High viral load is an independent risk factor for development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Antiviral therapy can reduce but not eliminate the risk of HCC. The aim of this study was to identify the risk factors for HCC development in CHB patients during antiviral therapy.CHB patients with HBV DNA level ≥10 copies/mL, with or without compensated cirrhosis receiving adefovir were followed up every 6 months for 10 years (2004-2014). The primary endpoint was the development of HCC. The cumulative incidence and risk factors of HCC were evaluated by the Kaplan-Meier method and multivariate Cox proportional hazards models.At baseline, 28 of the 120 patients (23.3%) were cirrhotic. One patient developed HCC within 1 year, and therefore 119 patients were analyzed. At the end-point of follow-up, 59.7% (71/119) patients achieved virological remission (VR). Overall, 16 patients developed HCC, giving a 10-year cumulative incidence of 15.73%. Multivariate analysis showed that cirrhosis at baseline and failure to achieve VR were significant risk factors for HCC. The 10-year incidence of HCC was significantly higher in cirrhotic than noncirrhotic patients (43.16% vs. 7.05%, P < .0001). For cirrhotic patients, the 10-year incidence of HCC was significantly higher in patients without VR than those with VR (62.24% vs. 27.78%, P = .0139).Cirrhosis at baseline and failure to achieve VR during antiviral therapy were significant risk factors for HCC development in CHB patients. Effective viral suppression is necessary to reduce HCC development in cirrhotic CHB patients.
Infectious Diseases (4), Immune System Diseases (4) Cirrhosis (3), Hepatocellular Carcinoma (2), Hepatitis B (2), more mentions
BACKGROUND AND AIMS: Liver steatosis has shown to be associated with coronary artery disease (CAD). The aim of our study was to evaluate the association between the presence and severity of CAD and Non-alcoholic fatty liver disease (NAFLD) assessed by transient elastography (TE) and controlled attenuation parameter (CAP).
METHODS: 576 Patients undergoing coronary angiography were enrolled in this prospective study, receiving at least 10 TE and CAP measurements using the FibroScan® M-probe. Clinically relevant CAD (CAD 3) was defined as stenosis with ≥75% reduction of the luminal diameter. NAFLD was determined by CAP ≥234 dB/m. NAFLD with advanced fibrosiswas determined by TE-values ≥7.9kPa in the presence of NAFLD and absence of congestive or right-sided heart failure. Rates and 95% confidence intervals are shown.
RESULTS: 505 patients were available for analysis of NAFLD. However, only 392 patients were available for analysis of NAFLD with advanced fibrosis, since 24 patients had to be excluded due to non valid TE-measurements and 89 patients due to congestive or right-sided heart failure or suspected concomitant liver disease, respectively. 70.5% (66.3%-74.4%) of patients had CAD 3, 71.5% (67.3%-75.4%) were diagnosed with NAFLD, and 11.2% (8.3%-14.8%) with NAFLD with advanced fibrosis. Patients with CAD 3 had higher median CAP-values (273±61 vs. 260±66 dB/m; p = 0.038) and higher degrees of steatosis as compared to patients without CAD 3. While NAFLD was significantly more often diagnosed in patients with CAD 3 (75.0% vs. 63.1%, p = 0.0068), no significant difference was found for NAFLD with advanced fibrosis (10.7% vs. 12.5%, p = 0.60).
CONCLUSIONS: Clinically relevant CAD is frequently associated with the presence of NAFLD, but not NAFLD with advanced fibrosis.
BACKGROUND/AIMS: Long-term follow-up studies validating the clinical benefit of sustained virological response (SVR) in people with chronic hepatitis C (CHC) infection are lacking. Our aim was to identify rates and predictors of liver fibrosis progression in a large, well characterized cohort of CHC patients in whom paired liver fibrosis assessments were performed more than 10 years apart.
METHODS: CHC patients who had undergone a baseline liver biopsy pre-2004 and a follow up liver fibrosis assessment more than 10 years later (biopsy or liver stiffness measurement (LSM) using transient elastography [FibroScan]) were identified. Subjects who had undergone a baseline liver biopsy but had no follow up fibrosis assessment were recalled for LSM. Fibrosis was categorised as mild-moderate (METAVIR F0-2 / LSM result of ≤ 9.5 kPa) or advanced (METAVIR F3-4/ LSM >9.5 kPa). The primary objective was to assess the association between SVR and the rate of liver fibrosis progression over at least 10 years, defined as an increase from mild-moderate fibrosis at baseline liver biopsy (METAVIR F0-2) to advanced fibrosis at follow-up liver fibrosis assessment.
