Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a progressive disease associated with rapid clinical worsening and high mortality. Early prediction of mortality and intervention can improve patient outcomes. We aimed to develop a dynamic prognostic model and compare it with the existing models. METHODS: A total of 1402 ACLF patients, enrolled in the APASL-ACLF Research Consortium (AARC) with 90-day follow-up, were analyzed. An ACLF score was developed in a derivation cohort (n = 480) and was validated (n = 922). RESULTS: The overall survival of ACLF patients at 28 days was 51.7%, with a median of 26.3 days. Five baseline variables, total bilirubin, creatinine, serum lactate, INR and hepatic encephalopathy, were found to be independent predictors of mortality, with AUROC in derivation and validation cohorts being 0.80 and 0.78, respectively. AARC-ACLF score (range 5-15) was found to be superior to MELD and CLIF SOFA scores in predicting mortality with an AUROC of 0.80. The point scores were categorized into grades of liver failure (Gr I: 5-7; II: 8-10; and III: 11-15 points) with 28-day cumulative mortalities of 12.7, 44.5 and 85.9%, respectively. The mortality risk could be dynamically calculated as, with each unit increase in AARC-ACLF score above 10, the risk increased by 20%. A score of ≥11 at baseline or persisting in the first week was often seen among nonsurvivors (p = 0.001). CONCLUSIONS: The AARC-ACLF score is easy to use, dynamic and reliable, and superior to the existing prediction models. It can reliably predict the need for interventions, such as liver transplant, within the first week.

Helicobacter pylori outer membrane protein and virulence marker differences in expatriate patients.

We studied the prevalence of Helicobacter pylori virulence markers, e.g. cytotoxin associated gene (cagA), cagA promoter, vacuolating associated cytotoxin A (vacA) alleles induced by contact with epithelium (iceA type), and outer membrane protein Q (hopQ) in expatriates and compared them with those in local residents. Gastric biopsies were obtained at endoscopy for culture, histology and PCR for virulence marker and hopQ. Of 309 patients, 236 (76%) were males with a mean age of 45 years. A total of 102 patients were expatriates. hopQ type 1 was present in 98 (47%) local residents compared to 88 (86%) expatriates (P < 0·001), while hopQ type 2 was present in 176 (85%) local residents, compared to 60 (59%) expatriates (P < 0·001). H. pylori virulence marker cagA was positive in 97 (47%) local residents compared to 86 (84%) expatriates (P < 0·001) while cagA-P was positive in 72 (35%) local residents compared to 87 (85%) expatriates (P < 0·001). iceA type 1 was positive in 157 (76%) local residents compared to 45 (44%) expatriates (P < 0·001), while iceA type 2 was positive in 81 (39%) local residents compared to 86 (84%) expatriates (P < 0·001). Distribution of H. pylori cagA, cagA promoter, iceA and hopQ type in local residents and expatriates was different. H. pylori virulence markers were associated with severe pathology in expatriates.

Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

The present and future disease burden of hepatitis C virus infections with today's treatment paradigm - volume 3.

The total number, morbidity and mortality attributed to viraemic hepatitis C virus (HCV) infections change over time making it difficult to compare reported estimates from different years. Models were developed for 15 countries to quantify and characterize the viraemic population and forecast the changes in the infected population and the corresponding disease burden from 2014 to 2030. With the exception of Iceland, Iran, Latvia and Pakistan, the total number of viraemic HCV infections is expected to decline from 2014 to 2030, but the associated morbidity and mortality are expected to increase in all countries except for Japan and South Korea. In the latter two countries, mortality due to an ageing population will drive down prevalence, morbidity and mortality. On the other hand, both countries have already experienced a rapid increase in HCV-related mortality and morbidity. HCV-related morbidity and mortality are projected to increase between 2014 and 2030 in all other countries as result of an ageing HCV-infected population. Thus, although the total number of HCV countries is expected to decline in most countries studied, the associated disease burden is expected to increase. The current treatment paradigm is inadequate if large reductions in HCV-related morbidity and mortality are to be achieved.

