Waleed Al-Hamoudi

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.

Cardiovascular changes in cirrhosis: Pathogenesis and clinical implications

Liver cirrhosis is associated with a wide range of cardiovascular abnormalities including hyperdynamic circulation, cirrhotic cardiomyopathy, and pulmonary vascular abnormalities. The pathogenic mechanisms of these cardiovascular changes are multifactorial and include neurohumoral and vascular dysregulations. Accumulating evidence suggests that cirrhosis-related cardiovascular abnormalities play a major role in the pathogenesis of multiple life-threatening complications including hepatorenal syndrome, ascites, spontaneous bacterial peritonitis, gastroesophageal varices, and hepatopulmonary syndrome. Treatment targeting the circulatory dysfunction in these patients may improve the short-term prognosis while awaiting liver transplantation. Careful fluid management in the immediate post-transplant period is extremely important to avoid cardiac-related complications. Liver transplantation results in correction of portal hypertension and reversal of all the pathophysiological mechanisms that lead to the cardiovascular abnormalities, resulting in restoration of a normal circulation. The following is a review of the pathogenesis and clinical implications of the cardiovascular changes in cirrhosis.

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.

Discriminant value of serum HBV DNA levels as predictors of liver fibrosis in chronic hepatitis B

Summary.  Current guidelines recommend antiviral therapy in chronic hepatitis B (HBV) patients with significant histological disease. We aimed to compare histological fibrosis (METAVIR, ≥F2) in patients with HBV DNA ≥20 000 IU/mL vs≥2000 IU/mL and identify predictors of fibrosis. We performed prospective liver biopsies on 203 HBeAg‐negative patients in four groups: Group I (n = 55): HBV DNA ≥20 000 IU/mL and persistently elevated alanine aminotransferase (ALT) levels (PEALT; >40 U/L); Group II (n = 34): HBV DNA ≥20 000 IU/mL and persistently normal ALT (PNALT); Group III (n = 40): HBV DNA <20 000 IU/mL and PEALT; and Group IV (n = 74): HBV DNA <20 000 IU/mL, and PNALT. We reanalysed all groups in relation to updated cut‐off for treatable viremia (2000 IU/mL). Genotype D was detected in 86% of patients. Hepatic fibrosis ≥F2 was detected in 72.7%, 52.9%, 57.5% and 18.9% in Groups I–IV, respectively (P < 0.0001). Except in Group II with a trend for lower ≥F2 fibrosis (P = 0.067), there was no significant difference by using HBV DNA cut‐off 20 000 vs 2000 IU/mL. Multivariate logistic regression analysis identified study Group IV (OR, 0.0276; CI: 0.088–0.868; P = 0.0276) and milder (A0–1) necroinflammatory grade (OR, 0.135; CI: 0.063–0.287; P < 0.0001) as independent predictors of ≥F2 fibrosis. The specificity, positive and negative predictive values for PEALT in detection of ≥F2 fibrosis for viremia ≥2000 IU/mL (80%, 69% and 65%, respectively) or ≥20 000 IU/mL (86%, 73% and 63%, respectively) were similar, with a marginal gain in sensitivity (51%vs 42%, respectively). Significant fibrosis is prevalent in a large proportion of HBeAg‐negative patients with high viremia and persistently normal ALT. Lower HBV DNA cut‐offs could be adopted with marginal gains in fibrosis detection and without loss of diagnostic accuracy.

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.

SASLT Practice Guidelines for the Management of Hepatitis B Virus

Gastroenterology Unit, College of Medicine, King Saud University, Riyadh, Saudi ArabiaAAddress for correspondence:ddress for correspondence: Dr. Waleed Al-Hamoudi, Gastroenterology and Hepatology Unit (59), Department of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia. E-mail: walhamoudi@gmail.com

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.

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.