Differences in branched-chain amino acid to tyrosine ratio (BTR) among etiologies of chronic liver disease progression compared to healthy adults.

BACKGROUND: The branched-chain amino acids (BCAAs) to tyrosine (Tyr) ratio (BTR) test is used to evaluate the progression of chronic liver disease (CLD). However, the differences across sex, age, body mass index (BMI) and etiologies are still unclear. METHODS: We retrospectively reviewed data from 2,529 CLD cases with free amino acids (FAAs) in peripheral blood from four hospitals and 16,421 general adults with FAAs data from a biobank database. In total, 1,326 patients with CLD (covering seven etiologies) and 8,086 healthy controls (HCs) were analyzed after exclusion criteria. We investigated the change of BTR in HCs by sex, age and BMI and then compared these to patients divided by modified ALBI (mALBI) grade after propensity score matching. RESULTS: BTR is significantly higher in males than females regardless of age or BMI and decreases with aging in HCs. In 20 types of FAAs, 7 FAAs including BCAAs were significantly decreased, and 11 FAAs including Tyr were significantly increased by mALBI grade in total CLD. The decreasing timings of BTR were at mALBI grade 2b in all CLD etiologies compared to HCs, however in chronic hepatitis C (CHC), chronic hepatitis B (CHB) and alcoholic liver disease (ALD), BTR started to decrease at 2a. There was a positive correlation between BCAAs and albumin among parameters in BTR and mALBI. The correlation coefficients in PBC, ALD and MASLD were higher than those of other etiologies. CONCLUSIONS: BTR varies by sex and age even among healthy adults, and decreasing process and timing of BTR during disease progression is different among CLD etiologies.

Effects of sodium glucose cotransporter 2 inhibitors and pioglitazone on FIB-4 index in metabolic-associated fatty liver disease.

BACKGROUND: The antidiabetic drugs sodium glucose cotransporter 2 inhibitors (SGLT2is) and thiazolidinediones have beneficial effects on the liver dysfunction of patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus (T2DM). We aimed to determine the efficacy of these drugs for the treatment of liver disease in patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and T2DM. METHODS: We undertook a retrospective study of 568 patients with MAFLD and T2DM. Of these, 210 were treating their T2DM with SGLT2is (n = 95), 86 with pioglitazone (PIO), and 29 with both. The primary outcome was the change in Fibrosis-4 (FIB-4) index between baseline and 96 weeks. RESULTS: At 96 weeks, the mean FIB-4 index had significantly decreased (from 1.79 ± 1.10-1.56 ± 0.75) in the SGLT2i group, but not in the PIO group. The aspartate aminotransferase to platelet ratio index, serum aspartate and alanine aminotransferase (ALT), hemoglobin A1c, and fasting blood sugar significantly decreased in both groups (ALT: SGLT2i group, -17 ± 3 IU/L; PIO group, -14 ± 3 IU/L). The bodyweight of the SGLT2i group decreased, but that of the PIO group increased (-3.2 kg and +1.7 kg, respectively). When the participants were allocated to two groups according to their baseline ALT (>30 IU/L), FIB-4 index significantly decreased in both groups. In patients taking pioglitazone, the addition of SGLT2i improved liver enzymes but not FIB-4 index for 96 weeks. CONCLUSIONS: Treatment with SGLT2i causes a larger improvement in FIB-4 index than PIO in patients with MAFLD over 96 weeks.

Clinical and molecular findings in three Japanese patients with N-acetylneuraminic acid synthetase-congenital disorder of glycosylation (NANS-CDG).

We report clinical and molecular findings in three Japanese patients with N-acetylneuraminic acid synthetase-congenital disorder of glycosylation (NANS-CDG). Patient 1 exhibited a unique constellation of clinical features including marked hydrocephalus, spondyloepimetaphyseal dysplasia (SEMD), and thrombocytopenia which is comparable to that of an infant reported by Faye-Peterson et al., whereas patients 2 and 3 showed Camera-Genevieve type SMED with intellectual/developmental disability which is currently known as the sole disease name for NANS-CDG. Molecular studies revealed a maternally inherited likely pathogenic c.207del:p.(Arg69Serfs*57) variant and a paternally derived likely pathogenic c.979_981dup:p.(Ile327dup) variant in patient 1, a homozygous likely pathogenic c.979_981dup:p.(Ile327dup) variant caused by maternal segmental isodisomy involving NANS in patient 2, and a paternally inherited pathogenic c.133-12T>A variant leading to aberrant splicing and a maternally inherited likely pathogenic c.607T>C:p.(Tyr203His) variant in patient 3 (reference mRNA: NM_018946.4). The results, together with previously reported data, imply that (1) NANS plays an important role in postnatal growth and fetal brain development; (2) SMED is recognizable at birth and shows remarkable postnatal evolution; (3) NANS-CDG is associated with low-normal serum sialic acid, obviously elevated urine N-acetylmannosamine, and normal N- and O-glycosylation of serum proteins; and (4) NANS-CDG is divided into Camera-Genevieve type and more severe Faye-Peterson type.

