Lu-Nan Yan

Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis‐4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: A systemic review and meta‐analysis

The aspartate aminotransferase‐to‐platelet ratio index (APRI) and fibrosis index based on the four factors (Fibrosis 4 index; FIB‐4) are the two most widely studied noninvasive tools for assessing liver fibrosis. Our aims were to systematically review the performance of APRI and FIB‐4 in hepatitis B virus (HBV) infection in adult patients and compare their advantages and disadvantages. We examined the diagnostic accuracy of APRI and FIB‐4 for significant fibrosis, advanced fibrosis, and cirrhosis based on their sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUROC). Heterogeneity was explored using metaregression. Our systemic review and meta‐analysis included 16 articles of APRI only, 21 articles of APRI and FIB‐4 and two articles of FIB‐4 for detecting different levels of liver fibrosis. With an APRI threshold of 0.5, 1.0, and 1.5, the sensitivity and specificity values were 70.0% and 60.0%, 50.0% and 83.0%, and 36.9% and 92.5% for significant fibrosis, advanced fibrosis, and cirrhosis, respectively. With an FIB‐4 threshold of 1.45 and 3.25, the sensitivity and specificity values were 65.4% and 73.6% and 16.2% and 95.2% for significant fibrosis. The summary AUROC values using APRI and FIB‐4 for the diagnosis of significant fibrosis, advanced fibrosis, and cirrhosis were 0.7407 (95% confidence interval [CI]: 0.7033‐0.7781) and 0.7844 (95% CI: 0.7450‐0.8238; (Z = 1.59, P = 0.06), 0.7347 (95% CI: 0.6790‐0.7904) and 0.8165 (95% CI: 0.7707‐0.8623; Z = 2.01, P = 0.02), and 0.7268 (95% CI: 0.6578‐0.7958) and 0.8448 (95% CI: 0.7742‐0.9154; (Z = 2.34, P = 0.01), respectively. Conclusions: Our meta‐analysis suggests that APRI and FIB‐4 can identify hepatitis B‐related fibrosis with a moderate sensitivity and accuracy. (Hepatology 2015;61:292–302)

Prophylaxis Against Hepatitis B Recurrence Posttransplantation Using Lamivudine and Individualized Low-Dose Hepatitis B Immunoglobulin

Although the combination of lamivudine (LAM) and high‐dose intravenous (IV) hepatitis B immunoglobulin (HBIG) is very effective in preventing hepatitis B virus (HBV) recurrence after liver transplantation (LT), the major limitation of this regimen is its high cost. A more cost‐effective, convenient and widely accepted regimen is urgently needed. We evaluated the safety and efficacy of another strategy using LAM and individualized low‐dose intramuscular (IM) HBIG. Between May 2002 and December 2009, a total of 254 adult patients undergoing LT for HBV‐related benign end‐stage liver diseases received this regimen in our center. The mean follow‐up of these patients was 41.2 ± 22.7 months. Their 1‐, 3‐ and 5‐year survival rates were 85.3%, 77.4% and 76.4%, respectively, and 1‐, 3‐ and 5‐year HBV recurrence rates were 2.3%, 6.2% and 8.2%. Fourteen patients experienced posttransplant HBV recurrence. Pretransplant high viral load and posttransplant prednisone withdrawal time were observed to be associated with recurrence. In conclusion, combination therapy with LAM and individualized low‐dose IM HBIG provides a safe and effective prophylaxis against HBV recurrence after LT at about 5% of the cost of conventional high‐dose IV HBIG regimens.

Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats

Because the role of Kupffer cells (KCs) in liver transplantation (LT) tolerance is not well understood, we investigated their role in liver allograft acceptance in rats. Male Sprague‐Dawley rats were randomly assigned to either an LT group or a transplantation group pretreated with GdCl3 (Gd group). The rats were postoperatively sacrificed at indicated times for histology and assessment of KC function, nuclear factor kappa B (NF‐κB) activity, and cytokine production. KCs and T cells (TCs) were isolated from allografts to assess Fas/Fas ligand (FasL) expression. Cytotoxicity of KCs against TCs was monitored by coculturing of 3H‐thymidine TCs with KCs at various effector‐to‐target ratios. The results were as follows. First, grafts were spontaneously accepted in the LT group with evident apoptosis of TCs; however, inhibition of KCs by pretreatment with GdCl3 decreased TC apoptosis and shortened the survival of allografts. Second, KCs in the LT group had increased levels of FasL messenger RNA and protein with respect to that in the Gd group. Third, by in vitro cocultivation assays, KCs induced TC apoptosis though elevated expression of FasL, and this process could be blocked by anti‐FasL antibody. Fourth, there was a positive correlation between activation of NF‐κB and FasL expression in KCs and interleukin‐4 production in the LT group, and the activation of NF‐κB was inhibited by pretreatment with GdCl3. In conclusion, KC‐induced depletion of TCs via the Fas/FasL pathway might play a critical role in LT tolerance. However, the tolerance is abrogated by suppression of FasL and IL‐4 expression via inhibition of NF‐κB activity by GdCl3. Liver Transpl 14:823–836, 2008.

