Sadettin Hulagu

Association of apolipoprotein E polymorphisms in patients with non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal hepatic steatosis in the absence of alcohol abuse worldwide. Non-alcoholic steatohepatitis (NASH) is the most progressive form of NAFLD. The aim of this study was to investigate the role of apolipoprotein E (APOE) polymorphisms in the development of NASH. We analysed 57 NASH patients and 245 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a case–control study. The diagnosis of the patients was based on liver biopsy. The serum levels of glucose, lipids, vitamin B12, folic acid, homocysteine, insulin, total biluribin, total protein, albumin, ferritin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined in all of the subjects. Body mass index (BMI), waist circumference (WC), AST, ALT, fasting blood sugar (FBS), total cholesterol, triglyceride (TG), low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, insulin and ferritin levels were significantly higher in the 57 patients with NASH compared with the 245 healthy controls. The APOE ε3 allele was overrepresented in the whole group of NASH patients (ε3=97.37% in NASH versus 82.45% in controls). The APOE polymorphism was statistically significantly associated with NASH (χ2=15.741; p=0.008). The APOE3/3 genotype (odds ratio [OR]=7.941; p=0.000) was strongly associated with increased risk for NASH in all NASH patients. Consequently, the APOE3/3 genotype may play a role in the aetiopathogenesis of NASH.

Clinical characteristics of inflammatory bowel disease in Turkey: a multicenter epidemiologic survey.

Aim To investigate the epidemiologic and clinical characteristics of inflammatory bowel disease (IBD) patients in a large multicenter, countrywide, hospital-based study in Turkey. Materials and Methods Twelve centers uniformly distributed throughout Turkey reported through a questionnaire the new IBD cases between 2001 and 2003. The incidence of ulcerative colitis (UC) and Crohns disease (CD) has been reported per 100,000 people. Epidemiologic features and clinical characteristics of both diseases were analyzed. Results During the study period, 661 patients of UC and 216 patients of CD were identified. The incidence in the referral population was 4.4/100,000 and 2.2/100,000 for UC and CD, respectively. The age of the patients showed the characteristic biphasic distribution with 2 peaks between 20 and 30 and 50 and 70 years. A male predominance was observed in both diseases. A history of smoking was detected in 15.5% of UC patients and 49.3% of patients with CD. Family history was positive in 4.4% in UC and 8.3% in CD patients. Concomitant amebiasis was observed in 17.3% of patients with UC and 1.3% of patients with CD. A history of appendectomy was reported in 15% of patients with CD and only 3% of patients with UC. Both extraintestinal and local complications were more frequent in CD patients, whereas arthritis was most common in both diseases. Conclusions IBDs are frequently encountered in Turkey. IBD incidence is lower than North and West Europe but close to Middle East in our country. The majority of IBD cases are diagnosed in young people (20 to 40 y) with predominance in males. The rate of both intestinal and extraintestinal complications in our population was low when compared with the data reported in the literature. IBD and especially UC, can coexist with amebiasis or become manifest with amebic infestation. The presence of concomitant ameba may create confusion and cause dilemmas in the diagnosis and treatment of UC.

The positivity of rheumatoid factor and anti-cyclic citrullinated peptide antibody in nonarthritic patients with chronic hepatitis C infection.

Chronic hepatitis C virus (HCV) has extrahepatic autoimmune properties and a variety of autoantibodies were found in patients with HCV. Patients with HCV infection may have rheumatic symptoms and signs, and 50–70% of the cases may contain rheumatoid factor (RF). The increased prevalence of RF in patients with HCV infection diminishes the diagnostic specificity of serum RF for rheumatoid arthritis (RA) in patients with HCV. Therefore, the presence of RF mostly does not help in distinguishing between RA and HCV-associated rheumatic symptoms. In this study, we studied whether cyclic citrullinated peptide (CCP) antibody, a highly specific biomarker for RA in the general population, was useful for the diagnosis of RA in nonarthritic patients with HCV (hepatitis C virus). Blood samples from 39 patients with chronic HCV infection, 87 normal sera from volunteer blood donors and 108 blood samples from patients with rheumatoid arthritis, from the rheumatology clinic, were taken. RF was measured using the Dade-Behring nephelometer and antibodies to CCP were measured with ELISA. According to statistical analysis, the sensitivity, specificity and positive predictive value of the anti-CCP test was superior to the RF test. Cyclic citrullinated peptide antibody is a more useful test than RF among patients with chronic HCV infection without arthritis.

