TASL Practice Guidance on the Clinical Assessment and Management of Patients with Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease and is significantly associated with obesity, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. NAFLD has become the most prevalent chronic liver disease in Western countries, and the proportion of NAFLD-related cirrhosis among patients on liver transplantation waiting lists has increased. In light of the accumulated data about NAFLD, and to provide a common approach with multi-disciplines dealing with the subject, it has become necessary to create new guidance for diagnosing and treating NAFLD. This guidance was prepared following an interdisciplinary study under the leadership of the Turkish Association for the Study of the Liver (TASL), Fatty Liver Special Interest Group. This new TASL Guidance is a practical application guide on NAFLD and was prepared to standardize the clinical approach to diagnosing and treating NAFLD patients. This guidance reflects many advances in the field of NAFLD. The proposals in this guidance are meant to aid decision-making in clinical practice. The guidance is primarily intended for gastroenterology, endocrinology, metabolism diseases, cardiology, internal medicine, pediatric specialists, and family medicine specialists.

The Prevalence of Minimal Hepatic Encephalopathy in an Outpatient Hepatology Clinic.

BACKGROUND: Minimal hepatic encephalopathy can only be detected by specific psychometric or neuropsychological tests. We aimed to determine the prevalence of minimal hepatic encephalopathy in a hepatology outpatient clinic of a tertiary center. METHODS: A total of 82 patients with chronic liver disease were involved prospectively in this study. Control groups consisted of healthy volunteers (n = 123) and chronic renal failure patients (n = 28). We used 2 different methods to detect minimal hepatic encephalopathy. First method was a battery of 5 psychometric tests (number connection tests A and B, digit symbol test, serial dot test, line tracing test) which was filled by all patients. The second method was critical flicker frequency test. Both methods were used in the whole group (n = 233). We applied linear regression analysis to the results of psychometric tests of healthy volunteers to establish equations to calculate the expected values of each test. Test results of the patients were evaluated according to the expected results obtained from these equations. RESULTS: The prevalence of minimal hepatic encephalopathy detected by psychometric tests and critical flicker frequency test was 13% and 14%, respectively. When the positivity of both tests was deemed necessary to diagnose minimal hepatic encephalopathy, the rate of minimal hepatic encephalopathy was 3.6% (n = 3) in a chronic liver disease patient group. CONCLUSION: Minimal hepatic encephalopathy is a difficult clinical condition to diagnose, and it is more appropriate to use psychometric tests and critical flicker frequency test together.

Investigation of Obesity-Related HAdV-36 in NAFLD Patients: a Case-Control Study.

BACKGROUND: HAdV-36 leads to adipocyte proliferation of adipose tissue through E4orf1 gene, leading to the development of obesity and related diseases. We aimed to investigate the presence and any association of HAdV-36 in non-alcoholic fatty liver disease (NAFLD) patients Methods: The patient group was composed of 116 patients; 30 obese patients with NAFLD (BMI > 30 kg/m2), 30 patients with Diabetes Mellitus (DM)+NAFLD (BMI > 30 kg/m2), 16 patients with NAFLD (BMI < 30 kg/m2), and operated obese group with NAFLD (BMI > 30 kg/m2). The control group comprised 81 non-obese healthy adults. Liver adipose tissue samples were obtained in 30 operated NAFLD patients. HAdV-36-DNA, HAdV-36 neutralizing antibodies, serum lipid, and adipokine levels were analyzed. RESULTS: HAdV-36 neutralizing antibodies (HAdV-36 Ab-positive) were detected in 10/116 and 2/81 participants in the study and control groups, respectively; the difference was statistically significant (p < 0.005). LDL, total cholesterol but not adipokine levels were found to be significantly higher in HadV-36 Ab-positive patients (p < 0.05). While HAdV-36 was identified as a risk factor with OR = 4.11 in univariate analyses, there was no significant difference in binary logistic regression analysis. HAdV-36-DNA was detected in the adipose tissue samples of two patients. CONCLUSIONS: We suggest that the presence of HAdV-36 may lead to the development of obesity with the increase in adipose tissue, and diseases such as hyperlipidemia, NAFLD, DM, and metabolic syndrome may develop on the basis of chronic inflammation caused by obesity. Thus, HAdV-36 may be a plausible risk factor for the development of NAFLD.

