Israel Medical Association Journal

Hepatitis E Virus (HEV), a single-stranded RNA virus, is the leading cause of viral-induced acute liver failure globally. It is estimated to infect 20 million people annually, resulting in 3.3 million symptomatic cases and 44,000 deaths, worldwide [1]. Transmission is fecal-oral through contaminated food and water, zoonotic spread, or blood transfusions, and usually results in a self-limiting disease. While prevalent in resource-limited countries, cases are sporadic in the developed world [1]. Established risk factors for severe HEV infection include pregnancy, immunocompromised state, and underlying liver disease, while reports of malignancy as a predisposing factor are not well documented [1]. Here we present a case of a patient who, without established risk factors, developed a severe HEV infection leading to multiorgan failure and death.

Background: Hepatitis D virus may cause a disease at various severities in the presence of hepatitis B virus, using hepatitis B surface antigen (HBsAg) on the external envelope in its replication process. Thus, people identified with HBsAg in blood tests should also be tested for hepatitis D virus.

Objectives: To describe the situation of performance of blood tests for detection of hepatitis D virus in patients positive for hepatitis surface antigen during 9 years in a population with heterogeneous origins in the north region of Israel.

Methods: We conducted a retrospective study using the database of Clalit Health Services.

Results: We found 3367 people were positive for HBsAg during the study period; 613 (18%) were tested for hepatitis D. People who tested for hepatitis D were younger (47.3 ± 15 years vs. 50.5) and showed a higher rate of visiting the gastroenterology clinic (80.6% vs. 41%). The rate of positive blood tests for hepatitis D was too small for analysis, but it still demonstrated tendency for higher rates in the Ethiopian Jewish group.

Conclusion: The recommendation for performance of blood test for hepatitis D virus was followed to a small extent. Considering the ethnic diversity of the population in Israel, activities to raise rates of performance should be considered.

Background: New direct acting antiviral agent (DAA) therapies are associated with a high sustained virological response rate (SVR) in hepatitis C virus (HCV) patients. The understanding of the impact of SVR on fibrosis stage is limited.

Objectives: To determine the effect of treatment with the DAAs on long-term liver fibrosis stages, as determined by shear-wave elastography (SWE) or FibroTest©.

Methods: Fibrosis stage was determined at baseline and at 6-month intervals after end of treatment (EOT), using two‐dimensional SWE or FibroTest©; APRI and FIB-4 scores.

Results: The study comprised 133 SVR12 patients. After a median follow-up of 15 months (range 6–33), liver fibrosis stage decreased by at least 1 stage in 75/133 patients (56%). Cirrhosis reversal was observed in 24/82 (29%). Repeated median liver stiffness SWE values in cirrhotic patients were 15.1 kPa at baseline (range 10.5–100), 13.4 kPa (range 5.5–51) at 6 months, and 11.4 kPa (range 6.1–35.8) at 12 months after EOT, P = 0.01. During the second year after EOT, no statistically significant differences in liver fibrosis stage in 12, 18, and 24 months were found. Splenomegaly was the only significant negative predictor of liver fibrosis regression during all time points of repetitive noninvasive assessment.

Conclusions: Following successful DAA treatment, the majority of our HCV patients with advanced fibrosis demonstrated significant improvement, as assessed by non-invasive methods. Advanced fibrosis stage was a negative predictor of fibrosis regression. Longer follow-up periods are required to further establish the impact of DAAs treatment in HCV patients with advanced fibrosis

Background: Point shear-wave elastography (pSWE) is a new method to assess the degree of liver fibrosis. It has been shown to be effective in detecting stiffness in viral hepatitis.

Objectives: To determine the feasibility of pSWE for assessing liver stiffness and fibrosis in liver diseases of different etiologies.

Methods: This prospective single-center study included a population of adult patients with chronic liver diseases from different etiologies, who were scheduled for liver biopsy, and a control group of healthy adults who prospectively underwent pSWE. Ten consecutive pSWE measurements of the liver were performed using a Philips iU22 ultrasound system. Stiffness degree was compared to liver biopsy results. Fibrosis degree was staged according to METAVIR scoring system.