RESULTS: 131 subjects were included in this analysis: 69% male, 82% Caucasian, 60% G1 HCV, 25% G3 HCV. The median age at F/U fibrosis staging was 57 (IQR 54-62) years with median estimated duration of infection 33-years (IQR 29-38). At F/U, liver fibrosis assessment was performed by LSM in 86% and liver biopsy in 14%. The median period between fibrosis assessments was 14-years (IQR 12-17). 109 (83%) participants had received interferon-based antiviral therapy. 40% attained SVR. At F/U, there was a significant increase in the proportion of subjects with advanced liver fibrosis: 27% at baseline vs. 46% at F/U (p = 0.002). The prevalence of advanced fibrosis did not change among subjects who attained SVR, 30% at B/L vs 25% at F/U (p = 0.343). However, advanced fibrosis became more common at F/U among subjects with persistent viremia: 10% at B/L vs 31% at F/U (p = 0.0001). SVR was independently associated with protection from liver fibrosis progression after adjustment for other variables including baseline ALT (p = 0.011), duration of HCV infection and mode of acquisition.
CONCLUSION: HCV eradication is associated with lower rates of liver fibrosis progression. The data support early treatment to prevent long-term liver complications of HCV infection.
Infectious Diseases (3), Immune System Diseases (1) Fibrosis (9), Liver Fibrosis (9), Infections (5), more mentions
RATIONALE: Tumor chemotherapy could weaken the immune system of patients, which might enhance the body sensitivities to the exogenous pathogens, among which the hepatitis B virus (HBV) infection should be concerned because of the higher chances of infection and the severe outcomes, especially in East Asia. The titer level of hepatitis B surface antibody (HBsAb) higher than 10 IU/L is considered to offer immunocompetent individuals adequate protection. However, whether this level is enough to the tumor patients during chemotherapy remains unclear.
PATIENT CONCERNS: A 58-year-old female lymphoma patient was admitted to our hospital for asthenia, nausea, vomiting, and abnormal liver function lasting over 1 week and diagnosed as acute hepatitis B. The patient just finished a course of chemotherapy with CHOP regimen and had recent record (78.61 IU/L) of HBsAb positive. The only risk of infection we could found was that the patient had received blood transfusion shortly after chemotherapy from a donor who was recovering from an asymptomatic acute HBV infection.
INTERVENTION: The patient was administered with entecavir and glycyrrhizic acid agent, and then the disease was resolved successfully with hepatitis B surface antigen serological conversion.
LESSONS: Tumor chemotherapy might have weakened the immune system of the patient and enhanced the body sensitivities to hepatitis B virus, then led to the infection. We concluded that HBsAb-positive status, at least "weakly positive," might not enough to provide protection for tumor patients on chemotherapy though this level was enough for health individuals and donors recuperating from subclinical acute hepatitis B might be another potential risk of HBV infection.
Infectious Diseases (11), Immune System Diseases (1) Hepatitis B (11), Infections (7), Neoplasms (4), more mentions
The relationship between hepatitis B virus (HBV) and the prognosis of hepatocellular carcinoma (HCC) after surgery remains uncertain. A retrospective cohort study was performed to evaluate the impact of pre-S deletions, T1762/A1764, and A1896 mutations on prognosis of HCC after curative resection. A total of 113 patients with positive serum HBV DNA (>200 IU/mL) who had underwent curative resection of pathologically proven HCC were recruited to determine the risk factors affecting the prognosis.The median follow-up time was 36.5 months and recurrence was detected in 67 patients (59.3%). The cumulative recurrence rates and overall survival rates at 1-, 3-, and 5-year after curative resection were 18.0%, 49.7%, 70.3%, and 93.7%, 61.0%, 42.5%, respectively. Patients with pre-S deletions showed significantly higher recurrence rates compared with those with wild type infection (HR: 1.822, P = .018), but not related with a significantly poor survival (HR: 1.388, P = .235). Subgroup analysis indicated that the patients with type III deletion had significant higher tumor recurrence rates than other deletion types (HR: 2.211, 95% confidence intervals [CI]: 1.008-4.846, P = .048). Multivariate analysis revealed that pre-S deletion, tumor size >3 cm in diameter, and the presence of microvascular invasion were independent risk factors for tumor recurrence. HBV pre-S deletions were found to be clustered primarily in the 5' end of pre-S2 region and were more often found between amino acids 120 and 142 of the pre-S2 domain. The domains most frequently potentially involved were the transactivator domain in pre-S2 and polymerized human serum albumin binding site.Our cohort showed that pre-S deletions at the time of resection could predict tumor recurrence in HCC patients after curative resection.