Efficacy and Safety of Ombitasvir/Paritaprevir/ Ritonavir + Dasabuvir ± Ribavirin Combinations in Patients with Genotype 1 Hepatitis C and Inherited Bleeding Disorders.

BACKGROUND: Hepatitis C is one of the leading causes of death in patients with inherited bleeding disorders. Currently, direct-acting antiviral drugs used for the treatment of hepatitis C have become an effective and a reliable option for people with inherited bleeding disorders. The aim of this study is to report the efficacy and safety of ombitasvir + paritaprevir/ritonavir and dasabuvir combination in the treatment of hepatitis C in patients with inherited bleeding disorders. METHODS: In this retrospective study, we evaluated the efficacy and safety of the combination of ombitasvir + paritaprevir/ritonavir and dasabuvir in 10 adult patients with hemophilia A, 4 patients with hemophilia B, and 1 patient with von Willebrand disease who were infected with hepatitis C genotype 1. RESULTS: Five patients had genotype 1a and 10 patients had genotype 1b chronic hepatitis C. One patient had Child A cirrhosis, 14 patients had chronic hepatitis C without cirrhosis. Hepatitis C virus ribonucleic acid was negative in all patients at week 4 and at the end of the treatment. Sustained virologic response was obtained in all patients. Serious side effects were detected in 3 patients, which were intra- muscular bleeding, erosive gastritis-related gastrointestinal bleeding, and pneumonia. CONCLUSION: Ombitasvir + paritaprevir combined with ritonavir and dasabuvir ± ribavirin is an effective treatment for patients infected with genotype 1 hepatitis C who have coagulation disorders. Tolerance and side effects are similar to other treatment options.

Characteristics of Newly Diagnosed Hepatocellular Carcinoma Patients Across Turkey: Prospective Multicenter Observational 3K Registry Study.

AIMS: To evaluate patient profile for epidemiological and clinicopathological characteristics and potential risk/prognostic factors in newly diagnosed hepatocellular carcinoma (HCC) patients across Turkey. METHODS: A total of 547 patients (mean (SD) age 62.6 (10.3) years, 81.9% were males) were included in this registry study. Data on patient characteristics, etiologies of HCC, laboratory values, and tumor characteristics and stages were recorded at study enrollment. RESULTS: HBV infection (68.2%) was the leading etiology, followed by HCV infection (17.2%), HDV infection (5.5%), alcohol (6.4%), and NAFLD (3.5%), as the major etiologies. Considering that 51.6% of the patients had >5 cm HCC, 44% were Child-Pugh B/C and 57% were BCLC B-D, it appears that a significant group of HCC patients were diagnosed at advanced stages. Of 540 patients, 271 (50.2%) were referred or applied with the diagnosis of HCC. Patients with HCC at presentation had larger tumor size (median (min-max) 6.6 (0-30) vs. 4.8 (0-90) cm, P < .001) and more advanced BCLC stage (Stage C-D in 40.8% vs. 26.4%, respectively, P = .005), compared to patients who were diagnosed during follow-up. CONCLUSIONS: Our findings revealed that HBV infection was the leading etiology and a moderate-to-advanced disease was evident in more than half of patients at the time of diagnosis. HCC patients diagnosed at follow-up had smaller tumor size and earlier BCLC stage.

The effect of direct antiviral treatment on the depression, anxiety, fatigue and quality-of-life in chronic hepatitis C patients.

OBJECTIVE: In this study, we aimed to investigate the effects of direct antiviral treatment on depression, anxiety, fatigue and quality of life in patients with chronic hepatitis C. METHODS: Subjects included in study were treatment experienced and treatment naive chronic hepatitis C patients admitted to the hepatology outpatient clinic between December 2016 and June 2017. Before and after the treatment, Beck depression, Beck anxiety, liver-specific quality of life and fatigue severity-impact scales were administered. Descriptive statistical methods, Kolmogorov-Smirnov distribution test Wilcoxon sign and kappa coefficient tests were used to evaluate the study data. RESULTS: Forty-four patients were included in the study; however, it was completed with 35 patients only, as some of the patients were excluded for various reasons. There was no significant difference between depression and anxiety scores of the patients before and after the treatment, but depression and anxiety were found to be recovered in 28.5% (4/14) and 23.5% (4/17) of the subjects, respectively. At the end of the treatment, fatigue severity-impact scales and liver-specific quality of life were not significantly different from those before the treatment. CONCLUSION: In this study, we found that direct antivirals did not lead to depression, anxiety or fatigue and did not decrease liver-specific quality of life. In some cases, depression and anxiety decreased after the treatment.

