Performance of serum-based biomarkers in fibrosis prediction of chronic hepatitis B patients in real life practice.

BACKGROUND: Few studies have addressed the performance and diagnostic accuracy of laboratory-based markers for fibrosis prediction in chronic hepatitis B (CHB) patients yielding heterogeneous results. We aimed to study the performance of the FIB-4 and neutrophil-to-lymphocyte ratio (NLR) markers for the differentiation between significant and non-significant hepatic fibrosis in real-life practice. METHODS: We prospectively recruited CHB patients attending the hepatology clinic to undergo shear wave elastography (SWE) and blood tests. The predictive accuracy of FIB-4 and NLR for liver fibrosis was assessed by receiver operating characteristics (ROC) analysis. RESULTS: Overall, 174 fully characterized CHB patients with an average age of 50.2±11.2 (29-86 years) and a male predominance (65.2%) were included. Of these, 23% had significant fibrosis (≥F2) per SWE (>7.1KPA). A significant and linear correlation was found between the SWE score and FIB-4 values (r=0.572; P<0.001). A lower cut-off of 1.43 has yielded an AUROC of 0.76, with a sensitivity of 68.8%, specificity of 79.8%, diagnostic accuracy of 78.5%, and NPV of 96%. On the contrary, NLR values were similar between significant and minimal fibrosis and were not found to be correlated with significant fibrosis (r=0.54, P=0.39). CONCLUSIONS: FIB4 has a moderate performance and may have a valuable role in excluding significant fibrosis in CHB patients in daily practice.

Chronic hepatitis B infection and diabetes mellitus: a double liver trouble?

BACKGROUND: Concomitant Diabetes mellitus (DM) is commonly recognized in patients with chronic hepatitis B (CHB) infection, although its impact on liver-related outcomes remains controversial. We aimed to evaluate the effect of DM on the course, management and outcome of patients with CHB. METHODS: We performed a large retrospective cohort study utilizing the Leumit-Health-Service (LHS) database. We reviewed electronic reports of 692106 LHS members from different ethnicities and districts in Israel from 2000-2019 and included patients with CHB diagnosis based on ICD-9-CM codes and supportive serology results. These were divided into two cohorts of patients with CHB and DM (CHD-DM) (N.=252) and those with CHB without DM (N.=964). Clinical parameters, treatment figures and patients' outcomes were compared and multiple regression models and Cox regression analysis were performed to investigate the association between DM and cirrhosis/HCC risk in CHB patients. RESULTS: CHD-DM patients were significantly older (49.2±10.9 vs. 37.9±14, P<0.001), and had higher rates of obesity (BMI>30) and NAFLD (47.2% vs. 23.1%, and 27% vs. 12.6%, P<0.001, respectively). Both groups had a predominance of inactive carrier (HBeAg negative infection) state, but the HBeAg seroconversion rate was significantly lower in the CHB-DM group (25% vs. 45.7%; P<0.01). Multivariable Cox regression analysis showed that DM was independently associated with increased cirrhosis risk (HR 2.63; P=0.002). Older age, advanced fibrosis and DM were associated with HCC, but DM did not reach significance (HR 1.4; P=0.12) possibly due to the small number of HCC cases. CONCLUSIONS: Concomitant DM in CHB patients was significantly and independently associated with cirrhosis and possibly with increased risk of HCC.

Human Neutrophil α-Defensins 1-3 Are Upregulated in the Microenvironment of Fibrotic Liver.

Background and Objectives: Neutrophil infiltration is an established signature of Non-Alcoholic Fatty Liver Disease (NAFLD) and Steatohepatitis (NASH). The most abundant neutrophilic peptide, alpha-defensin, is considered a new evolving risk factor in the inflammatory milieu, intimately involved in lipid mobilization. Our objective is to assess for potential association between alpha-defensin immunostains and NAFLD severity. Materials and Methods: We retrospectively investigated the liver biopsies of NAFLD/NASH patients, obtained at Hillel Yaffe Medical center between the years 2012 and 2016. Patients' characteristics were recorded, including relevant blood tests at the time of biopsy. Each biopsy was semi-quantitatively scored using NAFLD Activity Score (NAS) and NASH fibrosis stage. The biopsies were immunostained for alpha-defensin. The precipitation of alpha-defensin was correlated to NAS and fibrosis. Results: A total of 80 biopsies were evaluated: male ratio 53.2%, mean age 44.9 ± 13.2 years, 54 had fibrosis grades 0-2, and 26 were grade 3-4. Conventional metabolic risk factors were more frequent in the high-grade fibrosis group. Immunostaining for alpha-defensin disclosed higher intensity (a.u.) in grade 3-4 fibrosis relative to grades 0-2, 25% vs. 6.5%, p < 0.05, respectively. Moreover, alpha-defensin staining was nicely co-localized with fibrosis. Conclusions: In our group of NASH/NAFLD patients, higher metabolic risk profile was associated with higher fibrosis grade. Immunostaining for alpha-defensin showed patchy intense staining concordant with high fibrosis, nicely co-localized with histological fibrosis. Whether alpha-defensin is a profibrotic risk factor or merely risk marker for fibrosis must be clarified in future studies.

