The association between serum zinc levels and subjective symptoms in zinc deficiency patients with chronic liver disease.

This study aimed to analyze the association between serum zinc levels and major subjective symptoms in zinc deficiency patients with chronic liver disease. 578 patients with chronic liver disease were enrolled. The patients, whose serum zinc level of <80 µg/dl, completed a questionnaire to determine whether they had subjective symptoms of the five conditions (taste disorder, aphthous stomatitis, dermatitis, alopecia, and anorexia). Then, the association between these subjective symptoms and serum zinc levels was analyzed. In total, 193 patients (33.4%) experienced any subjective symptoms. The prevalence of each symptom was as follows: 36 patients with taste disorder (6.2%), 46 with aphthous stomatitis (8.0%), 77 with dermatitis (13.3%), 46 with alopecia (8.0%), and 53 with anorexia (9.2%). In total, 70.8%, 34.1%, and 26.1% patients with serum zinc levels of <40, ≥40 to <60, and ≥60 to <80 µg/dl, respectively, had these symptoms. When zinc deficiency was defined as a serum zinc level of <80 µg/dl, approximately one-third of patients displayed symptoms presumably originating from zinc deficiency. As serum zinc levels decreased, the prevalence of these symptoms increased. Dermatitis, especially, was relevant to zinc.

Predictors of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting antiviral treatment: relationship with serum zinc.

The recently approved direct-acting antivirals (DAA) agents are effective in terms of sustained virologic response (SVR) rates and are well tolerated in most hepatitis C virus (HCV) patients. This study aimed to analyze the association between serum zinc levels in patients who developed hepatocellular carcinoma (HCC) following HCV eradication after DAA treatment. The retrospective study included 769 HCV-infected patients who achieved SVR after DAA treatment. We calculated the annual incidence rate of HCC and identified risk factors associated with HCC development. We also assessed serum zinc and clinical factors at both baseline and end of treatment (EOT). During follow-up (median duration 35 months), HCC occurred in 18/769 (2.3%) patients. From the multivariate analysis, serum zinc <60 µg/dl [hazard ratio (HR) 5.936] and AFP ≥6.0 ng/dl (HR 5.862) at baseline, baseline-zinc <60 µg/dl (HR 6.283), EOT-serum zinc <63 µg/dl (HR 6.011), baseline-AFP ≥6.0 ng/dl (HR 8.163), and EOT-M2BPGi ≥2.5 (HR 12.194) at baseline and EOT were independently associated with increased HCC risk. In patients who achieved HCV eradication following DAA treatment, serum zinc levels before and at EOT could be a risk factor for developing HCC.

Bile duct adenoma: imaging features and radiologic-pathologic correlation.

PURPOSE: This study aimed to reveal characteristic imaging features of bile duct adenoma (BDA) by radiologic-pathologic correlation. MATERIALS AND METHODS: We retrospectively analyzed pathological and imaging findings of seven patients with BDA. RESULTS: The median maximum diameter of BDA was 5.5 mm. Six lesions had hemispheric morphology. Seven lesions were located in the liver subcapsular region, and proliferation of bile ductules without atypia and fibrous stroma was observed. Two lesions had different microscopic findings. In both lesions, proliferation of bile ductules without atypia was observed in the margin. In one lesion, the percentage of fibrosis and hyalinization was higher at the center than at the margin. In the other lesion, inflammatory cell infiltration was observed in the center. On contrast-enhanced imaging, BDAs showed hypervascularity in the early phase and prolonged enhancement in the delayed phase. On contrast-enhanced multidetector computed tomography during hepatic arteriography, two lesions showed ring-like enhancement in the first phase and prolonged enhancement in the second phase. These were the different histopathologic features of BDAs between the margin and center. CONCLUSION: Bile duct adenoma can be characterized as a small semicircular lesion located in the liver subcapsular region, which show hypervascularity in the early phase with prolonged enhancement.

