Yousif Qari

Autoimmune Hepatitis: Single-center Experience of Clinical Presentation, Response to Treatment and Prognosis in Saudi Arabia

Background /Aim: Autoimmune hepatitis (AIH) is a common cause of end-stage liver disease worldwide. It is a disease prevalent in children and adults, with female predominance and variable clinical presentations. AIH has favorable responses to steroids and immunomodulators. Diagnosis of AIH is based on clinical and laboratory criteria, as suggested by the International Autoimmune Hepatitis Group. Data on the disease pattern of AIH from the Middle East countries is scarce. Materials and Methods: In this retrospective analysis, we studied clinical and laboratory features, immunological data, radiological findings, liver biopsy findings and response to therapy in patients with AIH from the hepatology clinics of King Abdul Aziz, University Hospital, Jeddah, from 1994 to 2008. Results: We diagnosed 41 patients with AIH, and 33 were included in the analysis. The mean age was 32.3 years, with female predominance of 75.7%. De-compensated cirrhosis at presentation was found in 45.5% of the patients. Acute hepatitis was associated with significantly higher levels of the serum ALT and bilirubin (P=0.001 and P=0.03, respectively). All our patients had type 1 AIH. Treatment with prednisolone and azathioprine resulted in complete or partial remission in majority of the patients (54.8%). However, patients with advanced disease showed a poorer response to treatment (P=0.016). Six patients with poor compliance had relapse of AIH. Two patients had a flare of the disease during pregnancy, and they responded well with prednisolone. The longest follow-up was 14 years and the shortest was 2 months. Four patients died from liver disease. Conclusion: AIH patients in Saudi Arabia are likely to present with advanced disease at a young age and would have a poorer response to therapy as compared with patients in other countries worldwide.

High expression of matrix metalloproteinases: MMP-2 and MMP-9 predicts poor survival outcome in colorectal carcinoma

AIM To evaluate the expression pattern of matrix metalloproteinases (MMPs); MMP-2, MMP-7 and MMP-9 in colorectal cancer (CRC) and determine its prognostic potential. PATIENTS & METHODS CRC samples of 127 patients were studied. Protein expressions of MMP-2, -7 and -9 were analyzed by immunohistochemistry and association with clinicopathological variables was statistically analyzed. RESULTS Overexpressions of MMP-2 and MMP-9 correlated with poor outcome as evaluated by univariate Kaplan-Meier for disease-free survival (p = 0.04, p = 0.0001) and disease-specific survival (p = 0.01, p = 0.01), respectively. Cox analysis of MMP-2 and -9 were significant independent predictors of disease-free survival (p = 0.006, p = 0.018) and disease-specific survival (p = 0.004, p = 0.049), respectively. CONCLUSION MMPs expression patterns provide useful prognostic information in CRC, while predicting the patients at high risk for recurrent disease.

Variceal hemorrhage: Saudi tertiary center experience of clinical presentations, complications and mortality

AIM To determine the clinical presentation, underlying etiology and short- and long-term outcomes of acute variceal bleeding (AVB). METHODS A retrospective descriptive cohort study of cirrhotic patients with AVB who were admitted to King Abdul Aziz University Hospital between January 2005 and December 2009. We obtained demographic data for all patients. For each patient we also obtained the clinical data at presentation; cause of liver cirrhosis, bleeding presentation (hematemesis and/or melena), presence of ascites, hepatic encephalopathy and renal impairment (RI) or hepatorenal syndrome. We carried out complete blood count, prothrombin time evaluation, and liver function tests. We also report all episodes of re-bleeding after the first episode of AVB, both during the initial admission and after discharge. We recorded the length of stay for each patient and thereby calculated the mean duration of stay for all patients. The length of follow-up after the first AVB and the outcome for each patient at the end of the study period were recorded. Causes of mortality either related to liver disease or non-liver disease cause were determined. RESULTS A 125 patients were enrolled in the study. The number of episodes of AVB for each patients varied between 1 and 10. Survival from the first attack of AVB to death was 20.38 mo (SD 30.86), while the length of follow-up for the living patients was 53.58 mo (SD 24.94). Total number of AVB admissions was 241. Chronic hepatitis C, the commonest underlying etiology for liver disease, was present in 46 (36.8%) patients. Only 35 (28%) patients had received a primary prophylactic β-blocker before the first bleeding episode. The mean hemoglobin level at the time of admission was 8.59 g/dL (SD 2.53). Most patients had Child-Pugh Class C 41 (32.8%) or Class B 72 (57.6%) disease. Hematemesis was the predominant symptom and was found in 119 (95.2%) patients, followed by melena in 75 (60.0%) patients. Ascites of variable extent was documented in 93 (74.4%) patients. We identified hepatic encephalopathy in 31 (28.8%) patients and spontaneous bacterial peritonitis in 17 (13.6%). Bleeding gastric varices was the cause of AVB in 2 patients. AVB was associated with shock in 22 patients, 13 of whom (59.1%) had Child-Pugh class C disease. RI was noted in 19 (46.3%) of 41 patients in Child-Pugh class C and 14 (19.4%) of 72 patients in Child-Pugh class B. None of the patients with Child-Pugh class A disease had RI. Emergency endoscopy was effective in controlling the bleeding, although the re-bleeding rate was still high, 12 (9.6%) during the same admission and 55 (44%) after discharge. The re-bleeding rate was higher in patients with ascites, occurring in 40/55 (72.2%). The length of hospital stay was 1-54 d with a mean of 8.7 d. Three patients had emergency surgery due to failure of endoscopic treatment and balloon tamponade. The overall long term mortality was 65%. Survival from the first attack of AVB to death was 20.38 ± 30.86 mo, while the length of follow-up for the living patients was 53.58 ± 24.94 mo. Patients with Child-Pugh score C had a higher risk of liver disease-related mortality (67.6%). RI (developed during admission) was the main factor that was associated with mortality (P = 0.045). CONCLUSION The majority of patients with liver disease who present at the emergency unit for AVB are at an advanced stage of the disease. The outcome is poorer for patients who develop RI during hospitalization.