The impact of ethnicity on chronic hepatitis B infection course and outcome: big data analysis from Israel.

OBJECTIVES: The effect of ethnicity on chronic hepatitis B virus (CHB) infection's course and outcome has attracted little research. We aimed to compare different aspects of ethnic disparities in CHB patients, including prevalence, phenotypes, management, and outcome between two major ethnic groups in Israel. DESIGN: We conducted a large retrospective cohort study utilizing the Leumit-Health-Service database. Electronic reports of almost 700,000 members from different ethnicities and districts throughout Israel from 2000 to 2019 were reviewed. Patients' ethnicity was categorized based on the classification of the Israeli Central Bureau of Statistics into two main groups, Arabs and Jews. CHB diagnosis was based on ICD-9-CM codes and supportive serology results. Prevalence, clinical backgrounds, disease course, and patients' outcomes were compared between both groups. RESULTS: The prevalence of CHB in the Arab minority group was almost twice and a half-higher when compared to their Jewish counterparts (4.3% vs. 1.8%), but they had a lower rate of referral for HBsAg testing (7% vs. 7.9%). The Arab CHB patients were significantly younger at the time of diagnosis (37.6± 13.5 vs. 45.3± 15; P < 0.001). Male predominance was noted in both groups. The Arab patients had a higher rate of active hepatitis (HBeAg-positive and/or negative hepatitis) phase (36.4% vs. 29.8%; P = 0.01), as well as a significantly higher rate of HBeAg seroconversion (45.2% vs. 35.4%; P = 0.033). Nucleos/tide analogue treatment figures were similar, with most patients in both groups receiving a high barrier to resistance treatment. Patients' outcome was similar in both groups as the rate of hepatocellular carcinoma, cirrhosis, and advanced fibrosis (after stratification analysis) were comparable between both groups. CONCLUSION: Marked by a prominently higher prevalence of HBV infection, patients in the Arab ethnic group had a lower rate of referral for HBsAg testing but received comparable management and had a similar outcome compared to their Jewish counterparts.

Pulmonary embolism risk in hospitalized patients with nonalcoholic fatty liver disease: A case-control study.

Abundant research has associated nonalcoholic fatty liver disease (NAFLD) with atherosclerosis, but very few reports have evaluated the association between NAFLD and venous thromboembolism. We aimed to investigate the association between NAFLD and pulmonary embolism (PE) in hospitalized patients. In this retrospective case-control study, we included consecutive patients from 2 university-affiliated hospitals who were referred for CT pulmonary angiograms for a suspected PE. Patients with a history of excessive alcohol consumption, chronic liver diseases or cirrhosis were excluded. The imaging studies of the entire cohort were reviewed by 2 expert radiologists who confirmed the diagnosis of PE and examined the liver to detect and grade hepatic steatosis. Accordingly, patients were categorized into NAFLD patients and non-NAFLD controls. Patient demographics, medical history, hospitalization details as well as patients' outcomes were documented. Multivariate analysis was performed to identify predictors for developing PE and hazard ratios with corresponding 95% confidence intervals were estimated. A total of 377 patients (101 with NAFLD and 276 controls) were included. NAFLD patients had significantly higher BMI values (33.16 ±â€…6.78 vs 26.81 ±â€…5.6; P < .001) and prevalence of diabetes (41 (40%) vs 85 (30.8%); P = .03). The prevalence of PE was significantly higher in the NAFLD group (80 (79.2%) vs 147 (53.3%), P < .001). In a multivariate analysis, older age, recent surgery or trauma, active malignancy, smoking, and NAFLD (HR ratio = 4.339, P < .0001 and 95% CI = 2.196-8.572) were independently associated with PE development. Patients with NAFLD were associated with an increased risk of developing PE independent of other classical risk factors for PE.

Myocarditis following COVID-19 mRNA vaccination.

