Israel Medical Association Journal

Neuroendocrine tumors (NETs) are a group of rare, heterogenous neoplasms that maintain unique morphologic and clinical features of neuroendocrine neoplasia and account for approximately 0.5% of all newly diagnosed malignancies. NETs are divided into two groups based on their histopathological morphology: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Well differentiated NETs are classified as G1, G2, or G3 based on their proliferation rate, whereas NECs are highly proliferative and poorly differentiated by definition [1]. Neuroendocrine neoplasms can occur almost anywhere in the body; however, they are most often seen in the gastrointestinal tract, pancreas, and lungs [2]. The extrahepatic bile duct is one of the rarest primary sites for NETs, accounting for 0.1% to 0.2% of NETs of the gastrointestinal tract [3]. Signet ring cell bile duct NETs are extremely uncommon and have no established incidence and prognosis due to their rarity. There is sparse information available regarding these tumors, and only a few cases have been reported in the literature to date. In this report, we presented the clinical course and surgical management of a 31-year-old female patient with a Klatskin signet ring cell NET.

Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver disorders. Acute cholangitis (AC) is a life-threatening illness.

Objective: To determine whether NAFLD is a risk factor for the severity of AC.

Methods: We retrospectively studied hospitalized patients with a diagnosis of AC over 5 years. Patients were divided into a NAFLD group and a non-NAFLD group. We compared the two groups with regard to demographic characteristics, co-morbidities, laboratory data, and severity of AC (including Charlson Comorbidity Index [CCI] and Tokyo Consensus meeting criteria).

Results: In all, 298 of 419 hospitalized patients diagnosed with AC met the inclusion criteria. Of these, 73/298 (24.5%) were in the NAFLD group. NAFLD group patients were younger and more likely to be diabetic and obese than the non-NAFLD group. Participants in the NAFLD presented with higher serum C-reactive protein and higher liver enzymes (P < 0.05, for each parameter) and with more events of organ dysfunction (P < 0.001) and bacteremia (P < 0.005). Regarding the severity of AC according to Tokyo Consensus, among the NAFLD group more patients presented with Grade II (39.7 vs. 33.3%, P < 0.001) and Grade III (23.3 vs. 18.3, P < 0.001) cholangitis. More Grade I cholangitis was found among the non-NAFLD group (48.4 vs. 37%, P < 0.001). Multivariate logistic regression analysis showed that NAFLD was independently associated with severe AC, Grade III (odds ratio 3.25, 95% confidence interval 1.65–6.45, P = 0.038).

Conclusions: NAFLD is an independent risk factor for the severity of AC.

Background: Non-alcoholic fatty liver disease (NAFLD) is emerging as an important public health condition. The effect of Ramadan fasting on several metabolic conditions has been previously assessed.

Objectives: To assess the impact of Ramadan fasting on non-alcoholic steatohepatitis (NASH) severity scores.

Methods: A retrospective, case control study was conducted in Nazareth Hospital between 2017 and 2019. We included NAFLD patients who had been diagnosed by abdominal ultrasonography. The study population was divided in two matched groups: NASH subjects who fasted all of Ramadan and NAFLD/NASH subjects who did not fast (control). Metabolic/NASH severity scores, homeostatic model assessment of β-cell function and insulin resistance (HOMA-IR), NAFLD Fibrosis Score (NFS), BARD scores, and fibrosis-4 (FIB4) scores were assessed in both groups before and after the Ramadan month.

Results: The study included 155 NASH subjects, 74 who fasted and 81 who did not. Among the fasting group, body mass index decreased from 36.7 ± 7.1 to 34.5 ± 6.8 after fasting (P < 0.003), NFS declined from 0.45 ± 0.25 to 0.23 ± 0.21 (P < 0.005), BARD scores declined from 2.3 ± 0.98 to 1.6 ± 1.01 (P < 0.005), and FIB4 scores declined from 1.93 ± 0.76 to 1.34 ± 0.871 (P < 0.005). C-reactive protein decreased from 14.2 ± 7.1 to 7.18 ± 6.45 (P < 0.005). Moreover, HOMA-IR improved from 2.92 ± 1.22 to 2.15 ± 1.13 (P < 0.005).

Conclusions: Ramadan fasting improved on inflammatory markers, insulin sensitivity, and noninvasive measures for NASH severity assessment.

Background: While the routine performance of terminal ileum (TI) intubation during colonoscopy procedures is perceived to have a low yield, its utility during colonoscopies performed for specific indications have not been well studied.

Objectives: To assess the diagnostic yield of an indication-based ileoscopy in real-life practice.

Methods: The authors reviewed endoscopic reports of patients who underwent colonoscopies over an 8-year period (2011–2018) and had routine ileoscopy during these procedures. Demographic data, indications for colonoscopy, and endoscopic findings were documented. Diagnostic yield and odds ratio for TI findings were calculated.