PREVALENCE AND COMPARISONS OF FIVE DIFFERENT DIAGNOSTIC METHODS FOR HELICOBACTER PYLORI IN DIABETIC PATIENTS

Helicobacter pylori is now regarded as a major gastroduodenal pathogen that is etiologically linked with duodenal and gastric disease. It has been suggested recently as an important factor for nongastroenterologic conditions such as coronary heart disease and diabetes mellitus. In this study, we planned to investigate the prevalence of H. pylori in diabetic patients and to evaluate five different diagnostic tests. Group I consisted of 67 patients with type II diabetes mellitus and seventy-three aged-matched health people served as control in group II. Group I was divided in two subgroups with good (Group IA) and poor (Group IB) glycemic control. H. pylori was diagnosed by five different tests: 1) biopsy, 2) culture, 3) gram staining, 4) imprint cytology and 5) brushing cytology. The usefulness of each test for each group was statistically compared. There was a higher prevalence for H. pylori in diabetic patients. This study showed that two positive out of five tests was most reliable for predicting the H. pylori in diabetic and nondiabetic patients. In conclusion, the prevalence of H. pylori is high in diabetic patients. Peristaltic activity, and impaired nonspecific immunity must be evaluated as risk factors in diabetics. We recommend that the ‘gold standard’ should be regarded as two positive out of these five different tests.

Echinacea-induced severe acute hepatitis with features of cholestatic autoimmune hepatitis.

The use of herbal drugs has been increasing in all countries in recent years. Preparations made from plants of the genus Echinacea are widely used for the prevention and treatment of colds [1]. Hepatotoxicity related to phytomedicine requires a high level of suspicion, and the diagnosis is often delayed in clinical practice. There are no reports describing acute cholestatic autoimmune hepatitis (ACAH) induced by Echinacea in the medical literature. We herein report the case of a patient with ACAH due to Echinacea. A 45-year-old male patient was admitted to our hospital complaining of fatigue and jaundice of 1-week duration. The patient had caught a cold one month before admission. In spite of the disappearance of common cold symptoms within one week, fatigue and jaundice appeared one week before hospitalization. The patient denied use of medication in the initial history-taking; however, 3 days after he was admitted, he told us that he had started taking Echinacea (Echinacea root tb; 1500 mg/day) after catching the cold the previous month in order to strengthen his immune system. Physical examination revealed an icteric patient. Initial laboratory evaluation on admission showed a sedimentation rate of 54 mm/h, alanine aminotransferase 1260 IU/L (normal: b55 IU/L), aspartate aminotransferase 840 IU/L (normal: b34 IU/L), alkaline phosphatase 984 IU/L (normal: b150 IU/ L), gammaglutamyl transferase 672 IU/L (normal: b64 IU/L), total bilirubin 2.8 mg/dL (normal: b1 mg/dL), direct bilirubin 1.9 mg/dL (normal: b0.5 mg/dL), albumin 3.3 g/dL (normal: 3.5–5 g/dL), gamma globulin 5.2 g/dL (normal: 1.1–3.5 g/ dL), prothrombin time 19.2 s (normal: 12–15.5 s), and INR 1.3. The concentration of immunoglobulin G (IgG) was 2240mg/dL (normal: 751–1560mg/dL). Anti-smooth muscle antibodies (SMAs) were positive (titer 1:80). Anti-nuclear antibodies, anti-liver/kidney microsomes, anti-soluble liver antigen antibodies, and anti-mitochondrial antibodies were negative. Markers for viral hepatitis, ceruloplasmin, iron and ferritin levels, and alpha 1 antitrypsin level were not remarkable for acute hepatitis. Liver biopsy revealed interface hepatitis, prominent cholestasis, and portal lymphoplasmocytic and eosinophilic granulocyte infiltration. After admission, the patient stopped taking theEchinacea. By follow-up, the transaminases and cholestatic enzymes had spontaneously decreased. One month later, all laboratory values were normalized, except for SMA positivity. The presence of highly elevated liver enzymes, positive IgG and SMAs, and spontaneous normalization of laboratory values after dechallenge with Echinacea fit the diagnosis of Echinacea-induced ACAH. This is the first report of Echinacea-induced ACAH. Echinacea, with its effect of increasing the number and activity of immune system cells [2], may result in a breakdown of autoimmunity self-control in the liver, which may present with ACAH, in susceptible patients.

