Sorafenib eventually induced essential tumor-directed NK cell killing. Given that sorafenib increases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by MCL-1 suppression34 one may speculate that sorafenib could also sensitize tumor cells for NK cell activity.18 Finally, sorafenib triggered IFN-γ Regorafenib secretion of NK cells,35 which prevents Mϕ polarization by mitigating CSF-136 or IL437 signal transduction. IFN-γ secretion may therefore enhance pattern recognition by Mϕ38 or

could ameliorate their antiinflammatory IL1 receptor antagonist and IL10 expression.39, 40 Taken together, sorafenib primes proinflammatory responses of macrophages located within the HCC microenvironment and

perpetuates cytotoxic NK cell activity. This provides an additional mechanism of how tyrosine kinase inhibitors could elicit anticancer effects and may provide new insights for immune stimulatory treatments. We thank Ruth Hillermann, Lynette Henkel, and Daniel Kull for excellent technical assistance, Melissa Schlitter and Norbert Hüser for tissue preparation. We are grateful to Frank Chisari for providing mouse strain HBV1.3.32. Additional Supporting Information may be found in the online version of this article. “
“It was commonly accepted that chemotherapeutic cytotoxicity was the main cause for hepatic www.selleckchem.com/products/Lapatinib-Ditosylate.html failure in Hepatocellular carcinoma (HCC) patients after repeated transarterial chemoembolization (TACE). However, the effect of embolization-induced hypoxia on liver cirrhosis has rarely been concerned. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (ALB) were used to detect liver injury. Hepatic artery ligation (HAL) was performed in carbon tetrachloride (CCl4)-induced rat hepatic fibrosis model to mimic the effect of hepatic hypoxia on liver fibrosis after TACE. Sirius Red staining and immunohistochemical (IHC) analysis of alpha-smooth muscle actin (α-SMA) were used to detect the activation of hepatic stellate cells (HSCs). Moreover, the expression of Hypoxia and

fibrosis related molecules were analyzed at protein and/or mRNA level. patients showed MCE a significant increase in ALT and AST (P=0.006), accompanied by a decrease in ALB (P=0.005) after repeated TACE. HAL significantly promoted CCl4-induced rat liver fibrosis progression as indicated by Sirius Red and α-SMA staining, as well as increased expression of HIF-1α, TGF-β1 and VEGF. Conditioned media of hypoxia-treated L02 cells induced the expression of Collagen I and α-SMA in LX-2 cells, which was inhibited by HIF-1α small interfering RNA (siRNA). Finally, HIF-1α inhibitor LW6 attenuated the hypoxia-induced fibrosis progression in vivo. Our data demonstrate that TACE-induced hepatic hypoxia aggravates the fibrosis progression in peritumoral liver tissue, thus leads to the deterioration of liver function.

The purified virus particles from LEE011 fraction 3 were then subjected to western blot for CD59 detection. Two CD59 blockers, BRIC229 and rILYd4, were used in the current study to abrogate CD59 function. BRIC229, a mouse antihuman CD59 monoclonal Ab (mAb) (IBGRL, Bristol, UK), is a widely used CD59-blocking Ab, whereas rILYd4 is a recombinant form of the fourth domain of intermedilysin (ILY), and has been identified as a high-affinity inhibitor of human CD59.6 Microplates were coated with rabbit antihuman CD59 polyclonal Abs (pAbs, Santa Cruz, Santa Cruz,

CA) or control IgG at 1 μg/mL in phosphate-buffered saline (PBS) overnight at 4°C. After washing and blocking, plates were used for CD59 measurement or HCV capture. To measure CD59 levels, the wells were incubated with Triton