Macroscopic Portal Vein Thrombosis in HCC Patients.

Macroscopic portal vein invasion (PVT) by hepatocellular carcinoma (HCC) in the liver is one of the most important negative prognostic factors for HCC patients. The characteristics of a large cohort of such patients were examined. We found that the percent of patients with PVT significantly increased with increasing maximum tumor diameter (MTD), from 13.7% with tumors of MTD <5cm to 56.4% with tumors of MTD >10cm. There were similar numbers of HCC patients with very large tumors with and without PVT. Thus, MTD alone was insufficient to explain the presence of PVT, as were high AFP levels, since less than 50% of high AFP patients had PVT. However, the percent of patients with PVT was also found to significantly increase with increasing blood alpha-fetoprotein (AFP) levels and tumor multifocality. A logistic regression model that included these 3 factors together showed an odds ratio of 17.9 for the combination of MTD>5.0cm plus tumor multifocality plus elevated AFP, compared to low levels of these 3 parameters. The presence or absence of macroscopic PVT may therefore represent different HCC aggressiveness phenotypes, as judged by a significant increase in tumor multifocality and AFP levels in the PVT positive patients. Factors in addition to MTD and AFP must also contribute to PVT development.

Risk factors for recurrences in patients with hepatitis C virus after achieving a sustained virological response: a multicentre study from Turkey.

In this study, we aimed to determine the late relapse rate in hepatitis C patients with sustained virological response after interferon-based regimens, and evaluated the predictors of late relapse while comparing the real-life data of our country with that of others. A multicenter retrospective study was performed to investigate the data of patients infected with HCV who obtained sustained virological response after classical or pegylated interferon alpha (PegIFNα) and ribavirin (RBV) for 48 weeks. Sustained virological response was based on negative HCV RNA level by PCR at the end of six months after the therapy. The information of patients enrolled in the study was retrieved from the hospital computer operating system and outpatient follow-up archives. We evaluated the age, gender, HCV RNA levels, HCV genotype, six-month and further follow-up of patients with sustained virologic response, presence of cirrhosis, steatosis and relapse. In all, 606 out of 629 chronic hepatitis C patients (mean age was 53±12 years; 57.6% of them were female) with sustained virological response were evaluated. We excluded 23 patients who relapsed within six months after the end of treatment (EOT). The mean follow-up period of the patients was 71 months (range: 6-136) after therapy. Late relapse rate was 1.8% (n=11) in all patients. Univariate Cox proportional hazard regression models identified that cirrhosis and steatosis were associated with the late relapse [(p = 0.027; Hazard Ratio (HR) 2.328; 95% confidence interval (CI): 1.309-80.418), (p = 0.021; HR 1.446; 95% CI: 1.243-14.510, respectively]. In multivariable Cox regression analysis, steatosis was the only independent risk factor for late relapse (p = 0.03; HR 3.953; 95% CI: 1.146-13.635). Although the late relapse rate was approximately 2% in our study, clinicians should consider that pretreatment steatosis may be an important risk factor for late relapse.

Role of oxidative stress and insulin resistance in disease severity of non-alcoholic fatty liver disease.

