Diagnosis and treatment of acute graft-versus-host disease after liver transplantation: A report of 11cases.

OBJECTIVE: This study aims to summarize a clinical experience on the diagnosis and treatment of acute graft-versus-host disease (aGVHD) after liver transplantation. METHODS: Between April 2005 and August 2016, 11 recipients who underwent OLT developed aGVHD with clinical symptoms of fever, rash, diarrhea and pancytopenia. T lymphocyte chimerism was detected though STR-PCR. These patients were treated with immunosuppressant adjustment, methylprednisolone, basiliximab, etc. All the results were recorded and summarized. RESULTS: We demonstrated the diagnostic criteria of aGVHD based on our experiences: 1 aGVHD occurred from two weeks to two months after the liver transplantation. Fever, rash, digestive tract symptoms and bone marrow suppression were the four symptoms that appeared in any orde, All the percentages of donor T lymphocytes of aGVHD patients were more than 10%. All 11 recipients underwent treatments including immunosuppressant adjustment, glucocorticoids, IVIG and organ function support. Among these recipients, two survived due to successful treatment, while nine recipients died due to infection and cerebral and digestive tract hemorrhage. It is noteworthy that the occurrence of aGVHD was related to the dose of immunosuppressive agents, and we suggest the concept of "aGVHD induced by immunosuppression". CONCLUSIONS: The diagnostic criteria of aGVHD is mainly based on time, clinical symptoms, T-lymphocyte chimerism and histopathology. The concept of "aGVHD induced by immunosuppression" provides important guidance in immunosuppressant management, control, and prevention of infection. Support treatment is very important in the treatment of aGVHD.

Splenectomy with Portoazygous Disconnection for Correction of Systemic Hemodynamic Disorders in Hepatic Cirrhosis Patients with Portal Hypertension: A Prospective Single-Center Cohort Study.

Objective: To investigate the effect of splenectomy for correction of systemic hemodynamic disorders in hepatic cirrhosis patients with portal hypertension. Methods: Hepatic cirrhosis patients with portal hypertension were enrolled from April 2015 to July 2018. Systemic hemodynamic parameters (heart rate, mean arterial pressure (MAP), cardiac output, and total peripheral vascular resistance (TPR)) were prospectively measured at baseline and 1 week, 1, 3, and 6 months, and 1, 2, and 3 years postoperatively. Paired analysis was conducted. Results: Sixty-nine patients were eligible, and 55 (79.7%) cases had a history of upper gastrointestinal bleeding. Child-Pugh classification was grade A in 41 (59.4%) cases, grade B in 26 (37.7%) cases, and grade C in 2 (2.9%) cases. The heart rate was significantly higher at 1 week postoperatively versus the baseline (P < 0.001). Meanwhile, the heart rate was significantly lower from 3 months to 2 years postoperatively versus the baseline (P < 0.05). The MAP was significantly higher at 6 months to 2 years postoperatively versus the baseline (P < 0.05). At 1 month postoperatively and 6 months to 2 years, the cardiac output was significantly lower versus the baseline (P < 0.05). At 1 month postoperatively and 6 months to 2 years, the TPR was significantly higher versus the baseline (P < 0.05). Conclusion: Splenectomy corrects systemic hemodynamic disorder in hepatic cirrhosis patients with portal hypertension, and the effect is rapid and durable.

Long-term consequences of stopping HBIG and/or nucleotide analogues in liver transplant recipients administered hepatitis B vaccination to prevent HBV reinfection.

BACKGROUND: The long-term administration of nucleotide analogues (NAs) and hepatitis B immune globulin (HBIG) comprises standard prophylaxis for patients with hepatitis B virus (HBV)-related liver diseases to prevent HBV reinfection after liver transplantation (LT). However, prolonging the prophylaxis strategy involves safety issues, such as the development of escape mutations and/or emerging resistant strains, and is also associated with high costs; further, it remains unclear how long prophylactic treatment should be continued. METHOD: Liver transplantation recipients responding to hepatitis B vaccination due to HBV-related liver diseases were retrospectively analysed after stopping HBIG and/or NAs, administered to prevent HBV reinfection, after long-term follow-up. The safety and effectiveness of the strategy were then evaluated for these responders. RESULT: Seventy-eight responders were enrolled. All responders discontinued HBIG, among which 36 stopped both HBIG and NAs. During follow-up, four recipients experienced HBV reinfection, which was associated with HBV escape mutations, after the withdrawal of both HBIG and NAs. No death or graft loss occurred in recipients during the follow-up period. CONCLUSION: A careful withdrawal of HBIG and/or NAs is feasible and safe for responders to hepatitis B vaccination receiving transplants for HBV-related liver diseases.

