and are able to respond to bile duct epithelial loss with proliferation, differentiation, and maturation to restore epithelial integrity. The ex vivo spatiotemporal behavior of human PBG cells provides evidence for a pivotal role of PBG in biliary regeneration after severe injury.

10.
Liver Transpl ; 24(5): 655-664, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29369470

RESUMO

Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia/reperfusion injury (IRI). This study aimed to determine whether DHOPE reduces IRI of the bile ducts in donation after circulatory death (DCD) liver transplantation. In a recently performed phase 1 trial, 10 DCD livers were preserved with DHOPE after static cold storage (SCS; www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semiquantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as controls. Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, the degree of stroma necrosis (P = 0.002) and injury of the deep peribiliary glands (PBG; P = 0.02) increased after reperfusion compared with baseline. In contrast, in DHOPE-preserved livers, the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep PBG (P = 0.04) after reperfusion in the DHOPE group compared with controls. In conclusion, this study suggests that DHOPE reduces IRI of bile ducts after DCD liver transplantation. Liver Transplantation 24 655-664 2018 AASLD.


Assuntos
Temperatura Baixa , Doenças do Ducto Colédoco/prevenção & controle , Ducto Colédoco/transplante , Seleção do Doador , Transplante de Fígado/métodos , Preservação de Órgãos/métodos , Perfusão/métodos , Traumatismo por Reperfusão/prevenção & controle , Adulto , Biópsia , Ducto Colédoco/patologia , Doenças do Ducto Colédoco/etiologia , Doenças do Ducto Colédoco/patologia , Feminino , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Necrose , Países Baixos , Preservação de Órgãos/efeitos adversos , Preservação de Órgãos/instrumentação , Perfusão/efeitos adversos , Perfusão/instrumentação , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
11.
Biochim Biophys Acta Mol Basis Dis ; 1864(4 Pt B): 1524-1531, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28778591

RESUMO

The larger ducts of the biliary tree contain numerous tubulo-alveolar adnexal glands that are lined with biliary epithelial cells and connected to the bile duct lumen via small glandular canals. Although these peribiliary glands (PBG) were already described in the 19th century, their exact function and role in the pathophysiology and development of cholangiopathies have not become evident until recently. While secretion of serous and mucinous components into the bile was long considered as the main function of PBG, recent studies have identified PBG as an important source for biliary epithelial cell proliferation and renewal. Activation, dilatation, and proliferation of PBG (or the lack thereof) have been associated with various cholangiopathies. Moreover, PBG have been identified as niches of multipotent stem/progenitor cells with endodermal lineage traits. This has sparked research interest in the role of PBG in the pathogenesis of various cholangiopathies as well as bile duct malignancies. Deeper understanding of the regenerative capacity of the PBG may contribute to the development of novel regenerative therapeutics for previously untreatable hepatobiliary diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.


Assuntos
Doenças dos Ductos Biliares/etiologia , Ductos Biliares/fisiologia , Células Epiteliais/fisiologia , Células-Tronco Multipotentes/fisiologia , Regeneração/fisiologia , Doenças dos Ductos Biliares/patologia , Ductos Biliares/citologia , Ductos Biliares/ultraestrutura , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Cílios/fisiologia , Células Epiteliais/citologia , Células Epiteliais/ultraestrutura , Humanos , Células Estromais/fisiologia
12.
Liver Transpl ; 24(4): 528-538, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29281862

RESUMO

Normothermic machine perfusion (NMP) enables viability assessment of donor livers prior to transplantation. NMP is frequently performed by using human blood products including red blood cells (RBCs) and fresh frozen plasma (FFP). Our aim was to examine the efficacy of a novel machine perfusion solution based on polymerized bovine hemoglobin-based oxygen carrier (HBOC)-201. Twenty-four livers declined for transplantation were transported by using static cold storage. Upon arrival, livers underwent NMP for 6 hours using pressure-controlled portal and arterial perfusion. A total of 12 livers were perfused using a solution based on RBCs and FFPs (historical cohort), 6 livers with HBOC-201 and FFPs, and another 6 livers with HBOC-201 and gelofusine, a gelatin-based colloid solution. Compared with RBC + FFP perfused livers, livers perfused with HBOC-201 had significantly higher hepatic adenosine triphosphate content, cumulative bile production, and portal and arterial flows. Biliary secretion of bicarbonate, bilirubin, bile salts, and phospholipids was similar in all 3 groups. The alanine aminotransferase concentration in perfusate was lower in the HBOC-201-perfused groups. In conclusion, NMP of human donor livers can be performed effectively using HBOC-201 and gelofusine, eliminating the need for human blood products. Perfusing livers with HBOC-201 is at least similar to perfusion with RBCs and FFP. Some of the biomarkers of liver function and injury even suggest a possible superiority of an HBOC-201-based perfusion solution and opens a perspective for further optimization of machine perfusion techniques. Liver Transplantation 24 528-538 2018 AASLD.