Zinc deficiency in patients with chronic liver disease in Japan.

AIM: This study aimed to determine the distributions of serum zinc levels and the prevalence of zinc deficiency in patients with chronic liver disease (CLD) in actual clinical practice, and to analyze the association between serum zinc levels and clinical characteristics. METHODS: This study analyzed 1973 patients with CLD, including 749 with liver cirrhosis, who were admitted to Sapporo Kosei General Hospital in 2017. RESULTS: Zinc deficiency, defined as a serum zinc level of <60 µg/dL, was observed in 555 patients overall (28.1%), including 182 (14.9%) patients without liver cirrhosis and 373 (49.8%) with liver cirrhosis. When marginal zinc deficiency was included, zinc deficiency (serum zinc level <80 µg/dL) was observed in 1594 (80.8%) patients overall, including 924 (75.5%) patients without liver cirrhosis and 670 (89.5%) with liver cirrhosis. Serum zinc levels were most strongly correlated with serum albumin levels. Of the 257 CLD patients with an albumin level of <3.5 g/dL, 234 (91.1%) had a serum zinc level of <60 µg/dL. CONCLUSIONS: Zinc deficiency is common in patients with CLD. Serum zinc levels should be regularly measured, particularly in patients with liver cirrhosis.

Evaluation of treatment with zinc acetate hydrate in patients with liver cirrhosis complicated by zinc deficiency.

AIM: In Japan, no zinc preparation had been approved for therapeutic purposes before March 2017. Zinc acetate hydrate was recently approved for the treatment of hypozincemia. We evaluated the efficacy and safety of treatment with zinc acetate hydrate. METHODS: A total of 97 patients with cirrhosis complicated by hypozincemia were treated with zinc acetate hydrate, and their serum zinc normalization rates; factors contributing to normalization; changes in blood ammonia levels; branched-chain amino acids-to-tyrosine ratios; levels of albumin, hemoglobin, alkaline phosphatase, serum copper, and iron; incidence of adverse events; improvement in subjective symptoms; and serum zinc levels taken at 3 months post-treatment were determined. RESULTS: The cumulative serum zinc normalization rates, when normalization was defined as achievement of a serum zinc level ≥80 µg/dL, after 2, 4, and 6 months of treatment were 64.9%, 80.3%, and 82.5%, respectively. Multivariate analysis identified an albumin level of ≥3.3 g/dL and branched-chain amino acids to tyrosine ratio of ≥3.46 as factors contributing to zinc normalization within 3 months of treatment. Treatment resulted in a significant decrease in blood ammonia and serum copper levels, and significant increases in branched-chain amino acids-to-tyrosine ratios and alkaline phosphatase levels. Seven (7.2%) patients prematurely discontinued treatment due to hypocupremia. By the end of treatment, subjective symptoms had resolved in 46.2% of patients. By 3 months post-treatment, serum zinc levels had reverted to levels close to those at baseline. CONCLUSIONS: Treatment with zinc acetate hydrate resulted in normalization of serum zinc levels at a high rate. The main reasons for discontinuation of treatment included hypocupremia.

Analysis of hepatitis B surface antigen (HBsAg) using high-sensitivity HBsAg assays in hepatitis B virus carriers in whom HBsAg seroclearance was confirmed by conventional assays.