Seroprevalence of hepatitis E and Helicobacter pylori in a low socioeconomic area of a metropolitan city in a developing country.

This study aims to determine the prevalence of coinfection of H. pylori and hepatitis E virus (HEV) in the paediatric age group in an urban slum area of Karachi and identify risk factors associated with co-infection. Five hundred and forty children aged one to 15 years were investigated. Blood samples were collected and questionnaires completed on socio-demographic characteristics. Anti-H. pylori, HEV IgG and IgM antibodies were analysed by enzyme immunoassays (EIAs). The seroprevalence of H. pylori antibody was 47.2%, while that of HEV IgG and IgM was 14.4% and 2.4%, respectively. 12.4% exhibited seroprevalence for both H. pylori and HEV (IgG). In 67 (26%) cases positive for H. pylori IgG, HEV IgG positivity was also seen (P < 0.001). Only 13 (5%) positive for H. pylori were also positive for HEV IgM (P < 0.001). Only 11 (4%) HEV IgG-positive cases were H. pylori antibody-negative (P < 0.001). Hepatitis E virus was common in children who had access to municipal piped water (P = 0.025). H. pylori was common in children who used a non-flush toilet system (P < 0.001). Children exposed to H. pylori infection were also exposed to the risk of HEV.

Virulence markers of Helicobacter pylori in patients with diarrhoea-dominant irritable bowel syndrome.

Recent studies suggest that irritable bowel syndrome (IBS) is associated with low-grade inflammation. This study aims to determine the distribution of Helicobacter pylori cytotoxin-associated gene A (cagA) and vacuolating cytotoxin A (vacA) alleles (e.g., s1 and s2) in patients with diarrhoea-dominant IBS (IBS-D) as the latter causes vacuolation in colonic epithelial cells in vitro. One hundred and seventy patients meeting Rome III criteria for IBS-D (mean age: 40 +/- 15 years) were enrolled. Gastric biopsy was assessed histologically and DNA extraction was performed by polymerase chain reaction (PCR) for H. pylori genus 16S ribosomal DNA (16S rDNA), cagA and vacA allele s1 and s2. There was no age- or gender-related difference in H. pylori positivity in IBS-D compared to the control group. H. pylori was positive in 116 (68%) with IBS-D compared to 88 (55%) in the control group (P=0.01). cagA was positive in 73 (63%) with IBS-D compared to 42 (48%) in the control group (P=0.03). vacA s1 was positive in 61 (53%) with IBS-D compared to 32 (36%) in the control group (P=0.02). cagA s1 was positive in 39 (34%) with IBS-D compared to 13 (15%) in the control group (P=0.002).

Microsporidial infections due to Encephalitozoon intestinalis in non-HIV-infected patients with chronic diarrhoea.

We determined the prevalence of microsporidia Enterocytozoon (Ent.) bieneusi and Encephalitozoon (E.) intestinalis infection in patients with chronic diarrhoea and hepatocellular carcinoma (HCC). A total of 330 stool samples were examined from 171 (52%) patients with chronic diarrhoea, 18 (5%) with HCC while 141 (43%) were controls. Stool microscopy, polymerase chain reaction (PCR) with species-specific primers for Ent. bieneusi and E. intestinalis and sequencing were carried out. Microsporidia were found by trichrome staining in 11/330 (3%) and E. intestinalis by PCR in 13/330 (4%) while Ent. bieneusi was not detected. PCR for E. intestinalis was positive in 8/171 (5%) stool samples from patients with chronic diarrhoea, 2/141 (1·4%) samples from healthy controls and in 3/18 (17%) samples from patients with HCC. In the chronic diarrhoea group, E. intestinalis was positive in 4/171 (2·3%) (P=0·69) stool samples compared to 2/18 (11%) (P=0·06) in the HCC group and 2/141 (1·4%) from healthy controls. E. intestinalis infection was significantly associated with chronic diarrhoea and HCC in these patients who were negative for HIV. Stool examination with trichrome or species-specific PCR for microsporidia may help establish the cause of chronic diarrhoea.

