Khalid Alswat

Association between HLA Variations and Chronic Hepatitis B Virus Infection in Saudi Arabian Patients

Hepatitis B virus (HBV) infection is a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. Human leukocyte antigens (HLAs) play an important role in the regulation of immune response against infectious organisms, including HBV. Recently, several genome-wide association (GWAS) studies have shown that genetic variations in HLA genes influence disease progression in HBV infection. The aim of this study was to investigate the role of HLA genetic polymorphisms and their possible role in HBV infection in Saudi Arabian patients. Variations in HLA genes were screened in 1672 subjects who were divided according to their clinical status into six categories as follows; clearance group, inactive carriers, active carriers, cirrhosis, hepatocellular carcinoma (HCC) patients and uninfected healthy controls. Three single nucleotide polymorphisms (SNPs) belonged to HLA-DQ region (rs2856718, rs7453920 and rs9275572) and two SNPs belonged to HLA-DP (rs3077 and rs9277535) were studied. The SNPs were genotyped by PCR-based DNA sequencing (rs2856718) and allele specific TaqMan genotyping assays (rs3077, rs7453920, rs9277535 and rs9275572). The results showed that rs2856718, rs3077, rs9277535 and rs9275572 were associated with HBV infection (p = 0.0003, OR = 1.351, CI = 1.147–1.591; p = 0.041, OR = 1.20, CI = 1.007–1.43; p = 0.045, OR = 1.198, CI = 1.004–1.43 and p = 0.0018, OR = 0.776, CI = 0.662–0.910, respectively). However, allele frequency of rs2856718, rs7453920 and rs9275572 were found more in chronically infected patients when compared to clearance group infection (p = 0.0001, OR = 1.462, CI = 1.204–1.776; p = 0.0178, OR = 1.267, CI = 1.042–1.540 and p = 0.010, OR = 0.776, CI = 0.639–0.942, respectively). No association was found when polymorphisms in HLA genes were compared in active carriers versus cirrhosis/HCC patients. In conclusion, these results suggest that variations in HLA genes could affect susceptibility to and clearance of HBV infection in Saudi Arabian patients.

Epidemiological, clinical, and biochemical characteristics of Saudi patients with nonalcoholic fatty liver disease: a hospital-based study.

BACKGROUND The estimated prevalence of nonalcoholic fatty liver disease (NAFLD) in Saudi Arabia is 7% to 10%. Despite the high prevalence of risk factors including diabetes, obesity, and hyperlipidemia, no recent epidemiological studies have measured the disease burden. We aimed to determine the characteristics of Saudi NAFLD patients attending a university hospital, and study factors affecting alanine aminotransferase (ALT) levels. DESIGN AND SETTING A prospective study among patients referred for ultrasonography in King Khalid University Hospital in Riyadh, Saudi Arabia from February to May 2009. PATIENTS AND METHODS NAFLD was defined as an appearance of fatty liver on routine abdominal ultrasound in the absence of coexisting liver disease and alcohol consumption. Patients were classified into normal and high ALT (ALT >60 U/L) level groups for analysis. RESULTS The prevalence of NAFLD was 16.6% (218/1312). Patients with normal ALT had the mean (SD) age of 45.9 (10.6) years and the mean body mass index of 34.5 (7.9) kg/m2. Forty percent of the 151 patients with normal ALT had diabetes, 66.2% were obese, and 29.1% had hypertension. Forty-three patients (23%) had high ALT levels. These patients had significantly lower age (P=.003) and fasting blood sugar (P=.03) than the normal ALT group. Non-diabetic patients (odds ratio 0.30, 95% CI 0.1–0.8), men (female OR 0.23, 95% CI 0.1–0.5), lower cholesterol (P=.001), high-density lipoprotein (P=.006), and low-density lipoprotein (P=.008) levels were more likely to be observed among patients with high ALT levels. In a multivariate analysis, younger age (OR 0.96, 95% CI 0.93–0.99), being male (OR 0.23, 95% CI 0.09–0.57), and a lower cholesterol level (OR 0.55, 95% CI 0.37–0.82) were significant predictors of high ALT levels. CONCLUSION Based on the high prevalence of obesity and diabetes, the prevalence of NAFLD will continue to be high, unless awareness is inculcated among the local population.