BACKGROUND/AIMS: Oxidative stress and insulin resistance (IR) are major contributors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to find the relation between oxidative stress parameters and histopathological findings in NAFLD patients with and without insulin resistance (IR). MATERIALS AND METHODS: Thirty-two patients with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied (M/F: 17/15; mean age 46.5±11.4 years). Twenty-one NAFLD patients with IR were compared with 11 patients without IR. The fasting insulin level was measured, and the insulin resistance index was calculated using the homeostasis model assessment (HOMA) method. Malondialdehyde (MDA) and superoxide dismutase (SOD) activities were measured in tissue and serum specimens. Glutathione (GH) was measured in tissue homogenates. Nitric oxide (NO), vitamin E and C levels were measured in serum. RESULTS: Patients with IR had significantly higher tissue MDA levels (p=0.001) and significantly decreased tissue SOD and GH levels (p=0.001 and 0.002, respectively) than those without IR. The steatosis grade, necroinflammatory grade and stage were significantly higher in patients with IR (p=0.035, 0.003 and 0.001, respectively). HOMA IR significantly correlated with the necroinflammatory grade, stage, tissue MDA, SOD and GH (p=0.013, 0.001, 0.008, 0.001 and 0.001, respectively). Serum MDA (ß=1.88, p=0.002), serum SOD (ß=0.57, p=0.006), tissue MDA (ß=0.22, p=0.006), tissue SOD (ß=1.48, p=0.071) and stage (ß=2.81, p=0.003) were independently associated with increased HOMA IR. Increased MDA [OR: 1.51; 95% CI: (1.03-2.22); p=0.034] was a risk factor for non-alcoholic steatohepatitis (NASH), and increased SOD activity had a preventive effect against NASH [OR: 0.008; 95% CI: (0.001-0.98); p=0.04]. CONCLUSION: This study shows that insulin resistance in NAFLD correlates with enhanced oxidative stress. Histopathological disease severity significantly correlated with oxidative stress parameters. These data show that NAFLD patients with IR may have increased risk for disease progression.

Five-year results of oral antiviral therapy in HBeAg-negative chronic Hepatitis B.

BACKGROUND/AIMS: Several guidelines recommend the use of tenofovir or entecavir as the first-line treatment for hepatitis B due to the lower resistance rates of these drugs than lamivudine, although lamivudine may still be preferred because of its low adverse effect profile and cost. It is important to know which patients might benefit from lamivudine as the first-line treatment. We aimed to assess the success rates of lamivudine, entecavir, and tenofovir, as well as the resistance rates, frequencies of HBsAg clearance, and risk factors for lamivudine resistance. MATERIALS AND METHODS: A total of 191 patients with chronic HBeAg-negative hepatitis who were treated with lamivudine, entecavir, or tenofovir were included. Predictors of resistance to lamivudine were analyzed. RESULTS: The cumulative first-, second-, third-, fourth-, and fifth-year rates of virologic breakthrough during extended lamivudine therapy were 24%, 30%, 38%, 46%, and 54%, respectively. The rate of undetectable DNA at the 60th month of those who took lamivudine was 51%. Cox regression analysis revealed that positive HBV DNA at the sixth month (HR=15; 95% CI: [7.1-33], p=0.001), being aged 41 years or more (HR=3.4; 95% CI: [1.8-6.4], p=0.001), and baseline HBV DNA of 170,500 IU/mL or higher (HR=2.1; 95% CI: [1.2-3.7], p=0.01) were independently associated with the development of resistance to lamivudine. CONCLUSION: In HBeAg-negative chronic hepatitis B, baseline serum hepatitis B virus DNA levels exceeding 170,500 IU/mL, partial virologic response in the sixth month, and age of 41 years or more were independent predictors for virologic breakthrough. Moreover, 2% of these patients cleared HBsAg.

An outcome survey of 43 patients with Budd-Chiari syndrome due to Behçet's syndrome followed up at a single, dedicated center.

BACKGROUND: Behçet's syndrome (BS) is a well-recognized cause of Budd-Chiari syndrome (BCS); however, information about its clinical characteristics and outcome is limited. METHODS: We reviewed the records of about 9000 patients with BS registered at the multidisciplinary Behçet's syndrome outpatient clinic at Cerrahpasa Medical Faculty between July 1977 and October 2013. We identified 43 (40 M/3 F) patients who were diagnosed as having BCS. Their outcome was evaluated between September 2012 and October 2013. RESULTS: In total, 33 patients (77%) had presented with liver-related symptoms (Group I), while 10 (23%) were asymptomatic for liver disease (Group II). This latter group had presented with symptoms related to the presence of major vessel disease such as fever, leg swelling, or dyspnea. The site of venous obstruction determined in 41 patients was inferior vena cava (IVC) and hepatic veins combined in 25 (61%), IVC alone in 12 (29%), and only hepatic veins in 4 patients (10%). The number of patients with concurrent obstruction in the hepatic veins and the IVC was less in Group II than in Group I (3/10 vs 22/31, p = 0.06). A total of 20 (19 M/1 F) patients (47%) had died at a median of 10 months after diagnosis. Mortality was significantly lower in Group II (10%) than in Group I (58%), (p = 0.011). By the end of the survey, 23 patients were alive, of whom 21 could be re-evaluated at the clinic. CONCLUSIONS: BCS associated with BS is usually due to IVC thrombosis with or without hepatic vein thrombosis. Silent cases exist and have a better prognosis. The mortality rate among the patients symptomatic for liver disease remains high.