No increased risk of hepatocellular carcinoma after eradication of hepatitis C virus by direct-acting antivirals, compared with interferon-based therapy.

It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of hepatocellular carcinoma (HCC). However, whether IFN-free direct-acting antivirals reduce the risk of HCC is controversial. Therefore, this study aims to compare the incidence of HCC after the achievement of SVR between sofosbuvir combined with ledipasvir (SOF/LDV) and simeprevir with pegylated interferon plus ribavirin (Sim+IFN). Japanese patients with HCV infection (genotype 1) who achieved SVR between January 2013 and December 2014 by SOF/LDV (NCT01975675, n = 320) or Sim+IFN (000015933, n = 289) therapy in two nationwide, multicenter, phase III studies were prospectively monitored for the development of HCC by ultrasonography for 5 years after the end of treatment (EOT). No HCC was detected before the treatment. HCC was detected in 9 and 7 patients in the SOF/LDV and the Sim+IFN group in 5 years, respectively. The cumulative incidences of HCC rates 1, 3, and 5 years after EOT were similar between the two groups (1.5%, 2.7%, and 3.2% for the SOF/LDV and 1.8%, 2.8%, and 3.0% for the Sim+IFN group, respectively). No HCC was developed 3.5 years after EOT. Interestingly, a retrospective careful review of imaging taken before therapy revealed hepatic nodules in 50% of HCC patients, suggesting HCC was pre-existed before therapy. In conclusion, we could not find any differences in the incidence of HCC after the HCV eradication between the two therapeutic regimens, suggesting no enhancement of HCC development by DAA.

Blood angiopoietin-2 predicts liver angiogenesis and fibrosis in hepatitis C patients.

BACKGROUND: Pathological angiogenesis is involved in the development of hepatocellular carcinoma. In patients with chronic hepatitis C (CHC), the level of angiogenic factor angiopoietin (ANGP)-2 is reported to be increased in the blood, correlating with fibrosis. In this study, we aimed to clarify whether blood ANGP-2 is useful as a biomarker for liver angiogenesis and fibrosis in CHC patients and to further reveal the relationship between such pathology in a carbon tetrachloride (CCl4)-treated liver fibrosis mouse model. METHODS: Plasma levels of ANGP-2, expression of a liver sinusoidal endothelial cell (LSEC) marker (CD31), collagen deposition (Sirius Red staining) in the liver, clinical fibrosis markers (Mac-2 binding protein glycosylation isomer, virtual touch quantification, and liver stiffness measurement), and liver function (albumin bilirubin score) were examined in CHC patients. To determine the effects of an anti-angiogenic agent on liver fibrosis in vivo, sorafenib was administered to the CCl4-treated mice (BALB/c male). RESULTS: The plasma levels of ANGP-2 were increased in CHC patients compared to healthy volunteers and decreased by the eradication of hepatitis C with direct-acting antivirals. In addition, plasma ANGP-2 levels were correlated with CD31 expression, collagen deposition, clinical fibrosis markers, and liver function. Sorafenib inhibited liver angiogenesis and fibrosis in the CCl4-treated mice and was accompanied by decreased ANGP-2 expression in LSECs. CONCLUSIONS: ANGP-2 may serve as a useful biomarker for liver angiogenesis and fibrosis in CHC patients. In addition, angiogenesis and fibrosis may be closely related.

Placental abruption in each hypertensive disorders of pregnancy phenotype: a retrospective cohort study using a national inpatient database in Japan.