Entamoeba species associated with chronic diarrhoea in Pakistan.

We determined the prevalence of Entamoeba (E.) histolytica, E. dispar and E. moshkovskii in patients with chronic diarrhoea associated with abdominal pain or discomfort mimicking irritable bowel syndrome. Stool samples were collected from 161 patients with chronic diarrhoea and from 157 healthy controls. Stool microscopy with modified trichrome stain, culture and polymerase chain reaction (PCR) for Entamoeba spp. differentiation was performed. Microscopy demonstrated Entamoeba cysts in 44% (57/129) of patients with diarrhoea compared to 29% (44/151) of controls (P=0·009). In patients with diarrhoea, PCR for E. histolytica was positive in 9% (11/129) (P=0·008), E. dispar in 19% (24/129) (P=0·117) and E. moshkovskii in 19% (24/129) (P<0·001). E. histolytica and E. moshkovskii were significantly associated with diarrhoea while E. dispar was found equally in both groups.

Helicobacter pylori: association with gall bladder disorders in Pakistan.

Helicobacter species colonise the biliary tract and therefore this study explores the relationship between of Helicobacter pylori and cholecystitis. Bile and gall bladder tissue samples were obtained from 144 patients who underwent cholecystectomy. Of these, 89 had chronic cholecystitis with cholelithiasis, 44 had gall bladder carcinoma and 11 had gall bladder polyps. Histopathology examination included special staining and immunohistochemistry (IHC), while Helicobacter species (H. pylori, H. bilis and H. hepaticus) were detected by the polymerase chain reaction (PCR). Sequencing and BLAST query of PCR products was undertaken and samples were considered to contain H. pylori if both PCR and IHC were positive. Immunohistochemistry for H. pylori was positive in 22 (25%) cases compared to five (9%) in the control group (P=0.02). Testing (PCR) for 16S rDNA was positive in 23 (26%) cases compared to six (11%) controls (P=0.03). Negative PCR results were obtained for H. bilis and H. hepaticus. Twenty-four (89%) were positive by both 16S rDNA PCR and IHC for H. pylori (P<0.001). Both PCR for 16S rDNA and IHC were positive in 21 (24%) cases compared to five (9%) controls (P=0.03). Sequencing of 16S rRNA and glmM PCR products were consistent with H. pylori. In conclusion, H. pylori DNA was demonstrated in cases of chronic cholecystitis and gall bladder carcinoma associated with cholelithiasis, but this association requires further study.

Is full colonoscopic examination necessary in young patients with fresh bleeding per rectum?

BACKGROUND AND STUDY AIMS: Guidelines and practices differ regarding evaluation of young patients with fresh bleeding per rectum (FBPR). The aim of this study was to determine the frequency and site of endoscopic lesions in young patients with FBPR, and to thereby determine whether full colonoscopic examination is necessary in these patients. METHODS: Consecutive patients aged 18-50 years who were scheduled to undergo full colonoscopy for FBPR at Aga Khan University Hospital between May 2007 and October 2009 were enrolled in the study after giving informed consent. FBPR was defined as the passing of fresh blood per rectum with or without stools and/or noticing blood in the toilet bowl. Lesions were characterized as proximal or distal to the splenic flexure. Patients with positive family history of colorectal cancer, bleeding requiring blood transfusion, bleeding diathesis, or iron deficiency anemia were excluded. RESULTS: A total of 379 patients met the inclusion criteria and were analyzed. Of these, 248 patients (65.4%) were under 40 years of age and 131 (34.6%) were aged 40-50 years. Mean hemoglobin was 12.93 ± 1.78 g/dL. In patients < 40 years, seven (2.8%) adenomatous polyps and malignant lesions were found, all of which were located in the distal colon. In patients aged 40-50 years, 10 (7.6%) adenomatous polyps and malignant lesions were detected, one of which was located in the proximal colon. On univariate analysis, malignant and adenomatous lesions were significant in the 40-50 years age group (P = 0.031; OR, 2.84; 95% CI 1.05-7.65). CONCLUSION: Endoscopic lesions in patients younger than 40 years with FBPR are found mostly in the distal colon and hence flexible sigmoidoscopy seems to be a reasonable evaluation tool in young patients with no other alarm symptoms.