Prognostic significance of VEGFR1/Flt-1 immunoexpression in colorectal carcinoma.

Colorectal carcinoma (CRC) is a major cause of morbidity and mortality. Vascular endothelial growth factor 1/Fms-like tyrosine kinase 1 (VEGFR1/Flt-1) regulates monocyte migration, recruits endothelial cell progenitors, increases the adhesive properties of natural killer cells and induces of growth factors. Flt-1 is expressed on tumour cells and has been implicated in tumour growth and progression. The objective of this study is to address the relation of Flt-1 expression to tumour prognostication. Paraffin blocks from 143 primary CRC and 48 regional nodal metastases were retrieved from the archives of the Department of Pathology at King Abdulaziz University. Tissue microarrays were designed and constructed. Immunohistochemistry for Flt-1 was performed. Staining intensity and extent of staining were assessed and combined. Results were dichotomised as low expression and high expression. Flt-1 was overexpressed in primary tumours and nodal metastasis (p < 0.001 and 0.001) with no difference between primary and nodal metastasis (p = 0.690). Flt-1 immunoexpression was not associated with the clinicopathological parameters. Flt-1 overexpression was an independent predictor of positive margin status, positive lymphovascular invasion and local disease recurrence (p < 0.001, p < 0.001 and p = 0.003, respectively). Flt-1 was not associated with survival (log-rank = 0.003, p = 0.959). Flt-1 was overexpressed in primary CRC and their nodal metastases. Flt-1 expression was an independent predictor of margin status, lymphovascular invasion and local disease recurrence. Therefore, expression profiling of Flt-1 seems to have a prognostic potential in CRC. However, to elucidate the association of overexpression of Flt-1 with tumour characteristics and prognostication, more in vivo and in vitro molecular investigations are recommended.

p16 protein is upregulated in a stepwise fashion in colorectal adenoma and colorectal carcinoma

Background/Aims: p16 is tumor suppressor gene acting as a cell cycle regulator. The present study was conducted to compare p16 expression in normal, dysplastic, and malignant colonic mucosae, and to explore its relation to clinicopathological variables and follow-up data in colorectal carcinoma (CRC). Patients and Methods: Tissue microarrays were performed from 25 normal colonic mucosae, 41 colonic adenomas, and 191 CRC, with corresponding 50 nodal metastases. Immunohistochemistry was performed using anti-p16 antibody, sections were scored, and statistical analysis was performed. K-ras mutation detection was also performed. Results: Immunoexpression of p16 was significantly higher in CRC than in adenomas (P = 0.033) and normal colonic mucosa (P = 0.005). There was no statistically significant difference between p16 expression in CRC and nodal metastasis. There was no significant association between p16 immunoexpression in CRC and all clinicopathological data and survival probability. K-ras mutations were detected in 34% of CRC. However, there was no correlation between K-ras status and p16 expression (P = 0.325). Conclusion: Absence of p16 expression is correlated to a benign course of CRC adenomas. p16 has a key role in CRC progression and can be used as a marker for colorectal adenoma. On the other hand, it has no role as a predictive and/or prognostic factor in CRC. Further extended studies are required to explore the role of p16 as indicator of premalignant lesions in the colon and to test its relation with CRC histological grade, as well as to test its value as a new therapeutic target.