We designed a retrospective cohort study using the Diagnosis Procedure Combination database, a national inpatient database for acute-care inpatients in Japan, to examine whether recent global diagnostic criteria for preeclampsia, phenotypes of hypertensive disorders of pregnancy (HDP) and features of the disease are useful as predictors of placental abruption and whether other risk factors are associated with the onset of placental abruption. A total of 85,858 hospitalized patients with a diagnosis of HDP who gave birth during hospitalization between July 2010 and March 2018 were included in this study. We examined the associations between the occurrence of placental abruption after hospitalization and several factors, including gestational age (GA) at placental abruption onset, HDP subtypes, GA on admission, maternal age, body mass index, smoking, multiple pregnancy, prelabor rupture of membranes, diabetes mellitus, emergency admission by ambulance, and consciousness, using a multivariate logistic regression analysis. Placental abruption occurred in 541 patients (0.63%) after hospital admission, and the occurrence increased acutely after 32 weeks GA. A decrease in abruption was significantly associated with maternal BMI on admission (≥30 kg/m2; odds ratio [OR], 0.54; 95% confidence interval [CI], 0.41-0.70) and multiple pregnancy (OR, 0.29; 95% CI, 0.18-0.46). An increase in abruption was associated with earlier GA on admission (<34 weeks' GA; OR, 3.77; 95% CI, 3.13-4.53) and emergency admission by ambulance (OR, 1.34; 95% CI, 1.09-1.65). Individual features of severe PE showed no significant associations with the occurrence of abruption. In conclusion, HDP at an earlier GA was suggested to be a risk factor for placental abruption, and we recommend hospitalization and careful management of such patients to improve their prognosis.

Portal hypertension in prolonged anorexia nervosa with laxative abuse: a case report with liver and kidney biopsy data.

PURPOSE: We previously reported three cases of portal hypertension in patients with prolonged anorexia nervosa (AN) with laxative abuse and self-induced vomiting; we now report a fourth, similar case. METHODS: A 34-year-old woman with anorexia nervosa, binge-eating/purging type (AN-BP), presented to the Kohnodai Hospital National Center for Global Health and Medicine Psychosomatic Medicine Department for treatment of low body weight. We conducted hepatic and renal biopsies and cardiac magnetic resonance imaging (CMR) to evaluate her complicated liver disease, renal failure, and cardiac insufficiency, respectively. RESULTS: Enhanced computed tomography revealed ascites, splenomegaly, and gastroesophageal varices, indicating portal hypertension. The liver and kidney biopsies demonstrated chronic hepatitis without evidence of hepatic cirrhosis and tubulointerstitial nephritis, respectively. CMR demonstrated decreased myocardial mass. CONCLUSION: We found tubulointerstitial nephritis and decreased myocardial mass in a patient with non-cirrhotic portal hypertension and prolonged AN with laxative abuse and habitual self-induced vomiting. We propose that reciprocal interactions between multiple factors related to AN, including laxative toxicity, dehydration, renal disorder, and cardiac insufficiency, result in portal hypertension. Level of Evidence Level V.

Prematurity at less than 24 weeks of gestation is a risk for prolonged hyperglycemia in extremely low-birth weight infants.

Hyperglycemia in extremely low-birth weight infants (ELBWIs) is frequently observed during the acute perinatal phase, (i.e., first 1-2 weeks postnatal period); however it can occasionally persists for >2 weeks, extending to the post-acute phase. Since such prolonged hyperglycemia (PH) is not typical for ELBWIs, the aim of the present study was to further understand the clinical details of PH. Twenty-five hyperglycemic ELBWIs born before 28 weeks of gestation from 2015 to 2018 were included in the study. Based on the duration of hyperglycemia, we separated the subjects into two groups: non-prolonged hyperglycemia (NPH) who achieved remission within ≤2 weeks [n = 18, median 3.0 (range, 2.0-4.0) days], and PH, whose hyperglycemia persisted for >2 weeks [n = 7, median 50.0 (range, 33.5-66.0) days]. Compared to the NPH group, glucose metabolism of the PH group was more deteriorate. The peak blood glucose level was significantly higher in the PH group [PH: median 472 mg/dL, NPH: median 275 mg/dL, p < 0.001], and a higher proportion of subjects in the PH group required insulin therapy [PH: 100% (7/7) vs. NPH: 22% (4/22)]. Multivariate analysis revealed that among perinatal factors, prematurity was the only independent risk factor for PH (glucocorticoid therapy: p = 0.884, gestational age: p = 0.006), with a cutoff of 23W4D determined by receiver operating characteristic analysis. Our data revealed distinctive clinical features of PH, suggesting a type different from the previously reported hyperglycemia in ELBWIs. Specifically, extreme prematurity, less than 24 weeks of gestation, is a risk for PH, and aggressive interventions, such as insulin would be required.