The Effect of Splenectomy on the Reversal of Cirrhosis: a Prospective Study.

BACKGROUND: Studies have demonstrated that liver fibrosis can be reversed by medication treatments. After splenectomy, cirrhosis patients have short-term changes in several serum markers for cirrhosis and liver stiffness. AIMS: To investigate the effect of splenectomy on the severity of cirrhosis. METHODS: A total of 62 patients with cirrhosis and portal hypertension receiving splenectomy from December 2014 to July 2017 were enrolled. The degree of cirrhosis was preoperatively and postoperatively evaluated by serum markers, including hyaluronan (HA), laminin, amino-terminal propeptide of type III procollagen (PIIINP), type IV collagen (C-IV), liver stiffness (FibroScan), and liver volume. RESULTS: HA levels significantly increased at 1 week and 1 month postoperation (both P < 0.05), whereas the levels of PIIINP and C-IV significantly decreased from 1 month to 12 months postoperation (all P < 0.05). In addition, elastography examination demonstrated that the FibroScan score significantly reduced from 1 month to 24 months postoperation as compared with the baseline level (all P < 0.05). CT scan showed that the liver volume significantly increased at 6 months postoperation (P < 0.05). Furthermore, the alteration trends of these serum markers and the FibroScan score were further confirmed by the multivariate linear regression. CONCLUSIONS: These observations suggested that splenectomy may result in long-term reversal of cirrhosis.

Short-term effects of splenectomy on serum fibrosis indexes in liver cirrhosis patients.

OBJECTIVE: To determine the changing patterns of 4 liver fibrosis markers pre and post splenectomy (combined with pericardial devascularization [PCDV]) and to examine the short-term effects of splenectomy on liver fibrosis. METHODS: Four liver fibrosis markers of 39 liver cirrhosis patients were examined pre, immediately post, 2 days post, and 1 week post (15 cases) splenectomy (combined with PCDV). RESULTS: The laminin (LN) level decreased immediately post surgery compared with the preoperative LN level (P < 0.05). The type IV collagen level decreased immediately post surgery compared with that pre surgery (P < 0.05), it significantly increased (P < 0.05) 2 days post surgery and significantly decreased 1 week post surgery (P < 0.05). Hyaluronic acid and the procollagen III N-terminal peptide levels increased significantly 2 days post surgery compared with that pre and immediately post surgery, they significantly decreased 1 week post surgery compared to 2 days post surgery (P < 0.05). CONCLUSIONS: In the short-term, the 4 liver fibrosis markers and the FibroScans post splenectomy showed characteristic changes, splenectomy may transiently initiate the degradation process of liver fibrosis.

[A retrospective cohort study regarding the effect of sirolimus-based immunosuppression protocol on the long-term survival of hepatocellular carcinoma patients after liver transplantation].

OBJECTIVE: To evaluate the influence of sirolimus on the long-term survival of patients after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). METHODS: Clinic data of 165 consecutive patients who underwent OLT for HCC from February 2005 to March 2012 was analyzed retrospectively. Among them, 94 patients were treated with a sirolimus-based immunosuppressive protocol after OLT, while the other 71 patients with a FK506-based protocol. Postoperative survival time, survival, disease-free survival (DFS) and tumor recurrence rates between the two groups were compared. RESULTS: The 2 groups were comparable in all clinicopathologic parameters. The sirolimus-based group had higher patient survival rates than the control group at 1-year (87% vs. 97%, P = 0.03), 2-year (80% vs. 88%), 3-year (76% vs. 85%) and 5-year (63% vs. 75%). The 1-year, 2-year, 3-year and 5-year recurrence rates were 12% vs. 3%, 17% vs. 9%, 21% vs. 9% (P = 0.04) and 31% vs. 16% (P = 0.03). Early and mid-HCC (I - II stage) of 131 cases (control group 61 cases, sirolimus-based group of 70 patients). The 1-year, 2-year, 3-year and 5-year survival rates were 90% vs. 97% , 80% vs. 90%, 78% vs. 86% and 65% vs. 82% (P = 0.04) and recurrence rates were 10% vs. 3%, 16% vs. 8%, 18% vs. 8% and 29% vs. 11% (P = 0.01). CONCLUSION: The sirolimus-based immunosuppressive protocol reduce long-term postoperative recurrence rate and improve the survival rate of patients after OLT for HCC significantly (especially early-mid HCC).

Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming.

Obtaining fully functional cell types is a major challenge for drug discovery and regenerative medicine. Currently, a fundamental solution to this key problem is still lacking. Here, we show that functional human induced hepatocytes (hiHeps) can be generated from fibroblasts by overexpressing the hepatic fate conversion factors HNF1A, HNF4A, and HNF6 along with the maturation factors ATF5, PROX1, and CEBPA. hiHeps express a spectrum of phase I and II drug-metabolizing enzymes and phase III drug transporters. Importantly, the metabolic activities of CYP3A4, CYP1A2, CYP2B6, CYP2C9, and CYP2C19 are comparable between hiHeps and freshly isolated primary human hepatocytes. Transplanted hiHeps repopulate up to 30% of the livers of Tet-uPA/Rag2(-/-)/γc(-/-) mice and secrete more than 300 µg/ml human ALBUMIN in vivo. Our data demonstrate that human hepatocytes with drug metabolic function can be generated by lineage reprogramming, thus providing a cell resource for pharmaceutical applications.

[The therapeutic mechanisms of sirolimus treatment for ischemic-type biliary lesions after liver transplantation].

OBJECTIVE: To investigate the pathogenesis of ischemic-type biliary lesions (ITBLs) in post-liver transplant patients and the possible therapeutic mechanisms of sirolimus. METHODS: The clinic data of 32 post-liver transplant patients with ITBLs from May 2004 to December 2010 was analyzed. There were including 25 male and 7 female patients with a median age of 46 years (ranging from 19 to 61 years). Patients were divided into those who received sirolimus (sirolimus group) and those who did not (control group). The expression of IL-2, FoxP3, and IL-10 in the portal area, liver function indexes, and bile duct injury score were assessed pre-ITBL, when ITBLs were identified, and after 6 months of sirolimus treatment. RESULTS: Compared with pre-ITBL optical density (OD) values, there was a significantly increase in IL-2 OD(0.138 ± 0.050 in control group and 0.141 ± 0.052 in sirolimus group), but not FoxP3 and IL-10 OD in both groups at the time ITBLs were diagnosed. After 6 months of treatment, the IL-2, FoxP3, and IL-10 OD values in the control group were not different from those when ITBLs were diagnosed. There was a significant reduction in post-therapy IL-2 OD(0.107 ± 0.043, t = 2.087, P = 0.044), and a significant elevation in FoxP3(0.213 ± 0.039) and IL-10 OD(0.187 ± 0.048) in sirolimus group as compared with those when ITBLs were diagnosed(t = -3.822 and -4.350, both P < 0.01). There was a significant increase in serum levels of ALT, AST, total bilirubin, γ-glutamyl transpeptidase and ALP at the time ITBLs were diagnosed compared with pre-ITBL levels in both groups. After 6 months of treatment, the above indexes had not changed in the control group, but significantly improved in the sirolimus group, and the bile duct injury score in the sirolimus group had significantly decreased(4.4 ± 2.4, Z = -2.568, P = 0.010). The 1-year and 3-year graft survival rates in the control group were 6/13 and 5/13, respectively, and 17/19 and 13/19, respectively, in the sirolimus group (χ(2) = 7.166, P = 0.007; χ(2) = 5.398, P = 0.020, respectively). CONCLUSIONS: Sirolimus can downregulate IL-2 expression and upregulate FoxP3 and IL-10 expression, thereby stimulating FoxP3+ Treg cells, suppressing immunopathological damage, and promoting epithelial repair in bile ducts.