AIM: We investigated the utility of high-sensitivity hepatitis B surface antigen (HBsAg) assays compared with conventional HBsAg assays. METHODS: Using serum samples from 114 hepatitis B virus (HBV) carriers in whom HBsAg seroclearance was confirmed by conventional HBsAg assays (cut-off value, 0.05 IU/mL), the amount of HBsAg was re-examined by high-sensitivity HBsAg assays (cut-off value, 0.005 IU/mL). Cases negative for HBsAg in both assays were defined as consistent cases, and cases positive for HBsAg in the high-sensitivity HBsAg assay only were defined as discrepant cases. RESULTS: There were 55 (48.2%) discrepant cases, and the range of HBsAg titers determined by high-sensitivity HBsAg assays was 0.005-0.056 IU/mL. Multivariate analysis showed that the presence of nucleos(t)ide analog therapy, liver cirrhosis, and negative anti-HBs contributed to the discrepancies between the two assays. Cumulative anti-HBs positivity rates among discrepant cases were 12.7%, 17.2%, 38.8%, and 43.9% at baseline, 1 year, 3 years, and 5 years, respectively, whereas the corresponding rates among consistent cases were 50.8%, 56.0%, 61.7%, and 68.0%, respectively. Hepatitis B virus DNA negativity rates were 56.4% and 81.4% at baseline, 51.3% and 83.3% at 1 year, and 36.8% and 95.7% at 3 years, among discrepant and consistent cases, respectively. Hepatitis B surface antigen reversion was observed only in discrepant cases. CONCLUSIONS: Re-examination by high-sensitivity HBsAg assays revealed that HBsAg was positive in approximately 50% of cases. Cumulative anti-HBs seroconversion rates and HBV-DNA seroclearance rates were lower in these cases, suggesting a population at risk for HBsAg reversion.

Safety of Sofosbuvir and Ribavirin Combination Therapy in a Patient Who Developed Anemia due to Ribavirin.

Interferon (IFN) and ribavirin (RBV) combination therapy was previously the standard of care for treatment of hepatitis C virus (HCV) genotype 2 infection. But, it often induced hemolytic anemia. In 2014, sofosbuvir (SOF) was approved for the treatment of chronic HCV genotype 2 in Japan. SOF/RBV therapy is more effective against genotype 2 than IFN/RBV therapy. We report a case of a 74-year-old woman with chronic HCV genotype 2b infection. She received five treatments including RBV and IFN therapy before SOF was approved and all of them were ineffective. Therapies that included RBV induced severe anemia and led to discontinuation of treatment. With pegylated IFN/RBV therapy, the maximum change in hemoglobin (Hb) from baseline was -3.7 g/dL. However, SOF/RBV therapy was effective and she achieved sustained virologic response (SVR) with a maximum change in Hb from baseline of only -1.2 g/dL. We also found reticulocyte count was very low during treatment in this case and speculate it was one of the reasons that she developed hemolytic anemia with RBV. In conclusion, SOF/RBV therapy is effective and allowed the patient to achieve SVR. An SOF/RBV regimen is safe and effective for patients who have or are at risk of anemia induced by RBV.

Successful achievement of sustained virological response to triple combination therapy containing simeprevir in two patients with chronic hepatitis C who had failed asunaprevir:Daclatasvir combination therapy.

Patients 1 and 2 were treatment-naive women who had genotype 1b chronic hepatitis C. Both had IL-28B genotype TT, and amino acid substitutions of core 70 and 91 were both wild type. Search for the presence of resistance-associated variants (RAV) in non-structural (NS)3 and NS5A regions confirmed wild-type D168 and L31, along with Y93H, in both patients. These patients participated in a Japanese phase III clinical study of asunaprevir and daclatasvir at the age of 52 and 67 years, respectively, and were treated with the combination regimen for 24 weeks. However, both experienced post-treatment relapse, and then treated with triple combination therapy with simeprevir, pegylated interferon (IFN) and ribavirin at the age of 53 and 68 years, respectively, and achieved sustained virological response. A search for RAV prior to simeprevir treatment identified multiple resistance including D168E, Y93H and L31V in both patients. It has been demonstrated that, in many cases, a treatment failure with a combination of asunaprevir and daclatasvir results in acquisition of RAV in NS3 and NS5A regions and that drug-resistant mutants, particularly those in the NS5A region, survive for a long time. In these cases, direct-acting antivirals targeted towards the NS5A region may have a limited efficacy. The present case report is based on an idea that a regimen containing IFN with simeprevir could be a therapeutic option particularly for those who are likely to be highly sensitive and tolerable to IFN.