Portal hypertension in prolonged anorexia nervosa with laxative abuse: A case report of three patients.

OBJECTIVE: There has been no report on portal hypertension related to anorexia nervosa (AN). METHOD: We describe three cases of portal hypertension manifesting with collateral circulation represented by gastroesophageal varices in prolonged AN with laxative abuse and self-vomiting. These women, in their 20s to 50s, were diagnosed as having AN binging and purging type (AN-BP) that included self-induced vomiting and abuse of irritating laxatives (more than 100 tablets daily). RESULTS: Case 1 showed prominent ascites and a gastro-renal shunt on computed tomography scanning. Case 2 showed gastroesophageal varices on endoscopic examination. Case 3 showed gastroesophageal varices on computed tomography scanning and endoscopic examination. We performed liver biopsies in all patients and found only slight pericellular fibrosis. Our patients showed typical symptoms of portal hypertension, although liver cirrhosis was not present. DISCUSSION: We speculated that abnormal eating and purging behaviors were involved in the development of portal hypertension. We hypothesized that long-term laxative abuse, dehydration, and abnormal eating behavior are involved in the development of portal hypertension, considering these were common features in our patients. Portal hypertension and gastroesophageal varices should be considered as one of the potentially existing complications in prolonged AN-BP with self-induced vomiting and abuse of irritating laxatives.

Rifaximin-altered gut microbiota components associated with liver/neuropsychological functions in patients with hepatic encephalopathy: An exploratory data analysis of phase II/III clinical trials.

AIMS: Rifaximin (RFX), a non-systemic antibiotic, improves liver/neuropsychological functions in patients with hepatic encephalopathy (HE). We aimed to investigate the clinical profiles associated with gut bacterial loads using exploratory data analysis and the effects of RFX on the gut microbiota of patients with HE. METHODS: We analyzed the data from 17 patients with HE who underwent fecal microbiota examination in phase II/III trials in Japan. Profiles associated with genera Streptococcus, Veillonella, and Lactobacillus loads were analyzed using classification and regression trees (CART). Changes in gut microbial consortia of seven patients with HE were then assessed 2 weeks after RFX treatment by principal component analysis. RESULTS: In the CART, the first and second divergence variables for each higher bacterial load were as follows: (i) in Streptococcus, the number connection test-A ≥39.55 s and presence of portal-systemic shunt; (ii) in Veillonella, serum potassium levels <4.75 mEq/L and total cholesterol level <129.5 mg/dL; and (iii) in Lactobacillus, white blood cell counts ≥3.4 × 103 /µL and aspartate aminotransferase level ≥44.5 U/L. There was no significant change in total bacterial load before and after RFX treatment; however, there was a decrease in Streptococcus, Veillonella, and Lactobacillus counts after RFX treatment. CONCLUSION: We report clinical profiles associated with gut bacterial loads in patients with HE, and showed that RFX altered gut microbiota components associated with liver/neuropsychological functions. Thus, RFX could improve liver/neuropsychological functions through the regulation of the gut microbial consortia in patients with HE.

A patient with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and severe hypoganglionosis associated with a novel SOX10 mutation.

In this report, we present the case of a female infant with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH) associated with a novel frameshift mutation (c.842dupT) in exon 5, the last exon of SOX10. She had severe hypoganglionosis in the small intestine and entire colon, and suffered from frequent enterocolitis. The persistence of ganglion cells made both the diagnosis and treatment difficult in the neonatal period. She also showed hypopigmentation of the irises, hair and skin, bilateral sensorineural deafness with hypoplastic inner year, severe demyelinating neuropathy with hypotonia, and diffuse brain hypomyelination. The p.Ser282GlnfsTer12 mutation presumably escapes from nonsense-mediated decay and may generate a dominant-negative effect. We suggest that hypoganglionosis can be a variant intestinal manifestation associated with PCWH and that hypoganglionosis and aganglionosis may share the same pathoetiological mechanism mediated by SOX10 mutations.