X-100-pretreated supernatant from JFH-1-infected or uninfected Huh7.5.1 cells (100 μL/well) at 37°C for 1 hour. After incubation and washing, the bound CD59 was detected Selleck PS 341 by incubating with BRIC229 or control IgG, followed by incubating with HRP-labeled secondary Ab. Cell-free supernatant samples containing HIV-1 particles from two HIV-1-infected human monocytic cell lines, THP-1 (CD59-positive) and U1 (CD59-negative), were used as positive and negative controls, respectively, as HIV-1 particles derived from CD59-expressing THP-1 cells contain CD59, whereas HIV-1 particles derived from CD59-deficient U1 cells are CD59-negative.6 Cell-free supernatant from Ad5 (adenovirus serotype 5)-infected MCE公司 Huh7.5.1 cells were also included in the ELISA detection to rule out the possibility of cell-derived CD59. Ad5, a nonenveloped (naked) DNA virus, causes cytolytic infection and has no Env for CD59 incorporation. Therefore, any CD59 detected in these supernatant samples would be derived from dead cells and cell debris due to Ad5 cytolytic infection rather than Ad5 virions. To detect HCV capture, the wells were incubated with untreated cell-free supernatant from JFH-1-infected, uninfected Huh7.5.1 cells (100 μL/well), or purified virus fraction 3 at 37°C for 1 hour.

After incubation, free virus was removed by washing with PBS, and the remaining bound HCV was lysed with 200 μL of TRIzol (Invitrogen) for isolation of viral RNA, which was subjected to qPCR for measuring HCV RNA copy numbers as described in our Supporting Material. Cell-free supernatant samples from HIV-1-infected and uninfected THP-1 cells were used as positive and negative controls, respectively, as antihuman CD59 Abs have been reported to efficiently capture intact HIV-1 virions.5 PHHs and Huh7.5.1 cells treated or untreated with PI-PLC were lysed in 1× cell lysis buffer (Cell Signaling Technology, Danvers, MA), and then subjected to protein extraction and western blot as described in our Supporting Material. HCV particles purified from cell-free supernatant of JFH-1-infected Huh7.5.

It was shown previously that ethanol could

also increase CYP2E1 within mitochondria, although to a much smaller extent than in the microsomes.38 Alternatively, glutathione peroxidase might be the major enzyme responsible for the elimination of mitochondrial ROS. Glutathione peroxidase and glutathione homeostasis in mitochondria have been shown to be important for prevention of ethanol-induced oxidative injury PD-0332991 order in the liver.4, 33 We did not detect Prx IV-SO2 in the liver of ethanol-fed Srx−/− mice. Prx IV is a luminal ER protein, and, given that thioredoxin is not present inside the ER, Prx IV does not function as a peroxidase in this organelle but rather serves as a peroxide sensor for other proteins.37 It is thus possible that ROS produced by CYP2E1 are rapidly removed by Prx I before they can cross the ER membrane. Together, our results suggest that, among the 2-Cys Prxs, Prx

I is largely responsible for the reduction of ROS generated in the liver in response to ethanol exposure because of its proximity to CYP2E1. Prx I molecules are thus converted to the inactive, sulfinylated form (Prx I-SO2). Reactivation of such hyperoxidized Prx I requires the action of Srx, the expression of which is greatly increased in the liver of ethanol-fed mice. The pivotal roles of Srx and Prx I in protection of the liver against ethanol-induced oxidative stress were apparent in Srx−/− and Prx I−/− mice. Subjection of such mice to chronic ethanol feeding thus resulted in more severe oxidative damage to the liver, as revealed by carbonylation AZD2281 cost of soluble proteins