Infectious Diseases (4), Oncology (1) Neoplasms (5), Hepatitis B (4), Hepatocellular Carcinoma (2), more mentions
RATIONALE: Staged hepatectomy is an important surgical method for large hepatocellular carcinoma (HCC). However, the insufficient future liver remnant (FLR) is still the major barrier in stage II hepatectomy. We herein reported a case of laparoscopic associating liver tourniquet and portal ligation combined rescue transhepatic arterial embolization (TAE) for staged hepatectomy.
PATIENT CONCERNS: Laparoscopic associating liver tourniquet and portal ligation for staged hepatectomy (ALTPS) was performed for cirrhotic HCC in stage I. To stimulate the growth of FLR, a "rescue" TAE was initiated before stage II.
DIAGNOSE: HCC with hepatitis B cirrhosis.
OUTCOMES: Two weeks later after TAE, the FLR achieved sufficient hypertrophy and stage II surgery was successfully performed. The patient was discharged 7 days after the second stage without serious complication. During the follow-up at postoperative 6 months, the patient underwent radiofrequency ablation, because contrast-enhanced ultrasonography showed 1 cm tumor recurrence in the remnant liver.
LESSONS: Rescue TAE plays an important role to stimulate the increasing of FLR after ALTPS.
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation or precursor of metabolic syndrome, may increase nephrolithiasis, a renal manifestation of insulin resistance, but the prospective association between NAFLD and incident nephrolithiasis has not been evaluated. We examined the association of NAFLD with the development of nephrolithiasis in a large cohort of Korean men and women.
METHODS: We performed a cohort study of 208,578 Korean adults who underwent a health checkup examination between January 2002 and December 2014 and were followed-up annually or biennially through December 2014. NAFLD was defined as the presence of fatty liver in the absence of excessive alcohol use or other identifiable causes. Fatty liver and nephrolithiasis were determined based on ultrasonographic findings. We used a parametric Cox model to estimate the adjusted hazard ratios (HRs) of nephrolithiasis according to the presence of NAFLD.
RESULTS: During 1,054,887.6 person-year of follow-up, 16,442 participants developed nephrolithiasis. After adjusting for age, center, year of screening exam, smoking status, alcohol intake, physical activity, education level, body mass index, history of hypertension and diabetes, HOMA-IR, uric acid and C-reactive protein, male participants with NAFLD had a significantly increased risk of nephrolithiasis than those without NAFLD (adjusted HR 1.17, 95% CI 1.06-1.30). However, no association between NAFLD and nephrolithiasis was observed in women (adjusted HR 0.97, 95% CI 0.81-1.16).
CONCLUSIONS: In this large cohort study of young and middle-aged Koreans, NAFLD was significantly associated with an increased incidence of nephrolithiasis in men but not in women.
Endocrine Disorders (2), Cardiovascular Diseases (1), Anti-Obesity and Weight Loss (1) Nephrolithiasis (11), Alcoholic Fatty Liver (3), Fatty Liver (2), more mentions
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries. Both iron and lipid metabolism seem to be involved in its pathogenesis. We aimed to assess the relationship between levels of hepcidin, the master iron-regulatory protein, in plasma and the presence of NAFLD in morbidly obese (MO) patients, and to investigate the association between the hepatic expression of the main iron and lipid metabolism -related genes.