Genome-Wide Association Study Identifies ZNF354C Variants Associated with Depression from Interferon-Based Therapy for Chronic Hepatitis C.

The therapeutic use of interferon (IFN) is known to cause depression that frequently interrupts treatment. To identify genetic variants associated with IFN-induced depression, we conducted a genome-wide association study (GWAS) of 224 Japanese chronic hepatitis C patients receiving IFN-based therapy in a multicenter prospective study and stratified them into two groups according to the Beck Depression Inventory, Second Edition (BDI-II) score. In the GWAS stage, we selected 42 candidate single nucleotide polymorphisms (SNPs) to perform replication analysis in an independent set of 160 subjects. The SNP rs1863918 in strong linkage disequilibrium with SNPs located around the Zinc finger 354C (ZNF354C) gene on chromosome 5 showed a significant association when the results of GWAS and replication were combined (odds ratio = 2.55, P = 7.89×10-8 in the allele frequency model), suggesting that the rs1863918 T allele was associated with IFN-induced depression. Furthermore, logistic regression analysis showed that rs1863918 T allele, a history of depression, and younger age were independent predictive factors for IFN-induced depression. Interestingly, western blotting and immunofluorescence showed that ZNF354C was highly expressed in the hippocampus in mice, a region implicated in the pathology of psychiatric symptoms. In conclusion, we identified rs1863918 as significantly associated with IFN-induced depression, and revealed that the candidate gene ZNF354C is highly expressed in the hippocampus of mice. Our data might be useful for elucidating the pathogenic mechanisms of depression induced by drugs including IFN.

Usefulness of Magnetic Resonance Imaging for the Diagnosis of Hemochromatosis with Severe Hepatic Steatosis in Nonalcoholic Fatty Liver Disease.

The ratio of the number of patients with non-alcoholic steatohepatitis (NASH) to the total number of patients with liver dysfunction has increased in many countries around the world. Liver dysfunction is also caused by multiple blood transfusions in patients with leukemia and other hematological diseases, with liver dysfunction often accompanied by secondary hemochromatosis. This study describes a 25-year-old man with secondary hemochromatosis combined with NASH. Magnetic resonance imaging was useful for visualizing the distributions of both iron and fat in the liver of this patient in order to make a differential diagnosis and to evaluate the effect of treatment.

The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is an established independent risk factor for hepatocellular carcinoma (HCC). T2DM is associated with non-alcoholic steatohepatitis (NASH), which is a major cause of non-HBV and non-HCV-related HCC; nevertheless, it has been difficult to identify those patients with T2DM who have a high risk of developing HCC. The aim of this study was to identify genetic determinants that predispose T2DM patients to HCC by genotyping T2DM susceptibility loci and PNPLA3. METHODS: We recruited 389 patients with T2DM who satisfied the following three criteria: negative for HBs-Ag and anti-HCV Ab, alcohol intake <60 g/day, and history of T2DM >10 years. These patients were divided into two groups: T2DM patients with HCC (DM-HCC, n = 59) or those without HCC (DM-non-HCC, n = 330). We genotyped 51 single-nucleotide polymorphisms (SNPs) previously reported as T2DM or NASH susceptibility loci (PNPLA3) compared between the DM-HCC and DM-non-HCC groups with regard to allele frequencies at each SNP. RESULTS: The SNP rs738409 located in PNPLA3 was the greatest risk factor associated with HCC. The frequency of the PNPLA3 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 2.53, p = 1.05 × 10(-5)). Among individuals homozygous for the PNPLA3 G allele (n = 115), the frequency of the JAZF1 rs864745 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 3.44, p = 0.0002). CONCLUSIONS: PNPLA3 and JAZF1 were associated with non-HBV and non-HCV-related HCC development among Japanese patients with T2DM.

Appropriate use of virtual touch quantification and FibroScan M and XL probes according to the skin capsular distance.