and by the formation of 4-HNE and 3-NT adducts in the centrilobular regions, compared with that observed in ethanol-fed wildtype mice. Additional supporting information may be found MCE公司 in the online version of this article. “
“Potential curative therapies for hepatocellular carcinoma (HCC) include orthotopic liver transplantation, resection, and radiofrequency ablation (RFA). The intent of other therapies is to prolong survival by increasing the time to tumor progression (TTP) while not incurring significant hepatic injury. Transarterial chemoembolization (TACE) and sorafenib are the proposed treatments for intermediate and advanced HCC based on the positive results of randomized controlled trials (RCTs).1-3 Transarterial radioembolization (TARE) has gained popularity; however, enthusiasm for the procedure has been tempered by a lack of randomized controlled data. BCLC, Barcelona Clinic Liver Cancer; CP, Child-Pugh; HCC, hepatocellular carcinoma; OS, overall survival; PVT, portal vein thrombosis; RCT, randomized controlled trial; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; TTP, time to tumor progression. TARE is a form of intra-arterial therapy that is mechanistically distinct from TACE.

Severe and uncontrollable

bleeding contributes to an increased morbidity and mortality among patients with MHA and inhibitors. Inhibitors are frequently provoked by intensive treatment with therapeutic FVIII concentrates for surgery or trauma [8-11]. A cohort study of 41 patients with MHA that received perioperative FVIII replacement reported a 186-fold (95% CI 25–1403) increased risk of inhibitor development for surgery as the reason for first intensive exposure [11]. This extremely high risk arose by the extreme contrasts in the analysis: the time period of 3 months post surgery was compared to all other periods of 3 months during the study. As patients with MHA need therapeutic FVIII concentrates infrequently and months may pass without any exposure to FVIII concentrate, this comparison overestimates the risk that is inflated tremendously. Time post surgery Alisertib clinical trial was compared to time periods without any exposure to FVIII concentrates at all! This teaches us Ivacaftor cell line that the analysis of clinical risk factors in MHA inhibitor development requires a thoughtful methodological approach. Efforts should be made to compare patient groups that have similar baseline likelihood to develop inhibitors and only differ in the single factor that is under investigation (e.g. FVIII treatment for surgery vs. FVIII treatment for other reasons). Especially the number of previous EDs in both groups should

be as similar as possible. The inhibitor

risk of continuous infusion has been the subject of intense debate, as inhibitors were frequently observed following intensive treatment administered by continuous infusion [10, 11]. Other studies could not confirm this association [9, 12]. A large cohort study analysing 1079 continuous infusions in 742 patients with haemophilia A (severe, moderate or mild) established that the absolute inhibitor risk was limited as only nine patients (1.2%) developed an inhibitor [58]. There are over 500 reported causative missense mutations for MHA reported in the Haemophilia 上海皓元 A database (http://hadb.org.uk/). In patients with missense mutations the presence of circulating endogenous FVIII protein maintains a state of immunological tolerance towards FVIII. Nevertheless, there are certain missense mutations that predispose to inhibitor development in MHA [7, 59, 60] that are clustered in the A2 domain and the C1–C2 domains, e.g. Arg593Cys, Asn618Ser, Asp274Gly, Arg2150His, Arg2159Cys, Trp2229Cys. These missense mutations may contribute to T-cell epitopes that can bind to common HLA-II types. Furthermore, it appears that a class switch in the amino acid substitution (from small/hydrophobic, neutral, acidic or basic to any other of these classes) increases the inhibitor risk, as was recently established in a study of 720 patients with haemophilia and missense mutations [61].

A GTR+I+G model was applied to each subset regardless of partitioning strategy. Phycas stepping-stone analyses involved 10,000 cycles of a single Markov chain for each of 21 beta values. An additional 20,000 cycles were added at the beginning (beta = 1) to ensure adequate parameterization find more of the reference distribution. The tree topology was constrained to the one

shown in Figure 2 for all stepping-stone analyses. The second-most complex partitioning scheme scored best, and therefore the data set was divided into 13 subsets: rDNA (18S, 5.8S, and 28S), and each protein-coding gene divided by codon position (rbcL 1st positions, rbcL 2nd positions, rbcL 3rd positions, tufA 1st positions, etc.). A maximum likelihood (ML) analysis was conducted on the partitioned (by gene and codon position) 7-gene data set using Garli v.2.0 (Zwickl 2006), with five independent searches