Mallory-Denk Bodies in chronic hepatitis.

Mallory-Denk Bodies (MDB) are important as investigators, suggesting MDB as an indicator of the histologic severity of chronic hepatitis, causes of which include hepatitis C, primary biliary cirrhosis (PBC), and nonalcoholic fatty liver disease (NAFLD). Matteoni et al scored MDB in patients with NAFLD as none, rare and many, and reported that MDB plays a prominent role in this classification scheme in an earlier classification system. In this study, we evaluated 258 patients with chronic hepatitis due to metabolic, autoimmune and viral etiologies. Liver biopsy samples were evaluated with hematoxylin and eosin, periodic acid-Schiff-diastase, Gordon and Sweet's reticulin, Masson's trichrome, and iron stains. Both staging and grading were performed. Additionally, MDB were evaluated and discussed for each disease. We examined patients with nonalcoholic steatohepatitis (NASH; 50 patients), alcoholic hepatitis (10 patients), PBC (50 patients), Wilson disease (WD; 20 patients), hepatitis B (50 patients), hepatitis C (50 patients) and hepatocellular carcinoma (HCC; 30 patients). Frequency of MDB was as follows; NASH: 10 patients with mild in 60% and moderate in 40% and observed in every stage of the disease and frequently seen in zone 3. PBC: 11 patients with mild in 10%, moderate in 70%, and cirrhosis in 20%, and frequently seen in zone 1. WD: 16 patients with moderate and severe in 60% and cirrhosis in 40% and frequently seen in zone 1. Hep B: 3 patients with mild in 66% and severe in 34%. Hep C: 7 patients with mild in 40% and moderate in 60% and observed in every stage. HCC: 3 patients with hep B in 2 patients. We found that there is no relationship between MDB and any form of chronic hepatitis regarding histologic severity such as alcoholic steatohepatitis and NAFLD and variable zone distribution by etiology.

Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease.

A central issue in the understanding of the pathogenesis of nonalcoholic fatty liver disease is the problem of the underlying mechanisms which are not fully understood. In the setting of excessive central adiposity, insulin resistance is the major underlying cause of fat accumulation in hepatocytes. Because of the difficulties with human trials, several animal models have been developed for this purpose mainly characterized as follows: genetically disturbed or murine fatty liver, methionine-choline deficient diet fed or murine steatohepatitis, and high-fat or sucrose diet fed models. Although these animal models have provided useful information, none of them accurately reflect genetic, metabolic and biochemical characteristics of the human disease.

Effect of intravenous administration of paracetamol on morphine consumption in cancer pain control.

OBJECTIVE: The present study aimed to examine the effectiveness of intravenous administration of paracetamol added to morphine in the control of cancer pain and its possible contribution as reduction of opioid consumption and opioid-related side effects. MATERIALS AND METHODS: A total of 43 patients with chronic cancer pain without neuropathic origin aged between 18 and 76 years and receiving step 2 treatment according to the World Health Organization analgesic ladder were included. Patients were randomized to receive intravenous administration of saline (control) or 1 g of paracetamol on top of morphine. Visual analog scale (VAS), patient rating index (PRI), Eastern Cooperative Oncology Group (ECOG) status, patient satisfaction, and safety were evaluated. MAIN RESULTS: Both treatments resulted in improved VAS and PRI scores compared to baseline. However, groups did not differ in terms of VAS and PRI scores, morphine consumption, side-effect frequencies, laboratory values, ECOG status, and patient satisfaction. CONCLUSIONS: Although safe and there are signals for a true analgesic efficacy, our results failed to confirm any benefits of add-on treatment with intravenous administration of paracetamol. However, the study was underpowered, and future studies in this important area need to be wary of background noise and the risk of a type II error.