The Role of Endocannabinoids System in Fatty Liver Disease and Therapeutic Potentials

Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver morbidity and mortality with no proven effective therapy as of yet. Its prevalence is increasing globally in parallel with obesity and metabolic syndrome pandemic. The endocannabinoid (EC) system has been implicated in the pathogenesis of several diseases, including fatty liver diseases. This system refers to the cannabinoid receptors type 1 (CB1) and type 2 (CB2), with both their endogenous ligands and machinery dedicated to EC synthesis and degradation. There is accumulating evidence on the role CB1 as a key mediator of insulin resistance and liver lipogenesis in both animals and humans. On the other hand, CB2 receptors have been shown to promote inflammation with anti-fibrogenic properties. The pharmacological modulation of the EC system activity for the treatment of metabolic syndrome and NAFLD are promising yet premature. The initial limited success due to deleterious central nervous system side-effects are likely to be bypassed with the use of peripherally restricted drugs.

Genome-wide association study of chronic hepatitis B virus infection reveals a novel candidate risk allele on 11q22.3

Background Hepatitis B virus (HBV) affects millions of people worldwide. While some people are able to clear the virus following the first encounter, those who develop chronic infection manifest remarkable clinical heterogeneity that ranges from asymptomatic carrier state to cirrhosis and hepatocellular carcinoma. Despite extensive studies, little is known about genetic host factors that influence the outcome of chronic HBV infection. Thus, we conducted this study to investigate the genetic risk of developing active liver disease among chronic carriers of HBV. Methods In this study, we conducted a genome-wide association study (GWAS) on a cohort of patients with chronic HBV infection. Results One particular SNP that is 16 kb upstream of Ferredoxin 1 was found to have an association with complicated chronic HBV infection (cirrhosis and hepatocellular carcinoma) that reached GWAS significance, and was successfully validated on an independent set of samples. Conclusions This first GWAS in an Arab population further demonstrates the utility of this approach in elucidating the genetic risk of HBV infection-related complications and highlights the advantage of conducting GWAS in different ethnicities to achieve that goal.

Correlation Between Hepatitis B Surface Antigen Titers and HBV DNA Levels

Background/Aim: To assess the correlation between serum HBsAg titers and hepatitis B virus (HBV) DNA levels in patients with hepatitis B envelop antigen-negative (HBeAg −ve) HBV genotype-D (HBV/D) infection. Patients and Methods: A total of 106 treatment- naïve, HBeAg −ve HBV/D patients were included; 78 in the inactive carrier (IC) state and 28 in the active hepatitis (AH) stage. HBV DNA load and HBsAg titers were tested using TaqMan real-time polymerase chain reaction (PCR) and automated chemiluminescent microparticle immunoassay, respectively. Results: The median (range) log10 HBsAg titer was significantly lower in the IC group compared with AH group, 3.09 (−1 to –4.4) versus 3.68 (−0.77 to 5.09) IU/mL, respectively; P < 0.001. The suggested cutoff value of HBsAg titer to differentiate between the two groups was 3.79 log10 IU/mL. In addition, there was a significant positive correlation between HBsAg and HBV DNA levels in the whole cohort, AH, and IC groups (r = 0.6, P < 0.0001; r = 0.591, P = 0.001; and r = 0.243, P = 0.032, respectively). Conclusion: Serum HBsAg titers may correlate with HBV DNA in treatment-naïve HBeAg –ve HBV/D patients, and supports the use of HBsAg levels in clinical practice as a predictor of serum HBV DNA levels.

Genetic variation in interleukin 28B and correlation with chronic hepatitis B virus infection in Saudi Arabian patients

Several genome‐wide association studies have shown that genetic variations in the chromosomal region containing interleukin‐28B (IL28B) gene are associated with response to treatment in hepatitis C virus (HCV) infection. This study was conducted to examine the role of genetic variations in IL28B on disease progression in Saudi Arabian patients chronically infected with hepatitis B virus (HBV).

Correlation between Genetic Variations and Serum Level of Interleukin 28B with Virus Genotypes and Disease Progression in Chronic Hepatitis C Virus Infection

Recent studies have demonstrated that polymorphisms near the interleukin-28B (IL-28B) gene could predict the response to Peg-IFN-a/RBV combination therapy in HCV-infected patients. The aim of the study was to correlate the serum level of IL28B in HCV-infected patients with virus genotype/subgenotype and disease progression. IL28B serum level was detected and variations at five single nucleotide polymorphisms (SNPs) in IL28B gene region were genotyped and analyzed. The variation of IL28B genetic polymorphisms was found to be strongly associated with HCV infection when healthy control group was compared to HCV-infected patients with all P values <0.0001. Functional analysis revealed that subjects carrying rs8099917-GG genotype had higher serum level of IL28B than those with GT or TT genotypes (P = 0.04). Also, patients who were presented with cirrhosis (Cirr) only or with cirrhosis plus hepatocellular carcinoma (Cirr+HCC) had higher levels of serum IL28B when compared to chronic HCV-infected patients (P = 0.005 and 0.003, resp.). No significant association was found when serum levels of IL28B were compared to virus genotypes/subgenotypes. This study indicates that variation at SNP rs8099917 could predict the serum levels of IL28B in HCV-infected patients. Furthermore, IL28B serum level may serve as a useful marker for the development of HCV-associated sequelae.