Up-Regulation of IRAK-M is Essential for Endotoxin Tolerance Induced by a Low Dose of Lipopolysaccharide in Kupffer Cells

BACKGROUND Endotoxin tolerance (ET) is an important mechanism to maintain the homeostasis of Kupffer cells (KCs), because KCs are continually exposed to various pathogen-associated molecular patterns including lipopolysaccharide (LPS). ET involves multiple changes in cell signal transduction pathways; however, not all signaling pathways are down-regulated and some proteins are up-regulated. The latter proteins may be counter regulatory, including interleukin-1 receptor-associated kinase M (IRAK-M) expression. The aim of this study is to clarify weather or not IRAK-M is involved in the mechanisms of ET in KCs through dampening nuclear factor-kappa B (NF-kappaB) mediated pathway. MATERIALS AND METHODS KCs isolated from male C57BL/6J mice were seeded in 24-well plates at 1 x 10(6) cells/well and cultured overnight prior to transfection, were randomly divided into two groups: the pIRAK-M-short hairpin RNA (shRNA) group (transfected with IRAK-M shRNA) and the control group (transfected with control vector); 24 h after transfection, the two groups were further randomly divided into two subgroups: non-endotoxin pretreatment group (incubation in Dulbeccos modified Eagles medium [Invitrogen, Carlsbad, CA] with 10% fetal bovine serum) and endotoxin pretreatment group (incubation in the same medium containing 10 ng/mL LPS), named pIRAK-M-EP, pIRAK-M-NEP, pCV-EP, and pCV-NEP, respectively. Each subgroup contained 6 wells; 24 h later, fresh media containing LPS (100 ng/mL) was added to each subgroup and incubated for an additional 3 h. The expression of IRAK-M gene and protein level were determined by reverse transcription-polymerase chain reaction and Western blot, the activities of NF-kappaB were estimated by electrophoretic mobility shift assay and enzyme-linked immunosorbent assay, and the supernatant tumor necrosis factor-alpha levels were analyzed by enzyme-linked immunosorbent assay. RESULTS The recombinant plasmid of pIRAK-M-shRNA specifically inhibited IRAK-M expression after it was transfected into KCs. At 3 h after 100 ng/mL LPS was added to the medium, IRAK-M expression was significantly induced in pCV-EP than that in pCV-NEP; however, there was no difference between pIRAK-M-NEP and pIRAK-M-EP, accompanied with lowest level of NF-kappaB activation and tumor necrosis factor-alpha levels in pCV-EP, and a dramatic enhancement in the other three groups (P < 0.01). CONCLUSIONS Although a primary low dose of LPS stimulation obviously attenuated KCs response to the second LPS stimulation, the inhibitive influences were partly refracted in pIRAK-M-EP than in pCV-EP, indicating that the absence of IRAK-M caused abnormal enhancement of inflammatory effects. IRAK-M negatively regulates toll-like receptors signaling and involves in the mechanisms of ET in KCs through dampening NF-kappaB mediated pathway; therefore it may be a key component of this important control system, and a new target for the clinical treatment of sepsis.

A Miniaturized Dual-band Power Divider with Harmonic Suppression for Gsm Applications

In this paper, a miniaturized dual-band power divider based on artificial transmission lines is proposed for GSM applications. The design consists of four sections of recently developed planar artificial transmission lines, an LC tank circuit in shunt, and an isolation resistor. The experimental results show that the proposed configuration has good performance at both 0.9 GHz and 1.8 GHz. Meanwhile, it achieves a significant size reduction compared to traditional dual-band planar power dividers. At the center frequency 1.35 GHz, the dimension of the proposed dual-band power divider is only 43 mm × 21 mm, or equivalently 0.29λg × 0.14λg. With the harmonic suppression nature of artificial transmission lines and the shunt LC tank, the wideband response of the proposed dual-band power divider reveals good harmonics suppression.