Results: Over 30,000 colonoscopy reports performed during the study period were reviewed. Ilesocopy was performed in 1800 patients, 216 patients had findings in the TI (ileitis or ulcers). TI findings were more prevalent in younger ages (38.3 ± 17.6 vs. 43.6 ± 20, P < 0.05). The greatest yield of ileoscopy was evident when performed for the evaluation of chronic abdominal pain and diarrhea (14.4% vs. 9.3%, odds ratio [OR] 1.62, P < 0.05). Positive fecal occult blood test (FOBT) (OR 0.1, 95% confidence interval [95%CI] 0.02–0.5, P = 0.005) and constipation (OR 0.44, 95%CI 0.2–0.9, P = 0.04) were negatively associated with TI findings.

Conclusions: Ileoscopy may have the greatest utility in evaluating suspected inflammatory bowel disease (IBD) patients, but may not add value to the evaluation of constipation and positive FOBT

Background: Bariatric surgery has become the most common and effective therapeutic option for obesity. However, it is associated with morbidity and complications. Identification of predictors for surgical complications is an unmet need.

Objectives: To determine a simple non-invasive parameter that predicts early postoperative complications following bariatric surgery.

Methods: In this retrospective study of all patients who underwent elective bariatric surgery at Nazareth Hospital EMMS during a 4-year period (2015–2018). We collected clinical and laboratory parameters and determined predictors of complications.

Results: A total of 345 patients underwent bariatric surgery during the study period. Of the patients, 51 experienced early post-bariatric surgery complications as compared to 294 patients who had no complications. Univariate analysis revealed that neutrophil-to-lymphocyte ratio (NLR) (odds ratio [OR] 1.912, P < 0.0001) and platelet to lymphocyte ratio (OR 1.015, P < 0.0001) were associated with post-bariatric surgery complications. In a multivariate logistic regression analysis, only NLR remained a significant predictor (OR 1.751, 95% confidence interval 1.264–2.425, P = 0.0008) with a receiver operating characteristic curve for NLR of 0.8404.

Conclusions: We found that the NLR predicts post bariatric surgery early complications. Further prospective studies are needed to validate our findings.

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: Crohn’s disease and ulcerative colitis are the two major classic presentations of inflammatory bowel diseases (IBD). Studies have shown a wide variation in the incidence and prevalence attributed to different geographic and ethnic populations.

Objectives: To assess the clinical characteristics of IBD among Arabs in Israel and to compare them to characteristics of IBD among Ashkenazi Jews.

Methods: This retrospective, comparative study compared the clinical characteristics of IBD among 150 Arabs from the Holy Family Hospital and the Nazareth Hospital EMMS, both located in Nazareth, Israel, to those of 97 age- and sex-matched Ashkenazi Jewish patients from Shaare Zedek Medical Center, Jerusalem, Israel.

Results: The Arab cohort, which included 106 patients (70%) with Crohn's disease and 44 (29%) with ulcerative colitis, was compared to 97 Ashkenazi patients (81% with Crohn's disease and 17% with ulcerative colitis) (P < 0.05). Alcohol consumption was found in both groups, but Arabs smoked more (46% vs. 12%, respectively, P < 0.05). Obstructive phenotype was lower in Arabs (10% vs. 32%, P < 0.05). 5-aminosalicylic acid and anti-tumor necrosis factor alpha were prescribed for the Arab and Ashkenazi groups (89% and 21%, respectively). The need for surgical intervention due to disease severity and/or complications was not significant (22% vs. 24%).

Conclusions: Despite similar reports of NOD2/CARD15 mutations, Crohn's disease is more common than ulcerative colitis within the Arab-Israeli population. Increased smoking rates may explain milder disease severities in Arabs, as reflected by lower obstructive pattern and frequent use of milder therapeutic modalities.

Autoimmune pancreatitis (AIP) is a rare disease that has been classified into two subtypes. Type 1 is believed to be mediated by immunoglobulin G4 (IgG4) and type 2 is related to granulocytic epithelial lesions, but the pathogenetic mechanisms in both are still unknown. The patho-mechanism of AIP type 1 is suggested to be secondary to autoimmunity or allergy due to the increased serum IgG4 and immunoglobulin E levels, abundant infiltration of IgG4, plasmacytes and lymphocytes in the pancreas, and fibrosis. Both types of AIP respond to steroid treatment. The relapse rate after remission is high and reaches 30–50% within 6–12 months in AIP type 1; however, in AIP type 2 relapse is rare. The maintenance therapy and therapeutic strategy for relapsing patients with type 1 is managed with low dose steroids, however there are no consensus guidelines. In this review we discuss the current understanding of AIP, highlighting the emerging potential role of eotaxin in pathogenesis, classification, and management of the disease

Background: Recently, studies have found that non-alcholic fatty liver disease (NAFLD) is associated with bacterial infections. Attempts to identify risk factors for recurrent urinary tract infections (rUTIs) are still underway.

Objectives: To examine a possible association between NAFLD and rUTIs among premenopausal women.

Methods: In a case-control study, 1009 hospitalized premenopausal women with a UTI during a period of 3 years were retrospectively studied. A total of 186 subjects with rUTIs and 186 controls without a history of rUTIs were included in this study. Each participant had an abdominal ultrasonogram as part of the inclusion criteria. The two groups were compared in terms of risk factors for rUTIs, such as maternal history of rUTIs, use of contraceptives, frequency of sexual intercourse, metabolic syndrome, obesity, use of probiotics, serum levels of vitamin D, and NAFLD. An rUTI was defined as three or more episodes of UTI over a period of 1 year. NAFLD was diagnosed based on abdominal ultrasonography examination.