Assuntos
Aloenxertos , Transplante de Fígado , Fígado , Soluções para Preservação de Órgãos/química , Preservação de Órgãos/métodos , Poligelina , Adulto , Idoso , Biomarcadores/análise , Eritrócitos , Feminino , Hemoglobinas , Humanos , Masculino , Pessoa de Meia-Idade , Preservação de Órgãos/instrumentação , Perfusão/instrumentação , Perfusão/métodos , Plasma , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Temperatura Ambiente
13.
Pediatr Transplant ; 21(7)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28627016

RESUMO

In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions.


Assuntos
Cirrose Hepática/etiologia , Transplante de Fígado , Complicações Pós-Operatórias/etiologia , Adolescente , Biópsia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Incidência , Lactente , Recém-Nascido , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/patologia , Masculino , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/patologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , Tacrolimo/uso terapêutico
14.
HPB (Oxford) ; 19(6): 538-546, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28351756

RESUMO

BACKGROUND: Lack of oxygen and biomechanical stimulation during static cold storage (SCS) of donor livers compromises endothelial cell function. We investigated the effect of end-ischemic oxygenated hypothermic machine perfusion (HMP) on endothelial cell function of extended criteria donor (ECD) livers. METHODS: Eighteen livers, declined for transplantation, were transported to our center using static cold storage (SCS). After SCS, 6 livers underwent two hours of HMP, and subsequent normothermic machine perfusion (NMP) to assess viability. Twelve control livers underwent NMP immediately after SCS. mRNA expression of transcription factor Krüppel-like-factor 2 (KLF2), endothelial nitric oxide synthase (eNOS), and thrombomodulin (TM) was quantified by RT-PCR. Endothelial cell function and injury were assessed by nitric oxide (NO) production and release of TM into the perfusate. RESULTS: In HMP livers, mRNA expression of KLF2 (p = 0.043), eNOS (p = 0.028), and TM (p = 0.028) increased significantly during NMP. In parallel, NO levels increased during NMP in HMP livers but not in controls. At the end of NMP cumulative TM release was significantly lower HMP livers, compared to controls (p = 0.028). CONCLUSION: A short period of two hours oxygenated HMP restores endothelial cell viability after SCS and subsequent normothermic reoxygenation of ECD livers.


Assuntos
Temperatura Baixa , Células Endoteliais/metabolismo , Hepatectomia , Transplante de Fígado/métodos , Fígado/cirurgia , Preservação de Órgãos/métodos , Oxigênio/metabolismo , Perfusão/métodos , Doadores de Tecidos/provisão & distribução , Idoso , Sobrevivência Celular , Seleção do Doador , Células Endoteliais/patologia , Feminino , Regulação da Expressão Gênica , Hepatectomia/efeitos adversos , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Fígado/metabolismo , Fígado/patologia , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Preservação de Órgãos/efeitos adversos , Preservação de Órgãos/instrumentação , Perfusão/efeitos adversos , Perfusão/instrumentação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Trombomodulina/genética , Trombomodulina/metabolismo , Fatores de Tempo
15.
Hepatology ; 65(3): 907-919, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27880989

RESUMO

Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC-related death and liver transplantation), 2 (liver transplantation), and 3 (liver-related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow-up was 142 months. During follow-up, 31 patients died (20 PSC-related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver-related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49-6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17-3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10-2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10-1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19-5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09-3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22-3.77). Interobserver agreement was moderate for Nakanuma stage (κ = 0.56) and substantial for Nakanuma component fibrosis (κ = 0.67), Ishak stage (κ = 0.64), and Ludwig stage (κ = 0.62). CONCLUSION: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system-incorporating features of chronic biliary disease-again showed the strongest predictive value. (Hepatology 2017;65:907-919).