Results: The study group was comprised of 202 patients who underwent liver biopsy and pSWE test and a control group consisting of 14 healthy adults who underwent pSWE for validation. In the study group, the median stiffness was 5.35 ± 3.37 kilopascal (kPa). The median stiffness for F0–1, F2, F3, and F4 as determined by liver biopsy results were 4.9 kPa, 5.4 kPa, 5.7 kPa, and 8 kPa, respectively. The median stiffness in the control group was 3.7 ± 0.6 kPa. Subgroup analyses were conducted for viral hepatitis vs. non-viral hepatitis and steatohepatitis vs. non-steatohepatitis groups.

Conclusions: pSWE is a reproducible method for assessing liver stiffness and is in a linear relationship with fibrosis degree as seen in pathology. Compared with patients with non-significant fibrosis, healthy controls showed significantly lower values

Background: Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Several viral and host factors related to viral response have been reported in the era of treatment with pegylated (PEG)-interferon and ribavirin.

Objectives: To quantify histological findings from patients with chronic HCV using computerized morphometry and to investigate whether the results can predict response to medical treatment with peg-interferon and ribavirin.

Methods: We followed 58 patients with chronic HCV infection with METAVIR score F1 and F2 in our liver unit who were grouped according to treatment response sustained viral response (SVR) and non-SVR. Liver needle biopsies from these patients were evaluated and histological variables, such as inflammatory cells, collagen fibers and liver architecture, were quantified using computerized morphometrics. The pathologist who performed the histomorphometric analysis was blinded to previous patient clinical and histological information.

Results: Histomorphometric variables including the density of collagen fibers were collected. The number of inflammatory cells in the portal space and textural variable were found to be statistically significant and could be used together in a formula to predict response to treatment, with a sensitivity of 93% and a 100% specificity.

Conclusions: Histomorphometry may help to predict a patient's response to treatment at an early stage.

Background: Opposition to neonatal Hepatitis B vaccination is a growing trend in Israel.

Objectives: To assess the sociodemographic factors and attitudes associated with non-vaccination of term singleton newborns.

Methods: This prospective, pair-matched, controlled trial was conducted in a tertiary university-affiliated hospital. Data on maternal sociodemographic parameters, delivery, and infant care practices were gathered. Knowledge and references of Hepatitis B virus (HBV) vaccination, vaccination schedule, and health government policies were assessed. A follow-up telephone survey was completed at the age of 7 weeks postpartum regarding vaccine catch-up rate.

Results: Mothers in the study group were mostly Jewish white middle class married multiparous women with some higher education. Hepatitis B serology was not tested in most. Higher rates of rooming-in and exclusive breastfeeding were observed. Knowledge about HBV was stated, multiple sources of information were significantly associated with newborn non-vaccination. Many objected to the timing of the vaccine and its necessity. Multiple medical encounters are viewed as missed opportunities.

Conclusions: Multiple sources of vaccine information are associated with non-vaccination. Medical encounters prior and post-delivery should be used for vaccination education and may improve vaccination coverage.

Background: Autoimmune hepatitis (AIH) may be associated with other autoimmune diseases. Autoantibodies are common in AIH suggesting their potential role in the pathogenesis of the disease. Among these autoantibodies, thyroid autoantibodies have been reported in patients with chronic hepatitis, with greater prevalence in patients with chronic hepatitis C infection.

Objectives: To assess the prevalence of thyroid dysfunction among patients with AIH.

Methods: In this case-control, retrospective study, we examined patients diagnosed with AIH according to both the original and revised international AIH group scoring systems. Patients with other hepatic pathologies were excluded AIH was evaluated as an independent risk factor for thyroid disease by a logistic regression model. Univariate and multivariate regression analyses were conducted using hypothyroidism and hyperthyroidism as the dependent variables.

Results: Our cohort comprised 163 patients diagnosed with AIH and 1104 healthy age- and gender-matched controls. Hypothyroidism was more prevalent among those with AIH compared to controls (17.7% vs. 5%, respectively, 95% confidence interval [95%CI] 1.68–2.48, P <  0.001). Hyperthyroidism was more prevalent in AIH patients compared to controls (odds ratio 3.2% and 1.2%, respectively, 95%CI 1.68–2.47, P <  0.001). Using a multivariate logistic analysis, we found an independent association between AIH and hypothyroidism but not with hyperthyroidism.