Monitoring of hepatitis B virus surface antigen escape mutations and concomitantly nucleos(t)ide analog resistance mutations in Turkish patients with chronic hepatitis B

BACKGROUND The hepatitis B virus (HBV) polymerase gene completely overlaps with the envelope gene. In the present study we aimed to monitor the prevalence and pattern of the typical mutations for hepatitis B surface antigen (HBsAg) escape, and concomitantly nucleos(t)ide analog (NUC) resistance mutations, in Turkish patients undergoing different antiviral therapies and in treatment-naïve patients with chronic hepatitis B (CHB). METHODS The investigation was undertaken between March 2007 and August 2009 and involved a total of 142 patients under NUC therapy (88 males; mean age 42 years (range 13-68); hepatitis B e antigen (HBeAg) negativity in 94 patients; HBV DNA median log 4.3 log(10) IU/ml (range 2.0->6.0); alanine aminotransferase (ALT) median level 76.1 IU/ml (range 12-1082)) and 185 treatment-naïve CHB patients (120 males; mean age 39 years (range 1-76 years); HBeAg negativity in 132 patients; HBV DNA median log 3.5 log(10) IU/ml (range 2.0-6.0); ALT median level 60.7 IU/l (range 8-874)). RESULTS The overall prevalence of typical HBsAg escape mutations found in the CHB patients was 8.3% (27/327). In the NUC therapy group the prevalence was 8.5% (12/142), with the following patterns: sY100C+sI110V, sL109I, sP120T, sP127T, sG130R+sG145X, sS132A+sY134N, sY134N+sG145R, sC137G, sD144E, sG145R. In the treatment-naïve group the prevalence was 8.1% (15/185), with the following patterns: sL109I, sI110V, sS117INST, sP120T, sP127T, sM133I, sC137L+sG145R, sS143L. However, NUC resistance mutations were found in 7.7% (11/142) of the patients on NUC therapy and 3.8% (7/185) of the treatment-naïve group patients. Interestingly, the treatment-naïve patients had preexisting drug resistance mutations related to lamivudine (rtL180M+rtM204I), adefovir (rtA181V, rtQ215S, rtI233V), entecavir (intermediate susceptibility with rtL180M+rtM204IHBV variant), telbivudine (rtL180M+rtM204I), and tenofovir (rtA194T). CONCLUSIONS The findings of this study show preexisting typical HBsAg escape and NUC resistance mutations are possible. The genetic arrangement of the HBV genome with polymerase and surface genes overlapping has substantial public health and diagnostic implications and relevance.

Endothelial dysfunction in patients with ulcerative colitis.