BACKGROUND: Appropriate utilization of different diagnostic modalities is essential for the accurate liver stiffness measurements (LSM) in patients with chronic liver diseases. The aim of this study was to evaluate the efficacy of Virtual Touch Quantification (VTQ) and the FibroScan M and XL probes in term of accurate LSM and to identify factors associated with inadequate measurements in obese and non-obese Japanese patients. METHODS: A total of 664 consecutive patients with chronic liver disease were prospectively enrolled. LSM were evaluated concurrently with VTQ and the FibroScan M and XL probes. LSM quality was categorized as inadequate (success rate <60% and/or interquartile range/median value of ≥30%) or adequate. RESULTS: No significant differences in the rate of inadequate LSM were observed among the three diagnostic modalities. In multivariate analysis, skin capsule distance (SCD) was strongly associated with inadequate rates obtained with VTQ and the M probe [odds ratio (OR) 1.28, P < 0.0001 and OR 1.20, P < 0.0001, respectively]. Inadequate LSM rates with both VTQ and the M probe increased with longer SCD, with a significant difference between subgroups at an SCD of ≥22.5 mm (VTQ 54.0%; M probe 51.1%; XL probe 25.2%; P < 0.0001). The rates of inadequate LSM rates with VTQ were significantly lower than those with the XL probe at an SCD of <17.5 mm. A total of 15 liver biopsy specimens obtained from nonalcoholic fatty liver disease patients confirmed the diagnostic accuracy and high applicability of the XL probe. CONCLUSIONS: Long SCD reduced the diagnostic performance of the FibroScan® M probe and VTQ. LSM modalities should be selected according to SCD.

Size of the intracranial optic nerve and optic tract in neonates at term-equivalent age at magnetic resonance imaging.

BACKGROUND: The expected MRI-based dimensions of the intracranial optic nerve and optic tract in neonates are unknown. OBJECTIVE: To evaluate the sizes of the intracranial optic nerve and optic tract in neonates at term-equivalent age using MRI. MATERIALS AND METHODS: We retrospectively analyzed brain MRI examinations in 62 infants (28 boys) without intracranial abnormalities. The images were obtained in infants at term-equivalent age with a 1.5-tesla MRI scanner. We measured the widths and heights of the intracranial optic nerve and optic tract and calculated the cross-sectional areas using the formula for an ellipse. RESULTS: The means ± standard deviation of the width, height and cross-sectional area of the intracranial optic nerve were 2.7 ± 0.2 mm, 1.7 ± 0.2 mm and 3.5 ± 0.5 mm(2), respectively. The width, height and cross-sectional area of the optic tract were 1.5 ± 0.1 mm, 1.6 ± 0.1 mm and 2.0 ± 0.2 mm(2), respectively. Using univariate and multivariate analyses, we found that postmenstrual age showed independent intermediate positive correlations with the width (r = 0.48, P < 0.01) and cross-sectional area (r = 0.40, P < 0.01) of the intracranial optic nerve. The lower bounds of the 95% prediction intervals for the width and cross-sectional area of the intracranial optic nerve were 0.07 × (postmenstrual age in weeks) - 0.46 mm, and 0.17 × (postmenstrual age in weeks) - 4.0 mm(2), respectively. CONCLUSION: We identified the sizes of the intracranial optic nerve and optic tract in neonates at term-equivalent age. The postmenstrual age at MRI independently positively correlated with the sizes.

Association of serum IFN-λ3 with inflammatory and fibrosis markers in patients with chronic hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) is one of the major causes of liver cancer. The single nucleotide polymorphisms within the IFNL3 gene, which encodes interferon (IFN)-λ(3), are strongly associated with the response to pegylated IFN-α (PEG-IFN-α) plus ribavirin (RBV) therapy in chronic hepatitis C (C-CH) patients. However, the roles of IFN-λ(3) in chronic HCV infection are still elusive. In this study, we aimed to identify clinical and immunological factors influencing IFN-λ(3) and evaluated whether serum IFN-λ(3) levels are involved or not involved in the response to PEG-IFN-α plus RBV therapy. METHODS: We enrolled 119 C-CH patients with HCV genotype 1 infection who underwent 48 weeks of PEG-IFN-α plus RBV therapy. As controls, 23 healthy subjects and 56 patients with non-HCV viral hepatitis were examined. Serum IFN-λ(3) was quantified by chemiluminescence enzyme immunoassay, and 27 cytokines or chemokines were assayed by the multiplexed BioPlex system. RESULTS: Serum IFN-λ(3) levels were higher in C-CH patients or acute hepatitis E patients than in healthy volunteers. Such levels did not differ between the IFNL3 genotypes. In C-CH patients, serum IFN-λ(3) was positively correlated with aspartate aminotransferase, alanine aminotransferase, α-fetoprotein, histological activity, fibrosis index, IFN-γ-inducible protein 10, and platelet-derived growth factor. Multivariate analysis showed that IFNL3 single nucleotide polymorphisms, fibrosis score, and macrophage inflammatory protein 1α were involved in the sustained viral clearance in PEG-IFN-α plus RBV therapy; however, serum IFN-λ(3) levels were not involved. CONCLUSION: Serum IFN-λ(3) levels are increased in C-CH patients regardless of the IFNL3 genotype. IFN-λ(3) is a biomarker reflecting the activity and fibrosis of liver disease, but is not correlated with the responsiveness to PEG-IFN-α plus RBV therapy.