Liver transplantation in acute-on-chronic liver failure patients with high model for end-stage liver disease (MELD) scores: a single center experience of 100 consecutive cases.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation (LT) is the only curative option. However, there are little published data on risk factors and outcomes of LT for ACLF. METHODS: The objective of this study was to analyze preoperative, intraoperative, postoperative, and overall survival data on 100 consecutive cases with ACLF in order to try to determine for which patients LT are futile. RESULTS: One hundred consecutive patients with pathology-confirmed ACLF who underwent LT from June 2004 to September 2012 were enrolled. The preoperative data showed that all patients were in a serious condition with a median high model for end-stage liver disease (MELD) score of 32, total bilirubin of 440.20 umol/L, international normalized ratio (INR) of 3.012, and at least one organ dysfunction as assessed by a Sequential Organ Failure Assessment (SOFA) score of ≥9. The patients had either deceased or a living donor LT with an overall mortality of 20%. The 1-, 3-, and 5-year cumulative survival rates were 76.8%, 75.6%, and 74.1%, respectively, and graft 1-, 3-, and 5-y accumulative survival rates were 73.3%, 72.1%, and 70.6%, respectively. However, the area under receiver operating characteristic of SOFA score, MELD score, as well as Child-Pugh score were 0.552, 0.547, and 0.547, respectively. CONCLUSIONS: Both deceased and living donor LT are effective therapeutic options for patients with ACLF and the short- and long-term survival rates are encouraging. It is important to conduct more prospective and multi-center studies to define preoperatively which patients would benefit from LT.

Anticoagulation therapy prevents portal-splenic vein thrombosis after splenectomy with gastroesophageal devascularization.

AIM: To compare the incidence of early portal or splenic vein thrombosis (PSVT) in patients treated with irregular and regular anticoagulantion after splenectomy with gastroesophageal devascularization. METHODS: We retrospectively analyzed 301 patients who underwent splenectomy with gastroesophageal devascularization for portal hypertension due to cirrhosis between April 2004 and July 2010. Patients were categorized into group A with irregular anticoagulation and group B with regular anticoagulation, respectively. Group A (153 patients) received anticoagulant monotherapy for an undesignated time period or with aspirin or warfarin without low-molecular-weight heparin (LMWH) irregularly. Group B (148 patients) received subcutaneous injection of LMWH routinely within the first 5 d after surgery, followed by oral warfarin and aspirin for one month regularly. The target prothrombin time/international normalized ratio (PT/INR) was 1.25-1.50. Platelet and PT/INR were monitored. Color Doppler imaging was performed to monitor PSVT as well as the effectiveness of thrombolytic therapy. RESULTS: The patients' data were collected and analyzed retrospectively. Among the patients, 94 developed early postoperative mural PSVT, including 63 patients in group A (63/153, 41.17%) and 31 patients in group B (31/148, 20.94%). There were 50 (32.67%) patients in group A and 27 (18.24%) in group B with mural PSVT in the main trunk of portal vein. After the administration of thrombolytic, anticoagulant and anti-aggregation therapy, complete or partial thrombus dissolution achieved in 50 (79.37%) in group A and 26 (83.87%) in group B. CONCLUSION: Regular anticoagulation therapy can reduce the incidence of PSVT in patients who undergo splenectomy with gastroesophageal devascularization, and regular anticoagulant therapy is safer and more effective than irregular anticoagulant therapy. Early and timely thrombolytic therapy is imperative and feasible for the prevention of PSVT.

(E)-4-(2-Chloro-benzyl-ideneamino)-3-(2-chloro-phen-yl)-1H-1,2,4-triazole-5(4H)-thione-(E)-1,5-bis-(2-chloro-benzyl-idene)thio-carbonohydrazide-methanol (1/1/1).

In the title compound, C(15)H(12)Cl(2)N(4)S·C(15)H(10)Cl(2)N(4)S·C(2)H(6)O, the two chloro-phenyl rings of the triazole derivative form dihedral angles of 65.7 (2) and 44.2 (2)° with the triazole ring. In the thio-carbonohydrazide derivative, the dihedral angle between the two chloro-phenyl rings is 5.4 (2)°. In the crystal, the triazole, thio-carbonohydrazide and methanol mol-ecules are linked by N-H⋯O, N-H⋯S and O-H⋯S hydrogen bonds, forming a hexa-meric unit.