Background: Human intestinal microvessels from chronically inflamed ulcerative colitis (UC) show microvascular endothelial dysfunction. Whether generalized endothelial dysfunction could associate with UC has not been explored yet. Our aim was to assess the endothelial function in the patients with different UC activity and to hypothesize about the relationship of endothelial function to activity‐related extraintestinal complications (AREC) of UC. Methods: Twelve patients with mild UC, 14 patients with moderate UC, 16 patients with severe UC, and 24 healthy subjects were included in the study. The activity of UC is calculated according to the Seo Index. Endothelial functions of the brachial artery were evaluated by using high‐resolution vascular ultrasound. Endothelial‐dependent dilatation (EDD) was assessed by establishing reactive hyperemia and endothelial‐independent dilatation (EID) was determined by using sublingual isosorbide dinitrate. Results: EDD was significantly worse in patients with severe UC as compared with patients with mild UC (8.7 ± 1.6% versus 17.3 ± 5.6%, P < 0.05) and even in patients with moderate UC as compared with patients with mild UC (13.1 ± 3.2% versus 17.3 ± 5.6%, P < 0.05). EDD was not significantly worse in patients with mild UC as compared with healthy subjects (17.3 ± 5.6% versus 18.1 ± 8.1%, P > 0.05). EID was significantly worse in patients with severe UC compared with patients with moderate UC (10.5 ± 2.9% versus 13.4 ± 3.7%, P < 0.05) and even in patients with mild UC compared with healthy subjects (20 ± 6.7% versus 31.1 ± 12.6%, P < 0.05). EDD and EID were significantly worse in patients with AREC compared with patients with no AREC (9.5 ± 2.5% versus 14.9 ± 5.1%, P < 0.05; 11.6 ± 4.3% versus 16 ± 6.1%, P < 0.05, respectively). Conclusions: Increased activity of UC is associated with significant endothelial dysfunction, which may relate to the pathophysiology of AREC of UC.

Endoscopic submucosal dissection for premalignant lesions and noninvasive early gastrointestinal cancers.

AIM To investigate the indication, feasibility, safety, and clinical utility of endoscopic submucosal dissection (ESD) in the management of various gastrointestinal pathologies. METHODS The medical records of 60 consecutive patients (34 female, 26 male) who underwent ESD at the gastroenterology department of Kocaeli University from 2006-2010 were examined. Patients selected for ESD had premalignant lesions or non-invasive early cancers of the gastrointestinal tract and had endoscopic and histological diagnoses. Early cancers were considered to be confined to the submucosa, with no lymph node involvement by means of computed tomography and endosonography. RESULTS Sixty ESD procedures were performed. The indications were epithelial lesions (n = 39) (33/39 adenoma with high grade dysplasia, 6/39 adenoma with low grade dysplasia), neuroendocrine tumor (n = 7), cancer (n = 7) (5/7 early colorectal cancer, 2/7 early gastric cancer), granular cell tumor (n = 3), gastrointestinal stromal tumor (n = 2), and leiomyoma (n = 2). En bloc and piecemeal resection rates were 91.6% (55/60) and 8.3% (5/60), respectively. Complete and incomplete resection rates were 96.6% (58/60) and 3.3% (2/60), respectively. Complications were major bleeding [n = 3 (5%)] and perforations [n = 5 (8.3%)] (4 colon, 1 stomach). Two patients with colonic perforations and two patients with submucosal lymphatic and microvasculature invasion (1 gastric carcinoid tumor, 1 colonic adenocarcinoma) were referred to surgery. During a mean follow-up of 12 mo, 1 patient with adenoma with high grade dysplasia underwent a second ESD procedure to resect a local recurrence. CONCLUSION ESD is a feasible and safe method for treatment of premalignant lesions and early malignant gastrointestinal epithelial and subepithelial lesions. Successful en bloc and complete resection of lesions yield high cure rates with low recurrence.

Comparison of the effects of esomeprazole 40 mg, rabeprazole 20 mg, lansoprazole 30 mg, and pantoprazole 40 mg on intragastrıc pH in extensive metabolizer patients with gastroesophageal reflux disease.

BACKGROUND/AIMS Studies on the therapeutic efficacy of proton pump inhibitors (PPIs) in patients with gastroesophageal reflux disease (GERD) have been recently published. In most of these studies, comparison of only two PPIs have been made. There are few studies on the comparison of four or more PPIs. We aimed to compare the acid inhibitory effects of esomeprazole 40 mg, rabeprazole 20 mg, lansoprazole 30 mg, and pantoprazole 40 mg on days 1 and 5 of treatment in patients with GERD, who were extensive metabolizers in regard to the CYP2C19 genotype. MATERIALS AND METHODS Helicobacter pylori-negative with typical symptoms of GERD patients were randomly divided into four treatment groups. Efficacy analysis on days 1 and 5 were performed on the four groups which comprised 10 (esomeprazole), 11 (rabeprazole), 10 (lansoprazole), and 10 (pantoprazole) patients. RESULTS On day 1 of PPI treatment, the mean percentage of time with intragastric Ph>4 were 54%, 58%, 60%, and 35% for the groups, respectively, and on day 5, these values were 67%, 60%, 68%, and 59%, respectively. Esomeprazole, rabeprazole, and lansoprazole were found to be superior to pantoprazole on the first day of treatment. CONCLUSION Pantoprazole is a less potent proton pump inhibitor than the other PPIs tested on the first day of treatment. When the time needed to raise the intragatric pH to over 4 was evaluated, esomeprazole was found to have the most rapid action, followed by lansoprazole and rabeprazole.