Clinical characteristics of patients who developed hepatocellular carcinoma after hepatitis C virus eradication with interferon therapy: current status in Japan.

OBJECTIVE: We attempted to elucidate the clinical features of chronic hepatitis C patients who develop hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) to interferon (IFN) therapy. METHODS: The clinical features of 130 patients at 19 hospitals who developed HCC after obtaining an SVR were retrospectively reviewed. RESULTS: Overall, 107 (82%) of the 130 patients were men, with 92 (71%) being ≥60 years of age and 76, 38 and 16 developing HCC within 5, 5-10 and 10-16.9 years after IFN therapy, respectively. Before receiving IFN therapy, 92 (71%) patients had cirrhosis and/or a low platelet count (<15×10(4) cells/µL). Lower albumin (<3.9 g/dL) and higher alpha fetoprotein (AFP) (≥10 ng/mL) levels were identified in a multivariate analysis to be independent variables of the development of HCC within five years after IFN therapy. Among 4,542 SVR patients, HCC occurred in 109 (2.4%) during a 5.5-year follow-up period, thus resulting in an occurrence rate of 4.6% for men and 0.6% for women. CONCLUSION: SVR patients with lower albumin or higher AFP levels require careful assessments to prevent early HCC development after IFN therapy. HCC occurrence within >10 years of IFN therapy is not uncommon, and the risk factors remain uncertain, thus suggesting that all SVR patients should undergo long-term follow-up examinations for HCC development.

[Antiviral therapy for patients with chronic hepatitis B with multi-drug resistance to nucleoside analogues].

In 18 of 547 patients who had received nucleoside analogue preparations for 1 year or more, multi-drug resistance was detected, after a median follow-up of 53 months. No patient showed liver failure related to multi-drug resistance acquisition. Multi-drug resistance was associated with entecavir (ETV) therapy in 7 lamivudine (LAM) -resistant patients, combination therapy with adefovir dipivoxil (ADV) in 8 LAM-resistant patients, LAM switching to ETV in 2 patients, and initial ETV administration in 1. For treatment, combination therapy with LAM and ADV was performed. In non-responders, combination therapy with ADV and ETV was employed. In all LAM- and ADV-resistant patients, and the HBV DNA level decreased to 3.0LC/ml or less. However, a similar decrease was noted in 7 (58.3%) of 12 LAM- and ETV-resistant patients. Of the 18 patients, 1 did not respond to combination therapy with ADV and ETV. Therapy with tenofovir disoproxil fumarate (TDF) was required.

Antiviral effects of peginterferon alpha-2b and ribavirin following 24-week monotherapy of telaprevir in Japanese hepatitis C patients.

BACKGROUND/AIMS: Anemia is commonly observed as a side effect in a treatment with protease inhibitors combined with peginterferon alpha and ribavirin for hepatitis C virus infection. This study assessed the safety, tolerability, viral kinetics, and selection of variants in telaprevir monotherapy for 24 weeks, and outcomes of the off-study treatment with peginterferon alpha-2b and ribavirin among Japanese female patients at a median age of 54 years who were difficult to treat with the standard therapy (peginterferon alpha-2b and ribavirin) alone in Japan. METHODS: Four treatment-naïve patients with chronic hepatitis C virus subtype 1b infection received telaprevir (750 mg every 8 h) alone for 24 weeks. All patients then started the off-study treatment with peginterferon alpha-2b and ribavirin. Safety, tolerability, hepatitis C virus RNA levels, and emergence of telaprevir-resistant variants were monitored. RESULTS: During the 24 weeks of telaprevir monotherapy, there was no discontinuation due to adverse events, but 2 patients stopped the intake at weeks 6 and 15 because of viral breakthrough. Emergence of telaprevir-resistant variants was observed in 3 patients who showed viral breakthrough. These variants were eliminated by the off-study treatment, and sustained virological response was achieved in all patients. CONCLUSIONS: Anemia was manageable by carefully adjusting the ribavirin dosage in the standard therapy that followed telaprevir monotherapy. This sequential regimen seems to be safer and more tolerable than the triple combination of telaprevir, peginterferon alpha, and ribavirin, especially among elderly females with low baseline hemoglobin.