Results: Mean age of the 372 participants was 39.7 ± 5 years. NAFLD was diagnosed in 81/186 subjects (43.5%) with rUTIs vs. 40/186 controls (21.5%), P = 0.05. Women with rUTIs were more often obese and presented with lower serum levels of vitamin D than controls. Multivariate analysis showed that NAFLD (odds ratio = 1.6, 95% confidence interval 1.3–2.0, P = 0.04) were associated with rUTIs in premenopausal women.

Conclusions: NAFLD was associated with rUTI in premenopausal women, independent of metabolic syndrome. Further studies are needed to confirm this association.

Background: The prevalence of Helicobacter pylori varies geographically by age, race, and socioeconomic status (SES). However, the impact of ethnicity on endoscopic outcomes in infected individuals is not well known.

Objectives: To assess the impact of ethnicity among Israelis with biopsy-proven H. pylori infection.

Methods: A retrospective study, including patients who underwent gastroscopy and were diagnosed histologically with H. pylori infection, was conducted. Information on demographics, SES, medications, and co-morbidities were extracted from medical records. Univariate (Student's t-test, chi-square test) and multivariate (multinomial and logistic) regression analysis were conducted to examine the predictors of the clinical outcome.

Results: The study included 100 Israeli Jews and 100 Israeli Arabs diagnosed with biopsy-proven H. pylori infection. At univariate analysis, the number of households was higher among Arabs (P < 0.001), whose family income and parental education were lower than among Jews (P < 0.001 for both variables). The response to amoxicillin and clarithromycin differed between the two groups, being higher among Jews (P < 0.001).In clinical outcomes (gastritis severity, gastric and duodenal ulcer, intestinal metaplasia, atrophic gastritis, and MALT), no statistically significant differences could be detected between Jews and Arabs. Concerning intestinal metaplasia, lack of consumption of nonsteroidal anti-inflammatory drugs resulted a statistically significant protective factor (odds ratio 0.128, 95% confidence interval 0.024–0.685, P = 0.016).

Conclusions: Although in the literature ethnicity seems to be a risk factor for H. pylori colonization, no statistical significance was detected in various endoscopic and histological findings related to H. Pylori infection between Israeli Arabs and Jews.

Background: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease which refers to the presence of hepatic steatosis. Breast cancer is now the most common cancer in women and is the leading cause of death from cancer among women.

Objectives: To assess the relationship between NAFLD and newly diagnosed cases of breast cancer.

Methods: The results of mammography screening examinations in women referred to the Breast Center, Holy Family Hospital, Nazareth during a 4 year period were collected. We identified cases of women who were newly diagnosed with breast cancer and who underwent abdominal computed tomography (CT) within 1 month of the diagnosis. The control group comprised 73 women with normal mammography and breast ultrasonography who underwent abdominal CT within 3 months from the date of the breast cancer screening during the same study period. The control cases were matched by age and body mass index (BMI). We compared the cases with the controls in terms of the presence of diffuse hepatic fatty liver and other known risk factors for breast cancer.

Results: Of the 133 women who were screened, 73 with new diagnosis of breast cancer were eligible for the study. NAFLD was found in 33 of the women with breast cancer and in 12 in the control group (45.2% vs.16.4%, respectively, P = 0.002). Multivariate analysis showed NAFLD (odds ratio 2.82, 95% confidence interval 1.2–5.5, P = 0.016) to be associated with breast cancer.

Conclusions: NAFLD is associated with breast cancer.

Background: Hyperplastic polyps (HPs) of the colon are the most common colorectal polyps. Metabolic syndrome components such as obesity and hyperlipidemia are considered the most common etiological factors for HPs as well contributing to the pathogenesis of fatty liver disease. Objectives: To determine the possible association between biopsy-proven steatohepatitis and hyperplastic colonic polyps. 

Methods: This retrospective cohort observational study conducted at the Holy Family Hospital in Nazareth, Israel, included subjects who underwent screening colonoscopy over a 2 year period. Data were extracted from the patient charts and included demographics, anthropometric measurements, vital signs, underlying diseases, medical therapy, laboratory data, and results of the liver biopsy. The colonoscopy report and pathological report of each extracted polyp were also evaluated.

Results: A total of 223 patients were included in the study: 123 patients with biopsy-proven non-alcoholic steatohepatitis (NASH) and 100 patients without NASH who served as the control. Fourteen colonic adenomas (11% of patients) were found in the NASH group vs. 16 (16%) in the control group (P = 0.9); 28 HPs were found in the NASH group (22.7%) vs. 8 in the control group (8%) (P < 0.05). The multivariate analysis, after adjusting for, age, C-reactive protein and smoking, showed that the presence of NASH (OR 1.69, 95%CI 1.36–1.98, P < 0.01) was associated with increased risk for HP. 

Conclusions: Our study found an association between biopsy-proven steatohepatitis and the burden of hyperplastic polyp.