Assuntos
Colangite Esclerosante/mortalidade , Colangite Esclerosante/patologia , Transplante de Fígado/mortalidade , Adulto , Biópsia por Agulha , Colangite Esclerosante/cirurgia , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Internacionalidade , Estimativa de Kaplan-Meier , Transplante de Fígado/métodos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Variações Dependentes do Observador , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
16.
Cancer Med ; 5(7): 1373-80, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27062713

RESUMO

Frozen section analysis (FS) during cancer surgery is widely used to assess resection margins. However, in hilar cholangiocarcinoma (HCCA), FS may be less reliable because of the specific growth characteristics of the tumor. The aim of this study was to determine the accuracy and consequences of intraoperative FS of the proximal bile duct margins in HCCA. Between 1990 and 2014, 67 patients underwent combined extrahepatic bile duct resection and partial liver resection for HCCA with the use of FS. Sensitivity and specificity of FS was 68% and 97%, respectively. Seventeen of 67 patients (25%) displayed a positive bile duct margin at FS. The false-negative rate was 16% (eight patients). Ten patients (15%) with a positive bile duct margin underwent an additional resection in an attempt to achieve negative margins, which succeeded in three patients (4%). However, only one of these three patients did not have concomitant lymph node metastases, which are associated with a poor prognosis by itself. The use of FS of the proximal bile duct is of limited clinical value because of the relatively low sensitivity, high risk of false-negative results, and the low rate of secondary obtained tumor-free resection margins. Supported by the literature, a new approach to the use of FS in HCCA should be adopted, reserving the technique only for cases in which a substantial additional resection is possible.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Ductos Biliares Extra-Hepáticos/patologia , Secções Congeladas , Tumor de Klatskin/diagnóstico , Idoso , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Biópsia , Feminino , Secções Congeladas/métodos , Hepatectomia , Mortalidade Hospitalar , Humanos , Período Intraoperatório , Tumor de Klatskin/mortalidade , Tumor de Klatskin/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos Testes
17.
Liver Int ; 36(9): 1362-9, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26849025

RESUMO

BACKGROUND & AIMS: The significance of bile duct injury and ductular reaction in biopsies from autoimmune hepatitis patients is not clear. We aim to establish the prevalence and clinical relevance of both phenomena in autoimmune hepatitis. METHODS: Cases of newly diagnosed, untreated autoimmune hepatitis without overlap syndrome were selected. Pretreatment and follow up biopsies were scored for inflammation, fibrosis, bile ductal injury and ductular reaction. RESULTS: Thirty-five cases were studied of whom 14 cases had follow up biopsies. Bile duct injury was present in 29 cases (83%), mostly in a PBC-like pattern and was not correlated with demographical or laboratory findings. Ductular reaction, observed in 25 of 35 cases (71%) using conventional histology and in 30 of 32 cases (94%) using immunohistochemistry, was correlated with portal and lobular inflammation, interface hepatitis and centrilobular necrosis as well as bile duct injury and fibrosis. In 11 of 14 cases (79%) ductular reaction remained present on post-treatment biopsy whereas bile duct injury persisted in six of 14 (43%) of cases. CONCLUSIONS: Bile duct injury and ductular reaction are very common in newly diagnosed autoimmune hepatitis and cannot be predicted biochemically. Bile duct injury may subside in the majority of treated AIH cases while DR tends to persist during follow up. These findings show that the two phenomena are part of the spectrum of AIH with dissimilar responses to treatment and do not necessarily point towards an overlap syndrome. Persistence of ductular reaction after treatment supports the notion that it represents a regenerative response.