for the best tree and 100 bootstrap (BS) pseudoreplicates to estimate branch support. In addition to a combined partitioned analysis, each gene was analyzed separately using Phycas to assess phylogenetic signal coming from individual data subsets. In the cases of protein-coding genes, the data sets were partitioned by codon position. Similarly, phylogenetic signal from nuclear genes versus plastid genes was compared by analyzing these subsets of data separately, with plastid genes partitioned by gene and codon position. All Phycas analyses were run for 100,000 cycles with polytomies allowed, and the first 200 cycles were discarded as burn-in. Phycas scripts specifying settings and priors Maraviroc ic50 used are

provided in the supplementary 上海皓元 materials Appendix S1 in the Supporting Information. Because this is a study of taxa that have already proven difficult to place phylogenetically, we used Bayesian Concordance Analysis (BCA; Ané et al. 2007) to investigate the degree of phylogenetic concordance amongst the seven genes. Complete concordance means all genes share the same tree topology, while complete discordance means each gene evolved on a unique tree topology. Unlike other species tree approaches, BCA makes no assumptions about the underlying causes of discordance, using nonparametric Bayesian clustering to estimate the posterior distribution of gene-tree maps, which map each gene to a particular tree topology. BUCKy (Larget et al. 2010) was used to carry out BCA. BUCKy uses samples from the posterior distributions of single-gene analyses as input, but does not allow polytomies, so separate single-gene analyses (that did not consider polytomous trees) were performed in Phycas only for BCA. The newly characterized strains UTEX B2977, SAG 2265, BCP-ZNP1VF31, and UTEX B2979 resemble members of the genus Bracteacoccus morphologically (Fig. 1). Vegetative cells are spherical to somewhat irregular, and young cells (Fig.

A GTR+I+G model was applied to each subset regardless of partitioning strategy. Phycas stepping-stone analyses involved 10,000 cycles of a single Markov chain for each of 21 beta values. An additional 20,000 cycles were added at the beginning (beta = 1) to ensure adequate parameterization Wnt drug of the reference distribution. The tree topology was constrained to the one

shown in Figure 2 for all stepping-stone analyses. The second-most complex partitioning scheme scored best, and therefore the data set was divided into 13 subsets: rDNA (18S, 5.8S, and 28S), and each protein-coding gene divided by codon position (rbcL 1st positions, rbcL 2nd positions, rbcL 3rd positions, tufA 1st positions, etc.). A maximum likelihood (ML) analysis was conducted on the partitioned (by gene and codon position) 7-gene data set using Garli v.2.0 (Zwickl 2006), with five independent searches

for the best tree and 100 bootstrap (BS) pseudoreplicates to estimate branch support. In addition to a combined partitioned analysis, each gene was analyzed separately using Phycas to assess phylogenetic signal coming from individual data subsets. In the cases of protein-coding genes, the data sets were partitioned by codon position. Similarly, phylogenetic signal from nuclear genes versus plastid genes was compared by analyzing these subsets of data separately, with plastid genes partitioned by gene and codon position. All Phycas analyses were run for 100,000 cycles with polytomies allowed, and the first 200 cycles were discarded as burn-in. Phycas scripts specifying settings and priors RAD001 supplier used are

provided in the supplementary 上海皓元医药股份有限公司 materials Appendix S1 in the Supporting Information. Because this is a study of taxa that have already proven difficult to place phylogenetically, we used Bayesian Concordance Analysis (BCA; Ané et al. 2007) to investigate the degree of phylogenetic concordance amongst the seven genes. Complete concordance means all genes share the same tree topology, while complete discordance means each gene evolved on a unique tree topology. Unlike other species tree approaches, BCA makes no assumptions about the underlying causes of discordance, using nonparametric Bayesian clustering to estimate the posterior distribution of gene-tree maps, which map each gene to a particular tree topology. BUCKy (Larget et al. 2010) was used to carry out BCA. BUCKy uses samples from the posterior distributions of single-gene analyses as input, but does not allow polytomies, so separate single-gene analyses (that did not consider polytomous trees) were performed in Phycas only for BCA. The newly characterized strains UTEX B2977, SAG 2265, BCP-ZNP1VF31, and UTEX B2979 resemble members of the genus Bracteacoccus morphologically (Fig. 1). Vegetative cells are spherical to somewhat irregular, and young cells (Fig.