BACKGROUND: Clinical trials of the BNT162b2 vaccine, revealed efficacy and safety. We report six cases of myocarditis, which occurred shortly after BNT162b2 vaccination. METHODS: Patients were identified upon presentation to the emergency department with symptoms of chest pain/discomfort. In all study patients, we excluded past and current COVID-19. Routine clinical and laboratory investigations for common etiologies of myocarditis were performed. Laboratory tests also included troponin and C-reactive protein levels. The diagnosis of myocarditis was established after cardiac MRI. FINDINGS: Five patients presented after the second and one after the first dose of the vaccine. All patients were males with a median age of 23 years. Myocarditis was diagnosed in all patients, there was no evidence of COVID-19 infection. Laboratory assays excluded concomitant infection; autoimmune disorder was considered unlikely. All patients responded to the BNT162b2 vaccine. The clinical course was mild in all six patients. INTERPRETATION: Our report of myocarditis after BNT162b2 vaccination may be possibly considered as an adverse reaction following immunization. We believe our information should be interpreted with caution and further surveillance is warranted.

[PRIMARY BILIARY CHOLANGITIS: THERAPEUTIC APPROACH IN THE MODERN ERA].

INTRODUCTION: Primary biliary cholangitis (PBC) is a progressive, autoimmune cholestatic liver disease, predominantly affecting middle-aged women. Hallmark features include a persistent elevation of cholestatic liver enzymes, presence of anti-mitochondrial antibodies and characteristic histologic findings. PBC has a varied course of progression, ranging from mild uncomplicated disease to aggressive disease leading to cirrhosis and resulting in the need for liver transplantation. More than a half of the patients are asymptomatic, but the clinical phenotype varies, and symptoms may be debilitating and have a major impact on quality of life. The goals of PBC management are slowing disease progression, amelioration of associated symptoms and addressing complications of chronic liver disease. The introduction of ursodeoxycholic acid (UDCA) therapy and its universal use as the first-line therapy for PBC has favorably impacted long term prognosis and drastically changed the natural history and disease-related mortality. However, a substantial subpopulation of patients exhibits an incomplete response to UDCA, associated with a sustained disease progression and a poor outcome. Recently, obeticholic acid (OCA) was officially approved as an add-on treatment in patients not responding or intolerant to UDCA. Although evidence for biochemical improvement by OCA is compelling, long-term clinical impact is still under ongoing research. Novel treatment concepts and potential therapeutic options are under investigation. The current review addresses treatment aspects of PBC, while shedding light on the latest updates in patients' management and follow-up.

Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23.

SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24-q32. By using whole-exome sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3' UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with fibroblast growth factor. Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23.

Role of Plain Abdominal Radiographs in the Evaluation of Patients with Non-Traumatic Abdominal Pain.

BACKGROUND: Plain abdominal radiographs are still performed as a first imaging examination to evaluate abdominal pain in the emergency department (ED), despite uncertainty regarding their utility. OBJECTIVES: To describe the frequency and outcomes of the use of plain abdominal radiographs in the diagnosis of patients presenting with acute non-traumatic abdominal pain in the ED of a medical center. METHODS: We retrospectively reviewed the records of patients presenting to the ED with acute abdominal pain during a 6 month period. Further imaging (computed tomography, ultrasonography), when performed, was compared with the abdominal radiography. RESULTS: Of 573 consecutive patients, 300 (52%) underwent abdominal radiography. Findings were normal in 88% (n = 264), non-specific in 7.3% (n = 22), and abnormal in 4.7% (n = 14). For those with normal results, no further imaging was ordered for 43% (114/264). Of the 57% (150/264) who had follow-up imaging, 65% (98/150) showed abnormal findings. In 9 (3%) of the 300 patients, abdominal radiography identified bowel perforations and obstructions, and treatment was provided without the need for further radiologic examination. CONCLUSIONS: The use of plain abdominal radiography is still common despite the high rate of false positive results. Efforts are needed to decrease the indiscriminate use of radiography in patients presenting with abdominal symptoms.

[Israeli guidelines for the treatment of chronic hepatitis C infection--2012 Israeli Association for the Study of the Liver].