Adalimumab-induced psoriasis in a patient with Crohn's disease.

Sir: Inappropriate secretion of tumor necrosis factor alpha (TNF-α) leads to inflammation and tissue damage by causing excessive secretion of inflammatory cytokines especially IL-1 [1]. AntiTNF-α agents are used to treat a myriad of immune-based diseases. Although indicated in treating certain forms of psoriasis, TNF inhibitors have paradoxically been shown to cause or worsen psoriasis primarily in patients with underlying rheumatologic disease and inflammatory bowel diseases (IBD) [2, 3]. We present a case of plaque psoriasis in a patient with Crohn’s disease during adalimumab treatment. A 32-year-old female patient with the diagnosis of ileal Crohn’s disease for 5 years was started on adalimumab therapy (160 mg initially on day 1, followed by 80 mg on day 15, and a maintenance dose of 40 mg every other week) due to refractory disease. Following the loading dose, a marked improvement was seen in both clinical and laboratory indices (defined as a decrease in CDAI ≥100 points). In the fourth month of treatment, itchy irregular white desquamated plaques with surrounding hyperemia appeared on the extensor and partly flexor surfaces of the extremities and also on the scalp. Plaques with fissures were seen on the thenar parts of the hands (Fig. 1a, b). The patient was diagnosed with psoriasis. As psoriasis was believed to occur as a side effect of adalimumab, therapy was stopped and switched to methotrexate 15 mg/week plus infliximab 5 mg/kg/week in the 12th week of the treatment, laboratory findings were within normal range, and the patient suffered only from mild abdominal pain. Plaques were judged to show an improvement to a degree of approximately 90 % on the extremities and 50 % on the scalp. Treatment was maintained by adding topical therapies. Anti-TNF-α drugs play a key role in the treatment of IBD. Psoriasis is rarely seen in IBD patients using anti-TNF drugs and most of these cases are related to infliximab therapy [3–5]. The most common anti-TNF-α-related forms of psoriasis are plaque psoriasis and palmoplantar pustulosis [3, 5]. Signs occur after 1 to 96 months from the implementation of therapy [5]. Psoriasis development during anti-TNF-α therapy is believed to be a result of the disruption of the balance between TNF-α and interferon alpha [6]. Inhibition of TNF-α also leads to hyperproliferation of keratinocytes by decreasing levels of cytokines such as IL-6, IL-8, etc. [7]. Although there is no established treatment modality for such cases, stopping the offending drug provides a marked improvement. Switching to another drug from the same class, adding an immunomodulatory drug like methotrexate, and topical therapies (including vitamin D) are also recommended [3, 5, 6]. Although lesions might also heal during continuation of therapy, stopping the therapy yielded better responses [5]. In our case, both IBD and skin lesions (except scalp lesions) could be treated by stopping the offending drug and starting methotrexate along with infliximab (as Crohn’s disease was unresponsive to previous immunomodulatory therapies). Vitamin Dwhich has immunomodulatory effects (especially in plaque psoriasis) permits to lower the doses of other drugs used for the treatment of psoriasis [8]. Healing of plaques by vitamin D replacement is reported in adalimumab-induced psoriasis [9]. As skin lesions seen in IBD might be a manifestation of the disease, it should be always kept in mind that they might be the side effect of the drugs used for the treatment of the disease. U. Korkmaz (*) :A. E. Duman :G. Dindar :H. Yilmaz : A. Celebi :O. Senturk : S. Hulagu Department of Gastroenterology, Kocaeli University Medical Faculty, Umuttepe, 41900 Kocaeli, Turkey e-mail: drkorkmazugur@yahoo.com