The authors are grateful to Asahi Kasei-Kuraray check details Medical and JIMRO for providing fine photos. Also, we should like to thank Dr Abbi R Saniabadi of

JIMRO for providing beautiful artwork for this contribution. The authors have no conflict of interest in connection with the publication of this manuscript. “
“People detained in prisons and other closed settings are at elevated risk of infection with hepatitis C virus (HCV). We undertook a systematic review and meta-analysis with the aim of determining the rate of incident HCV infection and the prevalence of anti-HCV among detainees in closed settings. We systematically searched databases of peer-reviewed literature and widely distributed a call for unpublished data. We calculated summary estimates of incidence and prevalence among general population detainees and detainees with a history of injection drug use (IDU), and explored heterogeneity through stratification and meta-regression. The summary prevalence estimates were used to estimate the number of anti-HCV positive prisoners globally.

HCV incidence among general detainees was 1.4 per 100 person-years (py; 95% confidence interval [CI]: 0.1, 2.7; k = 4), and 16.4 per 100 py (95% CI: 0.8, 32.1; k = 3) among detainees with a history of IDU. The summary prevalence estimate of anti-HCV in general detainees was 26% MCE公司 (95% CI: 23%, 29%; PD0325901 mouse k = 93), and in detainees with a history of IDU, 64% (95% CI: 58%, 70%; k = 51). The regions of highest prevalence were Central Asia (38%; 95% CI 32%, 43%; k = 1) and Australasia (35%; 95% CI: 28%, 43%; k = 9). We estimate that 2.2

million (range: 1.4-2.9 million) detainees globally are anti-HCV positive, with the largest populations in North America (668,500; range: 553,500-784,000) and East and Southeast Asia (638,000; range: 332,000-970,000). Conclusion: HCV is a significant concern in detained populations, with one in four detainees anti-HCV-positive. Epidemiological data on the extent of HCV infection in detained populations is lacking in many countries. Greater attention towards prevention, diagnosis, and treatment of HCV infection among detained populations is urgently required. (Hepatology 2013;58:1215–1224) An estimated 2%-3% of people are infected with the hepatitis C virus (HCV) globally.[1, 2] The primary routes of transmission are injection drug use (IDU) and, in developing countries, medical procedures using nonsterile syringes and needles.[3] Perhaps two-thirds of the approximately 16 million people who inject drugs are HCV antibody (anti-HCV)-positive.[4, 5] Prisons and other closed settings (i.e.

The following section, therefore, examines the classification accuracy of the Stroop scores at a range of cut-offs. Note that because the Interference score was not significantly different between groups for the ANOVA and ROC analyses, it will not

be included in this analysis. The relevant indices of classification accuracy are Sensitivity, False Positive Error Rate (FP rate), and LR (Gouvier, Hayes, & Smiroldo, 1998; Hennekens & Buring, 1987). Sensitivity represents the percentage of malingerers correctly classified (true positives). The FP rate reflects the proportion of non-malingerers selleck kinase inhibitor whose scores fell in the malingering range according to a specified cut-off. The LR indicates the likelihood that a score was produced by a malingerer relative to non-malingerers (sensitivity/FP rate). An LR value of 1.0 indicates that a given score does not differentiate between groups, whereas a higher LR value indicates a higher probability that the observed www.selleckchem.com/products/Maraviroc.html score was produced by a malingerer (Grimes & Schulz, 2005). LRs from 2 to 5, 5 to 10, and greater than 10 yield small, moderate, and large increases in the post-test probability, respectively (Grimes & Schulz,