Analysis of infections in the first 3-month after living donor liver transplantation

AIM To identify factors related to serious postoperative bacterial and fungal infections in the first 3 mo after living donor liver transplantation (LDLT). METHODS In the present study, the data of 207 patients from 2004 to 2011 were reviewed. The pre-, intra- and post-operative factors were statistically analyzed. All transplantations were approved by the ethics committee of West China Hospital, Sichuan University. Patients with definitely preoperative infections and infections within 48 h after transplantation were excluded from current study. All potential risk factors were analyzed using univariate analyses. Factors significant at a P < 0.10 in the univariate analyses were involved in the multivariate analyses. The diagnostic accuracy of the identified risk factors was evaluated using receiver operating curve. RESULTS The serious bacterial and fungal infection rates were 14.01% and 4.35% respectively. Enterococcus faecium was the predominant bacterial pathogen, whereas Candida albicans was the most common fungal pathogen. Lung was the most common infection site for both bacterial and fungal infections. Recipient age older than 45 years, preoperative hyponatremia, intensive care unit stay longer than 9 d, postoperative bile leak and severe hyperglycemia were independent risk factors for postoperative bacterial infection. Massive red blood cells transfusion and postoperative bacterial infection may be related to postoperative fungal infection. CONCLUSION Predictive risk factors for bacterial and fungal infections were indentified in current study. Pre-, intra- and post-operative factors can cause postoperative bacterial and fungal infections after LDLT.

Living donor liver transplantation for Budd‐Chiari syndrome using cryopreserved vena cava graft in retrohepatic vena cava reconstruction

Objective To report the authors experience with the first case of an adult-to-adult living donor liver transplantation (LDLT) for Budd-Chiari syndrome (BCS) using cryopreserved vena cava graft in postheptic vena cava reconstruction. Methods A 35-year-old male patient with a diagnosis of BCS complicated with inferior vena cava (IVC) obstruction received medical treatment and radiologic intervention for nine months, no relief of the symptoms could be achieved. Finally, the patient underwent LDLT, which required posthepatic vena cava reconstructed using cryopreserved vena cava graft. Results The patient has had an uneventful course since the LDLT. Conclusion We believe that LDLT combined with posthepatic IVC reconstruction using cryopreserved vena cava graft is considered to be a sound modality for IVC obstructed BCS.

Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: A meta‐analysis

Many noninvasive methods for diagnosing liver fibrosis (LF) have been proposed. To determine the best method for diagnosing LF in nonalcoholic fatty liver disease (NAFLD), we conducted a systemic review and meta‐analysis to compare the performance of aspartate aminotransferase to platelets ratio index (APRI), fibrosis‐4 index (FIB‐4), BARD score, NAFLD fibrosis score (NFS), FibroScan, shear wave elastography (SWE), and magnetic resonance elastography (MRE) for diagnosing LF in NAFLD. We compared the sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUROC) of these noninvasive methods for detecting significant fibrosis (SF), advanced fibrosis (AF), and cirrhosis. Heterogeneity was explored using meta‐regression. Sixty‐four articles with a total of 13,046 NAFLD subjects were included. The overall mean prevalence of SF, AF, and cirrhosis was 45.0%, 24.0%, and 9.4% in NAFLD patients, respectively. With an APRI threshold of 1.0 and 1.5, the sensitivities and specificities were 50.0% and 84.0% and 18.3% and 96.1%, respectively, for AF. With a FIB‐4 threshold of 2.67 and 3.25, the sensitivities and specificities were 26.6% and 96.5% and 31.8% and 96.0%, respectively, for AF. The summary sensitivities and specificities of BARD score (threshold of 2), NFS (threshold of −1.455), FibroScan M (threshold of 8.7‐9), SWE, and MRE for detecting AF were 0.76 and 0.61, 0.72 and 0.70, 0.87 and 0.79, 0.90 and 0.93, and 0.84 and 0.90, respectively. The summary AUROC values using APRI, FIB‐4, BARD score, NFS, FibroScan M probe, XL probe, SWE, and MRE for diagnosing AF were 0.77, 0.84, 0.76, 0.84, 0.88, 0.85, 0.95, and 0.96, respectively. Conclusion: MRE and SWE may have the highest diagnostic accuracy for staging fibrosis in NAFLD patients. Among the four noninvasive simple indexes, NFS and FIB‐4 probably offer the best diagnostic performance for detecting AF. (Hepatology 2017;66:1486–1501).