MATERIALS AND METHODS: Enzyme-linked immunosorbent assay was used to measure plasma hepcidin levels in 49 normal-weight control women, 23 MO women with normal liver (NL) histology and 46 MO women with NAFLD. The mRNA expression of hepcidin, the main iron metabolism-related genes, and the main lipid-metabolism genes was quantified by qRT-PCR in liver biopsies from members of the MO group undergoing bariatric surgery.
RESULTS: Circulating hepcidin levels were significantly greater in MO than in normal-weight control women. However, there were no significant differences between MO women with NL and those with NAFLD. PCR analysis showed increased expression of hepcidin, FPN1, TfR1 and TfR2 in the liver of MO NAFLD women compared to those with NL. Moreover, a positive association of hepatic hepcidin mRNA expression and the iron metabolism-related genes was found with some key genes involved in the lipid metabolism.
CONCLUSION: These findings suggest that circulating hepcidin levels are associated with obesity but not with the presence of NAFLD. However, the hepatic expression of hepcidin and the iron metabolism-related genes seem to play a role in regulating lipid metabolism pathways in liver, which has implications for NAFLD pathogenesis.
Anti-Obesity and Weight Loss (5) Alcoholic Fatty Liver (3), Obesity (2), Liver Diseases (1), more mentions
BACKGROUND: Sarcopenia is a common syndrome in chronic diseases such as liver cirrhosis. The association between sarcopenia and outcomes, such as complications and survival has recently been described in various patient groups. However, study results remain inconclusive. Therefore, the aim of this study was to systematically review the impact of sarcopenia on outcome in patients with cirrhosis.
METHODS AND FINDINGS: We conducted a systematic review (SR) and meta-analysis (MA) on the impact of sarcopenia on outcome in liver cirrhosis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Of the 312 studies identified, 20 were eligible according to our inclusion criteria. Most of the studies used CT to diagnose sarcopenia. Two studies used bioelectrical impedance analysis (BIA), 10 studies used skeletal muscle index (SMI) and 8 studies used total psoas muscle area (TPA). Seven studies included Asian participants and the remaining 13 studies included Western participants. The prevalence rate of sarcopenia among participants was mean 48.1%, and appeared more among men with a rate of 61.6% whereas the rate was 36% for women. With respect to clinical outcomes, patients with sarcopenia had poorer survival rates and an increased risk of complications such as infection compared to those without sarcopenia. According to the analysis of race subgroup, Asians had a HR 2.45 (95% confidence interval (CI) = 1.44-4.16, P = 0.001) of mortality whereas Westerners had a HR 1.45 (95% CI = 1.002-2.09, P<0.05).
CONCLUSIONS: Based on this SR and MA, the presence of sarcopenia is related to a poor prognosis and occurrence of cirrhotic complications and could be used for risk assessment. Moreover, Asian participants had higher mortality related to sarcopenia compared to the Western participants.
Sarcopenia (12), Liver Cirrhosis (4), Cirrhosis (1), more mentions
BACKGROUND: Adult seroprevalence of HAV is decreasing in developed countries including South Korea, due to general sanitation improvement. Although hepatitis A vaccination was introduced in South Korea more than 20 years ago, recent infection rates have not decreased. In this study, we investigate the seroprevalence of anti-HAV IgG, and estimate the national disease burden of acute hepatitis A in adult population.
METHODS: Seroprevalence data were collected from health promotion center of Korea University Guro Hospital, in Seoul, Korea from 2010 to 2014. Data from adults (≥20-years) being tested for anti-HAV IgG were included. In addition, epidemiological and clinical data of patients diagnosed with acute hepatitis A from 2009 to 2013, were collected from Korean Statistical Information Service (KOSIS) and the National Health Insurance Service (NHIS) database. Data were stratified and compared by age groups.
RESULTS: A total of 11,177 subjects were tested for anti-HAV IgG from 2010 to 2014. Age-related seroprevalence showed relatively low seropositivity in young adults. Incidence of acute hepatitis A was highest in 2009 and lowest in 2013. When categorized by age group, adults in their 20s and 30s had more HAV infections and related-admissions than older adults. However, ICU admission rate and average insurance-covered cost was high in older adults.
CONCLUSION: The anti-HAV IgG seropositivity in Korean younger adult population was low while the incidence of acute hepatitis A was high, especially in the 20-39 aged. However, a substantial number of older adults were infected, and required more intensive procedures and incurred higher insurance-covered medical costs.