The current standard of care for the treatment of hepatitis C virus (HCV) is a combination of pegylated interferon alpha (PeglFN] -2a/2b and ribavirin for 24-48 weeks, according to the viral genotype. This treatment is associated with significant side effects and achieves sustained virologic response (SVR) in only 40%-50% of genotype 1 HCV-infected patients. The recent development of direct-acting antiviral agents (DAAs] targeting critical steps of the virus life-cycle led to a major breakthrough in the management of HCV infection. The DAAs include protease inhibitors and polymerase inhibitors. The recently approved protease inhibitors boceprevir and telaprevir, when given with PeglFN and ribavirin in HCV genotype 1 patients, result in a much higher SVR rate [70%] among treatment-naïve and treatment-experienced patients, compared with Peg-IFN and ribavirin. In specific groups of patients this enables a shorter duration of treatment. The DAA-containing regimens are approved for HCV genotype 1 infection in HCV treatment-naïve and HCV treatment-experienced including cirrhotic patients. The Israeli Ministry of Health has recently approved the use of boceprevir (Victretis) and telaprevir (Incivo) in combination with PeglFN and ribavirin for the current standard of care treatment of HCV genotype 1 patients. The consensus opinion of a panel of national HCV-experts appointed by the Israeli Association for the Study of the Liver is presented in this report. These Israeli consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection.

Reduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in patients with genotype 2 and 3 chronic hepatitis C.

BACKGROUND & AIMS: There is increasing interest in identifying patients with chronic hepatitis C genotype 2 or 3 infection in whom it is possible to lower the burden of therapy while retaining high levels of efficacy. METHODS: Treatment-naive patients with chronic hepatitis C genotype 2/3 infection were randomized to receive peginterferon alfa-2b (1.5µg/kg/wk) for 24weeks (group A); peginterferon alfa-2b (1.0µg/kg/wk) for 24weeks (group B); or peginterferon alfa-2b (1.5µg/kg/wk) for 16weeks (group C), each in combination with weight-based ribavirin (800-1200mg/d). The study population comprised two cohorts: the Hep-Net cohort enrolled in Germany and an International cohort enrolled at study sites throughout Europe and Asia. The primary end point was sustained virological response (SVR). RESULTS: The study included 682 patients; 80.2% had genotype 3 infection. In the intent-to-treat population, SVR rates were 66.5%, 64.3%, and 56.6% in groups A, B, and C, and were similar in Asian and white patients. Treatment differences (A vs. B and A vs. C) failed to reach the predefined margin for noninferiority of -10%; and thus groups B and C failed to show noninferiority relative to group A. Among patients with undetectable HCV RNA at week 4, SVR rates were 75.3%, 75.9%, and 72.4%, respectively. Relapse rates were 17.8%, 16.3%, and 29.3%, respectively. Treatment-emergent serious adverse events were highest in group A and lowest in group C, and adverse events leading to discontinuation were similar across treatment arms. CONCLUSIONS: For patients with chronic hepatitis C genotype 2/3 infection, 24weeks of peginterferon alfa-2b (1.5µg/kg/wk) plus weight-based ribavirin remains a standard-of-care therapy; however, treatment for 16weeks may be considered for patients with undetectable HCV RNA at week 4 of the treatment.

Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients.

AIM: To determine whether adding vitamin D, a potent immunomodulator, improves the hepatitis C virus (HCV) response to antiviral therapy. METHODS: Seventy-two consecutive patients with chronic HCV genotype 1 were randomized into two groups: the treatment group (n = 36, 50% male, mean age 47 ± 11 years) received Peg-α-2b interferon (1.5 µg/kg per week) plus ribavirin (1000-1200 mg/d) together with vitamin D3 (2000 IU/d, target serum level > 32 ng/mL), and the control group (n = 36, 60% male, mean age 49 ± 7 years) received identical therapy without vitamin D. HCV-RNA was assessed by real-time polymerase chain reaction (sensitivity, 10 IU/mL). The sustained virologic response (SVR) was defined as undetectable HCV-RNA at 24 wk post-treatment. RESULTS: Clinical characteristics were similar in both groups. The treatment group had a higher mean body mass index (27 ± 4 kg/m² vs 24 ± 3 kg/m²; P < 0.01), viral load (50% vs 42%, P < 0.01), and fibrosis score (> F2: 42% vs 19%, P < 0.001) than the controls. At week 4, 16 (44%) treated patients and 6 (17%) controls were HCV-RNA negative (P < 0.001). At week 12, 34 (94%) treated patients and 17 (48%) controls were HCV-RNA negative (P < 0.001). At 24 wk post-treatment (SVR), 31 (86%) treated patients and 15 (42%) controls were HCV-RNA negative (P < 0.001). Viral load, advanced fibrosis and vitamin D supplementation were strongly and independently associated with SVR (multivariate analysis). Adverse events were mild and typical of Peg-α-2b/ribavirin. CONCLUSION: Adding vitamin D to conventional Peg-α-2b/ribavirin therapy for treatment-naïve patients with chronic HCV genotype 1 infection significantly improves the viral response.

The role of endoscopy in the evaluation of iron deficiency anemia in premenopausal women.