Value of α-fetoprotein in association with clinicopathological features of hepatocellular carcinoma

AIM To explore the relationship between α-fetoprotein (AFP) and various clinicopathological variables and different staging system of hepatocellular carcinoma (HCC) thoroughly. METHODS A retrospective cohort study of consecutive patients diagnosed with HCC between January 2008 and December 2009 in West China Hospital was enrolled in our study. The association of serum AFP values with the HCC clinicopathological features was analysed by univariate and multivariate analysis, such as status of hepatitis B virus (HBV) infection, tumor size, tumor number, vascular invasion and degree of tumor differentiation. Also, patients were divided into four groups at the time of enrollment according to different cutoff values for serum value of AFP (≤ 20 μg/L, 21-400 μg/L, 401-800 μg/L, and ≥ 801 μg/L), to compare the positive rate of patient among four groups stratified by various clinicopathological variables. And the correlation of different kinds of tumor staging systems, such as TNM, Barcelona Clinic Liver Cancer (BCLC) staging classification and China staging, were compared with the serum concentration of AFP. RESULTS A total of 2304 HCC patients were enrolled in this study totally; the mean serum level of AFP was 555.3 ± 546.6 μg/L. AFP levels were within the normal range (< 20 μg/L) in 27.4% (n = 631) of all the cases. 81.4% (n = 1875) patients were infected with HBV, and those patients had much higher serum AFP level compared with non-HBV infection ones (573.9 ± 547.7 μg/L vs 398.4 ± 522.3 μg/L, P < 0.001). The AFP level in tumors ≥ 10 cm (808.4 ± 529.2 μg/L) was significantly higher (P < 0.001) than those with tumor size 5-10 cm (499.5 ± 536.4 μg/L) and with tumor size ≤ 5 cm (444.9 ± 514.2 μg/L). AFP levels increased significantly in patients with vascular invasion (694.1 ± 546.9 μg/L vs 502.1 ± 543.1 μg/L, P < 0.001). Patients with low tumor cell differentiation (559.2 ± 545.7 μg/L) had the significantly (P = 0.007) highest AFP level compared with high differentiation (207.3 ± 420.8 μg/L) and intermediate differentiation (527.9 ± 538.4 μg/L). In the multiple variables analysis, low tumor cell differentiation [OR 6.362, 95%CI: 2.891-15.382, P = 0.006] and tumor size (≥ 10 cm) (OR 5.215, 95%CI: 1.426-13.151, P = 0.012) were independent predictors of elevated AFP concentrations (AFP > 400 μg/L). Serum AFP levels differed significantly (P < 0.001) in the D stage of BCLC (625.7 ± 529.8 μg/L) compared with stage A (506.2 ± 537.4 μg/L) and B (590.1 ± 551.1 μg/L). CONCLUSION HCC differentiation, size and vascular invasion have strong relationships with AFP, poor differentiation and HCC size ≥ 10 cm are independent predictors of elevated AFP. BCLC shows better relationship with AFP.

The clinicopathological features of intraductal papillary neoplasms of the bile duct in a Chinese population

BACKGROUND Intraductal papillary neoplasms of the bile duct have been applied to certain types of papillary tumours occurring in the biliary tract. Although many cases have been sporadically reported, there remain controversies. AIMS To analyze the clinicopathologic characteristics and long-term survival of intraductal papillary neoplasms of the bile duct. METHODS The clinicopathologic data of 52 patients who underwent surgery for intraductal papillary neoplasms of the bile duct were retrospectively evaluated. RESULTS In our series, tumours located in intrahepatic and hilar bile duct, rather than in extrahepatic bile duct, were more commonly diagnosed as adenomas or borderline tumours (12/19 and 7/13 vs 6/20; P=0.046). And the gastric type was more commonly associated with adenomas or borderline tumour (85.7%), whilst the pancreaticobiliary type mainly comprised of noninvasive carcinoma or invasive carcinoma (93.8%). However, only the types of treatment (median survival: curative resection: 72 months and palliative groups: 12 months; P<0.001) and histologic grades (adenoma or borderline malignancy vs noninvasive carcinoma: P=0.018) were significantly associated with survival. CONCLUSION Intraductal papillary neoplasms of the bile duct are rare type of biliary neoplasms, long-term survival may be achieved with complete resection. However, further studies are needed to clarify the relationship between these variables like location, cellular types and histologic grades.