Conclusions: Thyroid dysfunction is more prevalent in patients with AIH. Whether thyroid dysfunction is the cause or a risk factor for AIH, or vice versa, is still unclear. Screening for thyroid dysfunction is warranted after AIH is diagnosed.

Background: In developed countries, hepatitis A virus (HAV) infection occurs mainly in adults. It is usually symptomatic and may cause acute liver failure (ALF). In patients with chronic liver disease, serum ferritin levels (SFL) can predict short-term prognosis.

Objectives: To determine whether admission SFL can serve as a prognostic marker in patients with HAV infection.

Methods: A retrospective analysis of 33 adults with HAV infection was conducted. Because none of our patients presented with ALF, the parameter "length of hospital stay," was used as a surrogate marker of disease severity.

Results: The mean (± SD) at admission SFL was 2529 ± 4336 ng/ml. SFL correlated with the levels of international normalized ratio (INR), liver enzymes, and degree of hemolysis that occurred during the disease course. SFL did not correlate with the levels of either albumin or bilirubin or with the length of the hospital stay. The mean length of hospital stay was 5.1 ± 2.0 days, which correlated with the levels of INR, albumin, and bilirubin as well as the degree of hemolysis. However, in multivariate analysis only albumin and bilirubin predicted the length of the hospital stay. Follow-up SFL, which were available only in eight patients, decreased during the hospital stay.

Conclusions: In adults with acute HAV infection, SFL may be increased. SFL correlated with the degree of liver injury and hemolysis that occur during the disease. However, in our cohort of HAV patients, who had a relatively benign disease course, SFL were of no prognostic value.

Serum rheumatoid factors are autoantibodies of different isotypes directed against the Fc fraction of immunoglobulin G (IgG) and represent paradigmatic autoantibodies that have been largely used in clinical practice for decades. Traditionally IgG has been associated with rheumatoid arthritis and more recently included also in the classification criteria for Sjӧgren’s syndrome. Researchers have established that rheumatoid factors are positive in a variety of infectious, autoimmune, and neoplastic disorders, thus requiring a comprehensive evaluation of seropositive patients. Of note, hepatitis B and C viruses represent a crossroad that includes the high rheumatoid factor seroprevalence and chronic inflammatory disease, as well as progression to non-Hodgkin's lymphomas. Chronic antigen stimulation is the likely common ground of these processes and rheumatoid factors may represent mere bystanders or drivers of pathology. Mixed cryoglobulinemia and lymphoproliferative disease are prime examples of the deleterious effects of rheumatoid factor-B cell activity, possibly associated with hepatitis B and C. More importantly, they show a clear association in a physiological host response to infection, chronic inflammation, and the slide toward autoimmunity and malignancy. The association between hepatitis B and C infections and the appearance of serum rheumatoid factors is further supported by prevalence data, which support a coexistence of these markers in a significant proportion of cases, with viral infections being frequent causes of rheumatoid factors in patients without a rheumatic condition. We provide a comprehensive overview of the known connections between hepatitis B and C infections and rheumatoid factors.

Background: Since the implementation of a hepatitis A virus (HAV) immunization program for children, which began in 1999 in Israel, HAV infections in the country have occurred mostly in adults. HAV infection in adults is usually symptomatic and may present with hepatic, as well as extrahepatic, abdominal complications.

Objectives: To estimate the prevalence of extrahepatic abdominal complications in patients diagnosed with HAV.

Methods: Most extrahepatic abdominal complications corresponding to HAV infection have ultrasonographic manifestations; therefore, we retrospectively collected findings from ultrasound examinations in addition to laboratory data from adult patients with HAV infection who were admitted to our medical center between 2004 and 2016. Associations between ultrasonographic findings and laboratory parameters that reflect disease severity were identified.