Infectious Diseases (7) Hepatitis A (7), Infections (2), more mentions
Concern has arisen about development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection treated with direct-acting antivirals (DAAs). To identify patients at risk for HCC, we evaluated serum levels of immune mediators before, during, and after DAA treatment of HCV infection. Our study included 13 patients who developed HCC within 18 months after treatment (3 with HCC recurrence and 10 with new HCC) and 10 patients who did not develop HCC (controls), within at least 24 months of treatment (median, 26 months). We identified a set of 12 immune mediators (cytokines, growth factors, and apoptosis markers) whose levels were significantly higher in serum before DAA treatment of patients who eventually developed de novo HCC compared to controls. A panel of 9 cytokines, measured in serum before treatment (MIG, IL22, TRAIL, APRIL, VEGF, IL3, TWEAK, SCF, IL21), identified patients who developed de novo HCC with an area under the receiver operating characteristic curve value higher than 0.8. Further analyses of changes in levels of inflammatory cytokines during DAA treatment also provides important information about HCV-induced carcinogenesis and the effects of DAAs.
Direct-acting antivirals have revolutionized the treatment of hepatitis C virus (HCV) infection in patients with chronic kidney disease, with implications for the timing of antiviral treatment among kidney transplant candidates and for the use of HCV viremic donors. A recent consensus conference reviewed the available data on the safety and cost-effectiveness of expanding access to HCV-positive organs to HCV-negative recipients. Early trials are promising, but larger trials and a plan for obtaining HCV therapy in the posttransplantation period are needed. Implications for the larger transplant community also need to be considered.
Infectious Diseases (3), Immune System Diseases (1), Kidney Disease (1) Hepatitis C (2), Infections (1), Chronic Kidney Diseases (1), more mentions
OBJECTIVES: To estimate hepatitis C virus (HCV) viremic rate, defined as the proportion of HCV chronically infected individuals out of all ever infected individuals, in the Middle East and North Africa (MENA).
METHODS: Sources of data were systematically-gathered and standardized databases of the MENA HCV Epidemiology Synthesis Project. Meta-analyses were conducted using DerSimonian-Laird random-effects models to determine pooled HCV viremic rate by risk population or subpopulation, country/subregion, sex, and study sampling method. Random-effects meta-regressions were conducted to identify predictors of higher viremic rate.
RESULTS: Analyses were conducted on 178 measures for HCV viremic rate among 19,593 HCV antibody positive individuals. In the MENA region, the overall pooled mean viremic rate was 67.6% (95% CI: 64.9-70.3%). Across risk populations, the pooled mean rate ranged between 57.4% (95% CI: 49.4-65.2%) in people who inject drugs, and 75.5% (95% CI: 61.0-87.6%) in populations with liver-related conditions. Across countries/subregions, the pooled mean rate ranged between 62.1% (95% CI: 50.0-72.7%) and 70.4% (95% CI: 65.5-75.1%). Similar pooled estimates were further observed by risk subpopulation, sex, and sampling method. None of the hypothesized population-level predictors of higher viremic rate were statistically significant.
CONCLUSIONS: Two-thirds of HCV antibody positive individuals in MENA are chronically infected. Though there is extensive variation in study-specific measures of HCV viremic rate, pooled mean estimates are similar regardless of risk population or subpopulation, country/subregion, HCV antibody prevalence in the background population, or sex. HCV viremic rate is a useful indicator to track the progress in (and coverage of) HCV treatment programs towards the set target of HCV elimination by 2030.
Infectious Diseases (3) Hepatitis C (3), Viremia (1), more mentions
OBJECTIVE: The purpose of this study is to discuss the imaging modalities and response criteria used for assessing hepatocellular carcinoma (HCC) response to (90)Y radioembolization, as well as the imaging appearances of treated tumors.
CONCLUSION: An understanding of the appearance of HCC after (90)Y radioembolization is crucial for accurate evaluation of treatment response. Residual tumor necrosis and enhancement are essential for assessing response. Multiparametric MRI, including DWI and perfusion imaging, plays an emerging role in response assessment and outcome prediction.