Appropriateness and diagnostic yield of upper gastrointestinal endoscopy in an open-access endoscopy system

Background/Aim: Open access endoscopy (OAE) decreases the waiting time for patients and clinical burden to gastroenterologist; however, the appropriateness of referrals for endoscopy and thus the diagnostic yield of these endoscopies has become an important issue. The aim of this study was to determine the appropriateness of upper gastrointestinal (GI) endoscopy requests in an OAE system. Patients and Methods: A retrospective chart review of all consecutive patients who underwent an upper gastroscopy in the year 2008 was performed and was defined as appropriate or inappropriate according to the American Society for Gastrointestinal Endoscopy (ASGE) guidelines. Endoscopic findings were recorded and classified as positive or negative. Referrals were categorized as being from a gastroenterologist, internist, surgeon, primary care physicians or others, and on an inpatient or out-patient basis. Results: A total of 505 consecutive patients were included. The mean age was 45.3 (standard deviation 18.1), 259 (51%) of them were males. 31% of the referrals were thought to be inappropriate. Referrals from primary care physicians were inappropriate in 47% of patients while only 19.5% of gastroenterologists referrals were considered inappropriate. Nearly, 37.8% of the out-patient referrals were inappropriate compared to only 7.8% for inpatients. Abnormal findings were found in 78.5% and 78% of patients referred by gastroenterologists and surgeons respectively while in those referred by primary care physicians it was (49.7%). Inpatients referred for endoscopy had abnormal findings in (81.7%) while in out-patients it was (66.6%). The most common appropriate indications in order of frequency were “upper abdominal distress that persisted despite an appropriate trial of therapy” (78.9%), “persistent vomiting of unknown cause” (19.2%), upper GI bleeding or unexplained iron deficiency anemia (7.6%). The sensitivity and specificity of the ASGE guidelines in our study population was 70.3% and 35% respectively. Conclusion: A large proportion of patients referred for endoscopy through our open-access endoscopy unit are considered inappropriate, with significant differences among specialties. These results suggest that if proper education of practitioners was implemented, a better utilization would be expected.

The natural history and long-term outcomes in patients with chronic hepatitis C genotype 4 after interferon-based therapy.

Hepatitis C virus (HCV) genotype 4 (G4) infection is common in the Middle East. Post‐treatment long‐term outcomes have not been reported in these patients. This study evaluates these outcomes in patients after interferon‐based therapy.

Clinical Characteristics of Patients with Hepatocellular Carcinoma in a Middle Eastern Population

Background Hepatocellular carcinoma (HCC) is one of the leading causes of death in Saudi male patients. Local clinical and demographic data of this disease are scarce. Objectives We sought to describe the clinical characteristics and outcomes of patients from two tertiary care centers in Saudi Arabia. Patients and Methods Data were collected for all patients diagnosed to have hepatocellular carcinoma between June 2003 and July 2008 who had been registered in a special research database (the Saudi Observatory Liver Disease Registry (SOLID)). Data were extracted from SOLID for clinical, biochemical, radiologic parameters and outcome. Results Data was available for 363 patients, the mean age of diagnosis was 66 years, 74% of patients were males, and Hepatitis C was the underlying cause of liver disease in 48%, while Hepatitis B in 29%. Most of the patients were diagnosed at an advanced stage, 53 % of patients had a CLIP score of 4 to 6 (advanced stage), 55% had large multi-nodular tumors and 16% had vascular invasion or extra-hepatic spread at the time of diagnosis. Most of the patients had decompensated cirrhosis; with child-pogh score B in 44% and C in 26% with presence of portal hypertension in 55%. Forty eight percent died during the study period. Predictors of poor survival in the univariate analysis were; presence of portal vein thrombosis (P = 0.03), portal hypertension (P < 0.0001), presence of ascites (P = 0.022), hepatic encephalopathy (P < 0.0001), advanced child-pough score (P < 0.0001), bilirubin > 22 (P < 0.0001) and INR > 1.2 (P = 0.02). On multivariate analysis, only the presence of portal hypertension, bilirubin > 22 and severe hepatic encephalopathy were significant with adjusted hazard ratio of 1.6 (95% CI; 1.04-2.47), 1.76 (95% CI; 1.12-2.8), and 3.18 (95% CI; 1.42-7.14) respectively. Conclusions The data from this cohort indicates that most of patients diagnosed with HCC present at late tumor and liver disease stages, when prognosis is usually dismal. Regular cancer surveillance in cirrhotic patients might change the outcomes. Further studies with results of treatment outcomes in this community are needed.