Results: A total of 43 consecutive adult patients were included in this study. None presented with fulminant hepatic failure. Thirty patients (70%) had at least one ultrasonographic finding. Ascites was noted in 8 patients, a thickened gallbladder wall was observed in 14, pericholecystic fluid was found in 8, and biliary sludge was observed in 4. Significant associations included the presence of any ultrasonographic finding and peak total bilirubin levels (P = 0.021), the presence of ascites with peak aspartate and alanine aminotransferase levels (P = 0.041 and P = 0.038, respectively), and the presence of biliary sludge and nadir albumin during the HAV disease course (P = 0.037).

Conclusions: Abdominal ultrasonographic findings, such as ascites and gallbladder abnormalities, are frequently observed during acute HAV infection and are significantly associated with disease severity.

Background: Shortened telomeres were found in patients with cirrhosis, probably reflecting chronic liver injury, continuous regeneration, and destruction of hepatic nodules.

Objectives: To test whether telomere shortening is a general marker of cirrhosis, independent of disease etiology.

Methods: We evaluated telomere length in patients with cryptogenic cirrhosis (largely a late sequela of steatohepatitis) compared to patients with cirrhosis caused by chronic hepatitis B and C (HBV/HCV). We also evaluated telomere aggregates, a sensitive parameter of telomere dysfunction and genetic instability. We analyzed peripheral lymphocytes from 25 patients with cryptogenic cirrhosis, 15 patients with cirrhosis due to chronic viral hepatitis, and 20 age-matched controls. Telomere length was analyzed using quantitative fluorescence in situ hybridization. Aggregate size was divided into three fusion groups of 2–5, 6–10, and 11–15 telomeres, relative to the size of a single telomere.

Results: Shorter telomere length was found in patients with cirrhosis from all three etiologies (mean 121.3 ± 24.1) compared to controls (mean 63.5 ± 23.5). In contrast, there was significantly more fusion of > 5 telomeres only in the HBV/HCV cirrhosis group compared to healthy controls (P = 0.023), but not in the cryptogenic cirrhosis group.

Conclusions: While shortened telomeres in peripheral lymphocytes are a general marker of liver cirrhosis, telomere aggregates may signify a more sensitive genetic instability parameter for the diverse, etiology-based malignant potential of cirrhosis. This finding is in agreement with the well-known higher tendency toward developing hepatocellular carcinoma with cirrhosis caused by chronic hepatitis relative to steatohepatitis.

Background: Accurate assessment of liver fibrosis is crucial for the management of patients with hepatitis C virus (HCV) infection.

Objectives: To evaluate the performance of liver segment-to-spleen volume ratio in predicting the severity of liver fibrosis.

Methods: Sixty-four consecutive HCV patients were enrolled in this retrospective study. All patients underwent contrast-enhanced computed tomography (CT) and were divided into three groups based on their hepatic fibrosis stage evaluated by shear-wave elastography (SWE): non-advanced (F0–F1, n=29), advanced (F2, n=19) and severe fibrosis (F3–F4, n=16). Using semi-automated liver segmentation software, we calculated the following liver segments and spleen volumes for each participant: total liver volume (TLV), caudate lobe (CV), left lateral segment (LLV), left medial segment (LMV), right lobe (RV) and spleen (SV), a well as their ratios: CV/SV, RV/SV, LLV/SV, LMV/SV and TLV/SV.

Results: RV/SV was found to discriminate between patients with non-advanced and advanced fibrosis (P = 0.001), whereas SV, CV, RV, TLV/SV, LMV/SV and RV/SV discriminated between patients with advanced and severe fibrosis (P < 0.05). RV/SV ≤ 3.6 and RV ≤ 2.9 were identified as the best cutoff values to differentiate non-advanced from advanced fibrosis and advanced from severe fibrosis with sensitivities of 72.2% and 92.7%, specificities of 72.7% and 77.8%, and with an area under the receiver operating characteristic (ROC) curve of 0.797 and 0.847, respectively (P ≤ 0.002).

Conclusions: RV/SV may be used for the assessment and monitoring of liver fibrosis in HCV patients prior to the administration of antiviral therapy, considering SWE as the reference method.