2005). The LRs were calculated using only the mild TBI groups. The data for the moderate–severe TBI and mixed-diagnosis cases are presented for comparison. Clinical diagnoses other than CVA were combined into one group due to small individual sample sizes. As can be seen in Table 5, sensitivity ranged from 12% to 32% for WR, 12% to 24% for CR, and 0% to 24% for CWR at cut-off scores associated

with a 0% to 9% FP rate. LRs for cut-off scores associated with a 5% FP rate MCE were 6.32 (95% CI = 1.48–26.96) for WR, 3.79 (95% CI = 0.82–17.62) for CR, and 1.26 (95% CI = 0.19–8.52) for CWR. Although CWR did not differentiate between groups at a 5% FP rate, post-test probability was greater at cut-off scores associated with a 9% FP rate (LR = 2.53; 95% CI = 0.83–7.70). WR was most effective at differentiating MND and non-MND TBI patients, detecting 29% of MND patients when the cut-off (−47) is associated with a 5% FP rate. There was, however, a high FP rate (19%) associated with this cut-off in patients with CVA. Based on these data, the indicators provide small-to-moderate probability that a score reflects invalid performance, depending on the indicator used. The following section examines the classification accuracy of the three Stroop variables in combination, rather than individually. Joint classification accuracy was examined to (a) determine whether sensitivity is increased by using a combined set of the indicators and (b) ensure that FP error rates are not increased when using the indicators in combination. Based on the score distributions, cut-offs were established to correspond to FP rates of 0%, 5%, and 9%, and the number of hits at each FP rate was combined (i.e.

2 Thiopurine

methyltransferase (TPMT) level was normal (53 nmol/g, range 35-79). Subsequently she started azathioprine (AZA) 75 mg daily (1 mg/kg). Her ALT and IgG normalized 6 weeks later. Following prednisolone reduction to 10 mg, her ALT increased to 147 IU/L despite AZA compliance. Forty milligrams prednisolone was reinstituted. On tapering to 10 mg she developed persistently fluctuating ALT (40-80 IU/L) despite increased AZA to 150 mg (2 mg/kg). A rise of ALT to 133 IU/L required 40 mg prednisolone again. Repeat liver biopsy revealed steatosis but much reduced interface hepatitis. Thiopurine metabolite levels (Lennard method) revealed a 6-thioguanine (6-TGN-the active moiety) level of 100 pmol/8 × 108 red blood cells (RBC) (normal range 250-450) and a 6-methyl mercaptopurine (6-MMP) level of 5800 pmol/8 × 108 RBC, consistent with hypermethylation this website and preferential shunting to 6-MMP. Allopurinol 100 mg once daily was added and her AZA dose reduced by 75%. Subsequently, her ALT normalized within 4 weeks (Fig. 1). This combination corrected her metabolite levels (6-TGN 202 pmol/8 × 108 RBC and 6-MMP 196 pmol/8 × 108 RBC). Prednisolone was withdrawn after 3 months; her ALT remains 10-15 IU/L 12 months later. AZA is essential in managing AIH, often obviating the need for long-term prednisolone. Between 3%-13% of inflammatory bowel disease (IBD) and AIH patients will develop AZA-induced

hepatotoxicity,3-5 which may be difficult to distinguish from AIH nonresponse or relapse without liver APO866 research buy biopsy. In this setting, measuring thiopurine metabolites can provide diagnostic guidance. The finding of increased 6-MMP >5700 pmol/8 × 108 RBC with low or normal 6-TGN (“shunting”) is associated with hepatotoxicity and other side effects including nausea, anorexia, and influenza-like symptoms in IBD patients.5 Our patient’s persistently elevated ALT was consistent with AZA-induced hepatotoxicity (raised ALT secondary to high 6-MMP.) Repeat liver biopsy revealed prednisolone-induced