1,5-Bis[(E)-cyclo-pentyl-idene]thio-carbono-hydrazide.

In the title mol-ecule, C(11)H(18)N(4)S, an intra-molecular N-H⋯N hydrogen bond [N⋯N = 2.558 (3)Å] is observed. The two cyclo-pentyl rings are disordered between two conformations in 1:1 and 2:1 ratios. In the crystal structure, weak inter-molecular N-H⋯S hydrogen bonds [N⋯S = 3.547 (3) Å] link pairs of mol-ecules into centrosymmetric dimers.

[Emergency right lobe adult-to-adult live-donor liver transplantation for the treatment of acute liver failure following severe hepatitis].

OBJECTIVE: To research the clinical feasibility of emergency right lobe adult-to-adult live-donor liver transplantation in treating acute liver failure following severe hepatitis. METHODS: Consecutive ten severe hepatitis patients (4 acute-on-chronic severe hepatitis and 6 acute severe hepatitis; 9 caused by HBV and 1 with drug-induced acute liver failure) underwent emergency right lobe adult-to-adult live-donor liver transplantation in our hospital from April 2007 to December 2007. The +/- s of model for end-stage liver disease score was 33.22 +/- 6.55. The outcomes of these recipients were prospectively analyzed. RESULTS: Among them, 8 ABO blood group were identical and 2 compatible. One was Rh sub-group negative. Except 2 recipients died (1 acute renal failure caused by veno cava thrombosis, 1 liver graft lose caused by hepatic artery thrombosis), the rest of recipients (80%) and all donors were safe. The mean graft-to-recipient weight ratio was (1.19 +/- 0.14)%, and graft volume to recipient estimated standard liver volume ratio was (65.13 +/- 8.75)%. Right lobe grafts with middle hepatic vein (MHV) 3 cases, without MHV 4 cases, without MHV but followed by V and VIII hepatic vein outflow reconstruction 3 cases. Encouraging outcome was achieved in this group of recipient: elevated serum creatinine, serum endotoxin, decreased serum prothrombin activity (PTA) and total bilirubin returned to normal about on postoperative day (POD) 3, POD 7, POD 14 and POD 28, respectively. CONCLUSIONS: Outcomes of emergency right lobe adult-to-adult live-donor liver transplantation for acute hepatic failure following severe hepatitis are fairly encouraging and acceptable. emergency right lobe adult-to-adult live-donor liver transplantation is an effective and life-saving modality for acute liver failure following severe hepatitis.

[Prophylaxsis against recurrance of hepatitis B virus after liver transplantation].

OBJECTIVE: To summarize the clinical data in preventing HBV recurrence after liver transplantation and explore a optimal individual protocol in prophylaxis of HBV recurrence. METHODS: We retrospected outcomes in 195 recipients who underwent a liver transplantation for HBV-related liver disease between June 2004 and July 2008. According to the anti-virus protocol these recipients are divided into two groups as following: group A received a protocol of combination treatment of lamivudine with HBIG, and group B with combination treatment of adefovir with HBIG. With mean follow-up of 23.7 months, HBV recurrent rate was observed in overall and each group separately. RESULTS: A total of 195 liver transplant recipients were identified that met the study criteria. At the sixth and eleventh month after operation, HBV recurrence appeared in 2 recipients, each in two groups, which were due to LAM cessation and HBV mutation respectively. Recurrent rate was 0.6% in group A, 3.7% in group B and 1% in total. There was no significant difference in HBV recurrent rate between group A and B. CONCLUSION: Lamivudine combined with HBIg should be considered as a reliable method in preventing HBV recurrence after liver transplantation. Better outcomes can be achieved by individual anti-virus protocol and HBIg administration according to HBV status in recipient.

[1,2-Bis(diisopropyl-phosphino)-1,2-dicarba-closo-dodeca-borane-κP,P']dichloridomercury(II).

In the title complex, [HgCl(2)(C(14)H(38)B(10)P(2))], the Hg(II) atom is in a distorted HgCl(2)P(2) tetra-hedral coordination environment. The chelation of the Hg atom by two P atoms and two C atoms from the carborane skeleton results in a nearly planar five-membered ring.