Ex vivo induction of IFN-λ3 by a TLR7 agonist determines response to Peg-IFN/ribavirin therapy in chronic hepatitis C patients.

BACKGROUND: Genetic variation around interleukin-28B (IL28B), encoding IFN-λ3, predict non-responders to pegylated interferon-α/ribavirin (Peg-IFN/RBV) therapy in chronic hepatitis C (CHC). However, it remains unclear the expression and the role of IL28B itself. The aim of this study is to develop easy and useful methods for the prediction of treatment outcomes. METHODS: The mRNA and protein levels of IFN-λ3 induced by ex vivo stimulation of peripheral blood mononuclear cells (PBMC) or magnetically selected dendritic cells (DCs) with toll-like receptor agonists (TLR3; poly I:C, TLR7; R-837) were measured by the quantitative real-time polymerase chain reaction and our newly developed chemiluminescence enzyme immunoassays, respectively, and compared with the clinical data. RESULTS: We found that BDCA-4(+) plasmacytoid and BDCA-3(+) myeloid DCs were the main producers of IFN-λs when stimulated with R-837 and poly I:C, respectively. Detectable levels of IFN-λs were inducible even in a small amount of PBMC, and IFN-λ3 was more robustly up-regulated by R-837 in PBMC of CHC patients with favorable genotype for the response to Peg-IFN/RBV (TT in rs8099917) than those with TG/GG. Importantly, the protein levels of IFN-λ3 induced by R-837 clearly differentiated the response to Peg-IFN/RBV treatment (p = 1.0 × 10(-10)), including cases that IL28B genotyping failed to predict the treatment response. The measurement of IFN-λ3 protein more accurately predicted treatment efficacies (95.7 %) than that of IL28B genotyping (65.2 %). CONCLUSIONS: Genetic variations around IL28B basically affect IFN-λ3 production, but different amounts of IFN-λ3 protein determines the outcomes of Peg-IFN/RBV treatment. This study, for the first time, presents compelling evidence that IL28B confer a functional phenotype.

[Primary adenosquamous carcinoma of the liver presenting with hematochezia due to tumor invasion of the colon].

A 69-year-old female was referred to our hospital with hematochezia. Dynamic computed tomography demonstrated a large tumor with rim enhancement and central necrosis that invaded into the transverse colon. The tumor was resected, and histopathological examination revealed mixed adenocarcinoma and squamous cell carcinoma with partial abscess formation. On the basis of a literature review and the findings from the present case, rim enhancement with central necrosis on imaging appears to be characteristic of this disease.

Scirrhous colonic metastasis from lobular carcinoma of breast.

A 68-year-old woman presented complaining of 2 months vague abdominal fullness and constipation. She had a history of surgery 5 years ago for invasive lobular carcinoma of the left breast. She had good appetite without any severe symptoms such as vomiting, diarrhea, or hematochezia. No abnormal subcutaneous lymph nodes were detected, and blood tests showed no abnormalities including serum tumor markers. Whole-body computed tomography and bone scintigraphy revealed no tumor recurrences. However, endoscopic findings demonstrated a smooth stenotic lesion with submucosal thickening in the transverse colon, but the colonic mucous membrane was grossly normal. The 3-cm-long stenotic lesion was confirmed by colon imaging using water-soluble contrast medium. A biopsy specimen revealed diffuse infiltration of noncohesive malignant cells with round, atypical nuclei from lamina propria to subserosa. Taken together with immunohistochemistry, a diagnosis of metastatic lobular carcinoma from the breast was made, and transverse segmentectomy was done. Colonic metastasis of breast cancer should be included as a differential diagnosis of any abdominal symptoms, even though mild, when patients have a present or previous history of breast cancer.