MCE公司 steatosis with only mildly active AIH. High 6-MMP levels do not always cause hepatotoxicity, however. Allopurinol acts through inhibition of xanthine oxidase, producing preferential AZA breakdown by the TPMT enzymatic pathway resulting in higher 6-TGN and lower 6-MMP (Fig. 2), although the exact mechanism is not fully understood. The combination requires AZA dose reduction to prevent excess 6-TGN production. This is the first reported adult case of allopurinol co-therapy in AIH for the management of AZA-induced hepatotoxicity. This strategy allowed our patient to discontinue prednisolone and avoid alternative immunosuppression. A study into the utility of measuring thiopurine metabolites identified AZA-induced hepatotoxicity, although the investigators found no role for measuring levels to monitor treatment response.

2 Thiopurine

methyltransferase (TPMT) level was normal (53 nmol/g, range 35-79). Subsequently she started azathioprine (AZA) 75 mg daily (1 mg/kg). Her ALT and IgG normalized 6 weeks later. Following prednisolone reduction to 10 mg, her ALT increased to 147 IU/L despite AZA compliance. Forty milligrams prednisolone was reinstituted. On tapering to 10 mg she developed persistently fluctuating ALT (40-80 IU/L) despite increased AZA to 150 mg (2 mg/kg). A rise of ALT to 133 IU/L required 40 mg prednisolone again. Repeat liver biopsy revealed steatosis but much reduced interface hepatitis. Thiopurine metabolite levels (Lennard method) revealed a 6-thioguanine (6-TGN-the active moiety) level of 100 pmol/8 × 108 red blood cells (RBC) (normal range 250-450) and a 6-methyl mercaptopurine (6-MMP) level of 5800 pmol/8 × 108 RBC, consistent with hypermethylation selleck chemicals llc and preferential shunting to 6-MMP. Allopurinol 100 mg once daily was added and her AZA dose reduced by 75%. Subsequently, her ALT normalized within 4 weeks (Fig. 1). This combination corrected her metabolite levels (6-TGN 202 pmol/8 × 108 RBC and 6-MMP 196 pmol/8 × 108 RBC). Prednisolone was withdrawn after 3 months; her ALT remains 10-15 IU/L 12 months later. AZA is essential in managing AIH, often obviating the need for long-term prednisolone. Between 3%-13% of inflammatory bowel disease (IBD) and AIH patients will develop AZA-induced

hepatotoxicity,3-5 which may be difficult to distinguish from AIH nonresponse or relapse without liver check details biopsy. In this setting, measuring thiopurine metabolites can provide diagnostic guidance. The finding of increased 6-MMP >5700 pmol/8 × 108 RBC with low or normal 6-TGN (“shunting”) is associated with hepatotoxicity and other side effects including nausea, anorexia, and influenza-like symptoms in IBD patients.5 Our patient’s persistently elevated ALT was consistent with AZA-induced hepatotoxicity (raised ALT secondary to high 6-MMP.) Repeat liver biopsy revealed prednisolone-induced

上海皓元医药股份有限公司 steatosis with only mildly active AIH. High 6-MMP levels do not always cause hepatotoxicity, however. Allopurinol acts through inhibition of xanthine oxidase, producing preferential AZA breakdown by the TPMT enzymatic pathway resulting in higher 6-TGN and lower 6-MMP (Fig. 2), although the exact mechanism is not fully understood. The combination requires AZA dose reduction to prevent excess 6-TGN production. This is the first reported adult case of allopurinol co-therapy in AIH for the management of AZA-induced hepatotoxicity. This strategy allowed our patient to discontinue prednisolone and avoid alternative immunosuppression. A study into the utility of measuring thiopurine metabolites identified AZA-induced hepatotoxicity, although the investigators found no role for measuring levels to monitor treatment response.