Hepatocellular Carcinoma (3), Necrosis (1), Carcinoma (1), more mentions
At the moment of the diagnosis of hepatocellular carcinoma (HCC), 70% of patients have only access to palliative treatments, with very few therapeutic options. Liver immunology is very specific, and liver immunotolerance is particularly developed because of the constant and massive influx of antigens. Deregulation of hepatic immunotolerance is implicated in chronic liver diseases development and particularly in liver carcinogenesis. For these reasons, HCC may be an excellent candidate for anticancer immunotherapies such as immune checkpoint inhibitors targeting CTLA-4 and PD-L1/PD-1. Nonetheless, because of the specific immune environment of the liver and the frequent association of HCC with hepatocellular insufficiency, the safety and the efficacy of these new treatments have to be properly studied in this situation. Thus, multiple phase II and III studies are in progress studying immune checkpoint inhibitor monotherapies, combination of different immunotherapies or local strategies such as transarterial chemoembolization combined with immune checkpoint inhibitors. Currently, only the final results of the tremelimumab phase II and the Nivolumab phase I/II study (CheckMate-040) are available. The latter is promising but need to be confirmed by the ongoing phase III studies to confirm the place of immunotherapy in the treatment of HCC. With many new molecular targets and therapeutic combination, immunotherapy represents a new hope in treating HCC patients although serious evaluation is still needed to confirm its interest.
Passive hepatic congestion may result from a variety of distinct cardiovascular conditions. Injury to the liver caused by congestion is often asymptomatic and may not be recognized clinically. Diagnosis of congestive hepatopathy is important as it has the potential to cause complications including hepatic fibrosis and development of benign and malignant liver masses. This review will summarize the pathophysiologic mechanisms of congestive hepatopathy and provide both description and examples of its multimodality imaging findings. Examples of alternative disease which may have a similar imaging appearance will be provided. Knowledge regarding the characteristic imaging findings of congestive hepatopathy will allow for its accurate identification. Reviewing both the benefits and limitations of imaging performed to evaluate congestive hepatopathy and its complications will help to avoid pitfalls and enable recommendation of appropriate next steps in diagnostic evaluation.
Magnetic resonance elastography (MRE) has been introduced for clinical evaluation of liver fibrosis for nearly a decade. MRE has proven to be a robust and accurate technique for diagnosis and staging of liver fibrosis. As clinical experience with MRE grows, the possible role in evaluation of other diffuse and focal disorders of liver is emerging. Stiffness maps provide an opportunity to evaluate mechanical properties within a large volume of liver tissue. This enables appreciation of spatial heterogeneity of stiffness. Stiffness maps may reveal characteristic and differentiating features of chronic liver diseases and focal liver lesions and therefore provide useful information for clinical management. The objective of this pictorial review is to recapture the essentials of MRE technique and illustrate with examples, the utility of stiffness maps in other chronic liver disorders and focal liver lesions.
BACKGROUND: Randomized controlled trails (RCTs) on viral hepatitis in China have been increasing, but few studies have been systematically conducted to evaluate the reporting quality of RCTs in this field. In the present study, we assessed the reporting quality of RCTs on the treatment of hepatitis B or C from 1991 to 2015 in China.
METHODS: Articles published between January 1991 and December 2015 were identified via PubMed, Medline, and Embase by using the key words "randomized clinical trials," "treatment," "therapy," "hepatitis B," "HBV," "hepatitis C," "HCV," "China," and "Chinese." The reporting quality was assessed against the Consolidated Standards of Reporting Trials (CONSORT) checklist.
RESULTS: In total, 211 RCTs on the treatment of hepatitis B or C were included. The number of articles focusing on these RCTs increased rapidly with time, while the reporting quality improved steadily with time. Overall, the compliances to key components of the CONSORT checklist were low, with only 8.5%, 3.8%, and 11.4% of the articles fulfilling the reporting requirements of randomization, allocation concealment, and blinding, respectively.
CONCLUSION: Both the number and the quality of the RCT articles steadily increased in the last two decades. However, the compliance to key components of CONSORT still needs improvement. We hope the present results will help to better understand and improve the reporting quality of clinical trials on hepatitis B or C in China.
Infectious Diseases (9) Hepatitis B (6), Hepatitis C (2), Hepatitis (1), more mentions