Risk Stratification of Patients with Crohn's Disease: A Retrospective Analysis of Clinical Decision Making and Its Impact on Long-Term Outcome

Background and Aims: Complications such as need for bowel resections and hospitalization due to Crohns disease (CD) occur when disease activity persists due to ineffective therapy. Certain “high-risk” features require an early introduction of anti-tumor necrosis factor-α therapy to prevent such complications. We aim to evaluate the prevalence of “high-risk” features among a cohort of patients with CD and examine the association between discordance of early therapy with baseline risk stratification and disease outcome. Patients and Methods: All adult patients with CD were retrospectively identified and their medical records were reviewed. Clinical, endoscopic, laboratory, and radiological data were collected. Patients were divided into “low” and “high” risk groups according to the presence or absence of penetrating disease, perianal involvement, foregut involvement, extensive disease seen on endoscopy or cross-sectional imaging, young age at the time of diagnosis (<40), persistent cigarette smoking and frequent early requirements for corticosteroid therapy. Initial treatment selection and treatment approach (“step-up” vs. “accelerated step-up” vs. “top-down”) within 6 months of diagnosis were recorded. Rates of CD-related bowel resections and hospitalization within 5 years of diagnosis were calculated. Logistic regression analysis was used to examine the association between “discordance” of early treatment selections and risk stratification categories with outcomes. Results: Eighty-five CD patients were included. The median age and duration of disease were 25 (interquartile range [IQR] 19-32) and 5 (IQR 4-6) years, respectively. Sixty five percent were females and 66% were native Saudis. Smoking was reported in 12% of patients and perianal disease in 18%. “High-risk” features were identified in 43 (51%) patients, of which only 6 (14%) were treated with “top-down” therapy and 7 (16%) with “accelerated step-up” care. The risk of requiring a bowel resection, and hospitalization was higher for “high-risk” patients compared to “low-risk” patients (risk ratio [RR] 13.67, 95% CI 1.88-99.41; p = 0.003, and RR 1.86, 95% CI 0.03-0.43; p = 0.0312, respectively). “Discordance” occurred in 34% of cases. Bowel resection was required in 15/85 (18%) patients and 32/85 (38%) required at least one hospitalization within 5 years of diagnosis. Logistic regression analysis identified a statistically significant association between “discordance” and need for bowel resections (OR 6.50, 95% CI 1.59-26.27, p = 0.009), and hospitalizations (OR 3.01, 95% CI 1.08-8.39, p = 0.035) within 5 years of diagnosis. Conclusions: “Discordance” between patient risk-profile and treatment selection early in the course of CD has a significant impact on disease outcome, specifically need for bowel resection and hospitalization, which are more likely to occur in the presence of “high-risk” features. Early identification of “high-risk” features could help prevent long-term complications.

A cross-sectional survey of multi-generation inflammatory bowel disease consanguinity and its relationship with disease onset

Background\Aim: Consanguinity influences the phenotypic variations of some hereditary and immune-mediated disorders, including inflammatory bowel disease. This study estimated the prevalence of consanguinity among the ancestors of patients with inflammatory bowel disease and examined the effect of various consanguinity levels on inflammatory bowel disease onset. Patients and Methods: Patients with inflammatory bowel disease who were seen at two gastroenterology outpatient clinics were consecutively recruited and surveyed for demographics, disease onset, and presence of ancestral consanguinity within three generations. The prevalence of different consanguinity levels was calculated. The association between age at inflammatory bowel disease onset and consanguinity was examined. Results: Two hundred seventeen patients were recruited. The mean age, mean age at diagnosis, and mean illness duration were 32.9 ± 13.4, 18.6 ± 11.5, and 8.6 ± 7.7 years, respectively. Of the cohort, 53.5% were women, and 74.2% were native Saudis. Cigarette smoking was reported in 17.1%; 51% had Crohns disease, while the remaining patients had ulcerative colitis. A family history of inflammatory bowel disease was reported in 29.5% of patients; consanguinity within three generations was reported in 57.6%. Consanguinity in more than one generation was reported in 38.7%; 17.5% had consanguinity in three consecutive generations. There was no association between inflammatory bowel disease onset and multi-generation consanguinity, but there was an association with disease subtype in favor of ulcerative colitis (b coefficient = 7.1 [95% confidence interval = 4.1, 10]). Conclusions: Consanguinity is extremely common among Saudi patients with inflammatory bowel disease but does not seem to influence age at disease onset. Genetic studies are needed to further clarify the effect of consanguinity on disease behavior.