[Beneficial effect of glucocorticosteroids for esophageal varices due to idiopathic portal hypertension following systemic lupus erythematosus].

A 54-year-old female experienced morning stiffness and arthralgia of the hands from November 2001 and consulted her local doctor in January 2002. Hematological data showed liver dysfunction and antinuclear antibody was positive. In February 2002, the patient was admitted to our hospital to investigate these abnormalities of liver function further. The features of arthritis, thrombocytopenia with elevated platelet-associated IgG, positive antinuclear antibody, and anti-DNA antibody lead to a diagnosis of systemic lupus erythematosus. Liver biopsy revealed infiltration of Glisson's capsule by plasma cells, compatible with autoimmune hepatitis. We performed hepatic venography to investigate severe pancytopenia, remarkable splenomegaly and esophageal varices. Wedged hepatic venous pressure was mildly elevated, and hepatic veins displayed sharp angles, smooth walls and development of anastomosis with each other. These findings suggested idiopathic portal hypertension. Cytopenia and liver dysfunction gradually improved on treatment with 40 mg/day prednisolone. Esophageal varices were disappeared, and splenomegaly had improved after 6 months. As autoimmune factors are considered to underlie the development of idiopathic portal hypertension with systemic lupus erythematosus, steroid administration represents a therapeutic option in this condition.

Differential roles of alterations of p53, p16, and SMAD4 expression in the progression of intraductal papillary-mucinous tumors of the pancreas.

Intraductal papillary-mucinous tumors (IPMTs) of the pancreas are characterized by dilated pancreatic ducts and ductules that are lined by tall columnar mucin-producing neoplastic epithelial cells. IPMTs have been suggested to be distinct neoplasms with a less aggressive phenotype than that of conventional ductal adenocarcinomas of the pancreas. Molecular mechanisms underlying tumorigenesis of IPMTs are beginning to be characterized. Allelic losses have frequently been detected at 9p, 17p, and 18q, suggesting that inactivation of tumor suppressor genes at these loci play a role in tumorigenesis of IPMTs. Using immunohistochemistry, we analyzed 38 IPMTs, including 9 hyperplasia, 16 adenoma, and 13 carcinoma tissues, for expression of p53, Ki-67, p16, and SMAD4. Nuclear p53 expression was observed in 5 (38%) of 13 carcinoma tissues but not in hyperplasia or adenoma tissues. Partial loss of p16 expression was observed in 9 (56%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. Partial loss of p16 expression was observed even in adenomas with mild atypia. Partial loss of SMAD4 expression was observed in 6 (38%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. The SMAD4 negative index was significantly higher in invasive carcinomas than in non-invasive carcinomas. Our results suggest that loss of p16 is an early event and p53 alteration is a late event during the progression of IPMTs. SMAD4 inactivation appears to be an early event but also involved in invasive tumor growth. Our results suggest that these alterations accumulate during the progression of IPMTs, reflecting results of analysis of allelic losses that showed a stepwise accumulation of genetic changes during progression.

[Overview of recent monoclonal antibody therapy].

It has been 27 years since Milstein and Köhler stunned the world of biology by announcing the discovery of monoclonal antibodies. Novel MoAb improved forms of chimeric and humanized antibodies with high antigen-binding affinities are currently being developed by both genetic and chemical methods. The rapid growth of molecular techniques will permit the development of novel antibodies, which should significantly improve conventional therapeutic strategies. This report overviews recent advances in the field of monoclonal antibodies and provides insight regarding the promises and limitations of this novel therapeutic approach.