Assuntos
Ductos Biliares/patologia , Hepatite Autoimune/complicações , Cirrose Hepática Biliar/patologia , Fígado/patologia , Adolescente , Adulto , Idoso , Ductos Biliares/lesões , Biópsia , Feminino , Fibrose , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Necrose/patologia , Países Baixos , Estudos Retrospectivos , Adulto Jovem
18.
Transplantation ; 100(4): 825-35, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26863473

RESUMO

BACKGROUND: The mechanism through which oxygenated hypothermic machine perfusion (HMP) improves viability of human extended criteria donor (ECD) livers is not well known. Aim of this study was to examine the benefits of oxygenated HMP after static cold storage (SCS). METHODS: Eighteen ECD livers that were declined for transplantation underwent ex situ viability testing using normothermic (37 °C) machine perfusion (NMP) after traditional SCS (0 °C-4 °C) for 7 to 9 hours. In the intervention group (n = 6), livers underwent 2 hours of oxygenated HMP (at 12 °C) after SCS and before NMP. Twelve control livers underwent NMP without oxygenated HMP after SCS. RESULTS: During HMP, hepatic ATP content increased greater than 15-fold, and levels remained significantly higher during the first 4 hours of NMP in the HMP group, compared with controls. Cumulative bile production and biliary secretion of bilirubin and bicarbonate were significantly higher after HMP, compared with controls. In addition, the levels of lactate and glucose were less elevated after HMP compared with SCS preservation alone. In contrast, there were no differences in levels of hepatobiliary injury markers AST, ALT, LDH, and gamma-GT after 6 hours of NMP. Hepatic histology at baseline and after 6 hours of NMP revealed no differences in the amount of ischemic necrosis between both groups. CONCLUSIONS: Two hours of oxygenated HMP after traditional SCS restores hepatic ATP levels and improves hepatobiliary function but does not reduce (preexisting) hepatobiliary injury in ECD livers.


Assuntos
Isquemia Fria , Seleção do Doador , Hipotermia Induzida , Transplante de Fígado/métodos , Fígado/cirurgia , Oxigênio/farmacologia , Perfusão/métodos , Doadores de Tecidos/provisão & distribução , Trifosfato de Adenosina/metabolismo , Idoso , Bicarbonatos/metabolismo , Bile/metabolismo , Bilirrubina/metabolismo , Biomarcadores/metabolismo , Isquemia Fria/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Fígado/enzimologia , Fígado/patologia , Fígado/fisiopatologia , Testes de Função Hepática , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Necrose , Consumo de Oxigênio/efeitos dos fármacos , Fatores de Tempo , Sobrevivência de Tecidos
20.
Ann Surg Oncol ; 22 Suppl 3: S1107-15, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26178761

RESUMO

BACKGROUND: Lymph node metastases on routine histology are a strong negative predictor for survival after resection of hilar cholangiocarcinoma. Additional immunohistochemistry can detect lymph node micrometastases in patients who are otherwise node negative, but the prognostic value is unsure. The objective of this study was to assess the effect on survival of immunohistochemically detected lymph node micrometastases in patients with node-negative (pN0) hilar cholangiocarcinoma on routine histology. METHODS: Between 1990 and 2010, a total of 146 patients underwent curative-intent resection of hilar cholangiocarcinoma with regional lymphadenectomy at two university medical centers in the Netherlands. Ninety-one patients (62 %) without lymph node metastases at routine histology were included. Micrometastases were identified by multiple sectioning of all lymph nodes and additional immunostaining with an antibody against cytokeratin 19 (K19). The association with overall survival was assessed in univariable and multivariable analysis. Median follow-up was 48 months. RESULTS: Micrometastases were identified in 16 (5 %) of 324 lymph nodes, corresponding to 11 (12 %) of 91 patients. There were no differences in clinical variables between K19 lymph node-positive and -negative patients. Five-year survival rates in patients with lymph node micrometastases were significantly lower compared to patients without micrometastases (27 vs. 54 %, P = 0.01). Multivariable analysis confirmed micrometastases as an independent prognostic factor for survival (adjusted Hazard ratio 2.4, P = 0.02). CONCLUSIONS: Lymph node micrometastases are associated with worse survival after resection of hilar cholangiocarcinoma. Immunohistochemical detection of lymph node micrometastases leads to better staging of patients who were initially diagnosed with node-negative (pN0) hilar cholangiocarcinoma on routine histology.


Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/mortalidade , Linfonodos/patologia , Recidiva Local de Neoplasia/mortalidade , Adulto , Idoso , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/secundário , Ductos Biliares Intra-Hepáticos/metabolismo , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Linfonodos/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida
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