BACKGROUND: Men and postmenopausal women with iron deficiency anemia are routinely evaluated to exclude a gastrointestinal source of suspected internal bleeding. Iron deficiency anemia in premenopausal women is often treated with simple iron replacement under the assumption that the condition is due to excessive menstrual blood loss. OBJECTIVES: To determine the yield of endoscopy evaluations in premenopausal women with iron deficiency anemia. METHODS: Upper and lower gastrointestinal endoscopic examinations were conducted in 45 premenopausal women with iron deficiency anemia not related to gynecologic or nutritional causes. RESULTS: Forty-three of the 45 women fulfilled the entry criteria and were enrolled. Their mean age was 35 +/- 15 years and their mean hemoglobin level 9.3 +/- 2.3 g/dl. Twenty-eight upper gastrointestinal lesions were demonstrated in 24 of the 43 patients (55.8%): erosive gastritis in 12 (27.9%), erosive duodenitis in 4 (9.3%), erosive esophagitis in 3 (7.0%), hiatus hernia (with Cameron lesions) in 3 (7.0%), active duodenal ulcer in 1 (2.3%) and hyperplastic polyp (10 mm) in 1 (2.3%). Five lower gastrointestinal lesions were detected in 5 patients (16.3%): 2 (4.6%) had adenocarcinoma of the right colon, 2 (4.6%) had pedunculate adenomatous polyp > 10 mm, and 1 (2.3%) had segmental colitis (Crohn's disease). One patient (2.3%) had pathologic findings in both the upper and lower gastrointestinal tracts. CONCLUSIONS: Our findings of a gastrointestinal source of chronic blood loss in 28 of 43 premenopausal women with iron deficiency anemia (65.1%) suggest that this population will benefit from bi-directional endoscopic evaluation of the gastrointestinal tract.

Trends in incidence of colorectal cancer in Jewish and Arab populations in central Israel.

BACKGROUND/AIMS: To compare the current differences with our earlier findings on the incidence and locations of colorectal cancer (CRC) among Israeli-born Jews and Arabs living within the same central coastal region in Israel. METHODS: Data on demographics and the incidence and locations of malignancies were retrieved from hospital files of pathology-diagnosed patients with CRC throughout 1997-2003 and compared with equivalent data from 1988 to 1996. RESULTS: Of the 624 patients recently diagnosed as having CRC, 562 (90.1%) were Jews and 62 (9.9%) were Arabs (p < 0.001). The average age of the entire cohort was significantly lower since our earlier study (72.9 +/- 12.5 compared to 67.9 +/- 12.7 years, p < 0.0001). The Jewish patients were significantly younger (p < 0.0001) but the Arab patients were not. The percentage of the adenocarcinoma being located in the right colon was significantly lower (p < 0.0006) and significantly higher in the rectum (p < 0.008). The reverse was true among the Jewish patients, but not significantly. CONCLUSIONS: Both study groups were younger than those in our earlier study. The lower incidence of CRC among the Arab patients persisted over time, but the location of their adenocarcinoma changed significantly. The increased incidence of CRC in 'westernized' countries is reflected in the Jewish but not the Arab community.

A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32.

We updated the clinical features of a consanguineous Arab Israeli family, in which four of seven children were affected by spastic paraplegia complicated by skin pigmentary abnormalities. A genomewide linkage screen performed for the family identified a new locus (SPG23) for this form of hereditary spastic paraplegia, in an approximately 25cM region of chromosome 1q24-q32, with a peak logarithm of odds score of 3.05.

Geographic clusters of primary biliary cirrhosis.

Genetic and environmental factors have been widely suggested to contribute to the pathogenesis of primary biliary cirrhosis (PBC), an autoimmune disease of unknown etiology leading to destruction of small bile ducts. Interestingly, epidemiologic data indicate a variable prevalence of the disease in different geographical areas. The study of clusters of PBC may provide clues as to possible triggers in the induction of immunopathology. We report herein four such unique PBC clusters that suggest the presence of both genetic and environmental factors in the induction of PBC. The first cluster is represented by a family of ten siblings of Palestinian origin that have an extraordinary frequency of PBC (with 5/8 sisters having the disease). Second, we describe the cases of a husband and wife, both having PBC. A family in which PBC was diagnosed in two genetically unrelated individuals, who lived in the same household, represents the third cluster. Fourth, we report a high prevalence of PBC cases in a very small area in Alaska. Although these data are anedoctal, the study of a large number of such clusters may provide a tool to estimate the roles of genetics and environment in the induction of autoimmunity.