Risk factors associated with Helicobacter pylori infection treatment failure in a high prevalence area.

Triple therapy is commonly used for the treatment of Helicobacter pylori infection. We determined risk factors associated with its failure in compliant patients focusing on H. pylori density, virulence marker and 23S ribosomal RNA (rRNA) point mutations associated with clarithromycin resistance. H. pylori infection was diagnosed by 14C urea breath test (14C UBT) and rapid urease test or histology. Triple therapy with esomeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d. and clarithromycin 500 mg b.i.d. was prescribed for 10 days. 14C UBT was repeated 4 weeks after treatment. In total, 111 patients [69 (62%) males] with a mean age of 46±16 years were enrolled. The mean age of treatment failure was 39±14 years compared to 48±16 years with eradication (P=0·002). Treatment failure was associated with younger mean age, point mutations in the 23S rRNA gene of H. pylori and vacA s1a and m1 when associated with cagA negativity.

Effectiveness of educational interventions in improving clinical competence of residents in an internal medicine residency program in Pakistan.

INTRODUCTION: Medical education is a continuously evolving field. Training institutes and programs should have a process in place to gather continuous feedback and then make appropriate modifications in order to provide education and training effectively. Our study aimed to assess the effect of a quality improvement cycle approach in using various educational interventions within a residency. Effects were measured on the key educational outcomes of residents; medical knowledge, skills and professional attitudes using results of postgraduate examination with both written and clinical skills components. METHODOLOGY: A number of educational interventions were implemented which included changes in work hours with increased time for self-study, new educational activities including a Residents Hour, a Residents Slide Session, Grand Rounds and Journal Clubs, Clinico-pathological conferences, and a two- week postgraduate course for senior residents. Newer and improved assessment tools were also implemented, including an annual in-training mock exam based on the format of the postgraduate examination. Pass rates in postgraduate examinations (Fellow of College of Physicians and Surgeons exam and Member of Royal College of Physicians exam) were compared before and after the interventions to assess the effectiveness of the interventions. RESULTS: The first group of residents after introduction of the educational interventions completed residency training in 2001. Postgraduate exam pass rates (sometimes after two or more attempts) were 59.2% (42 of 71 graduates) before 2001 and 86.4% (38 of 44 graduates after 2001 (p = 0.002). The number of candidates passing the examinations in either their first or second attempts before 2001 was 17 of 42 (40.5%), which increased to 33 of 38 (86.8%) after 2001 (p = <0.001). CONCLUSIONS: Our study describes a number of interventions that were successful in bringing about an improvement in the performance of our residents. These can serve as a guide for postgraduate training programs, particularly those of Internal Medicine, in implementing strategies to strengthen training and enhance the performance of trainees.

Prevalences of Giardia lamblia and Cryptosporidium parvum infection in adults presenting with chronic diarrhoea.

Giardia lamblia and Cryptosporidium parvum are both waterborne pathogens associated with diarrhoea in developing countries. In a recent study based at the Aga Khan University in Karachi, 334 adults aged 16-83 years (178 patients with chronic diarrhoea and 156 diarrhoea-free volunteers who acted as controls) were checked for infection with these parasites, using stool microscopy and/or PCR. Overall, 21 (6.3%) and 29 (8.7%) of the subjects were found positive for G. lamblia by microscopy and PCR, respectively, while the corresponding values for C. parvum were 13 (3.9%) and 14 (4.2%). Although, compared with the diarrhoea-free controls, the patients with diarrhoea were not significantly more likely to be found infected with Giardia, either by microscopy [15 (8.4%) v. six (3.8%); P=0.085] or PCR [19 (10.7%) v. 10 (6.4%); P=0.167], they were significantly more likely to be found infected with C. parvum, both by microscopy [11 (6.2%) v. two (1.3%); P=0.024] and by PCR [12 (6.7%) v. two (1.3%); P=0.014]. The 19 patients found PCR-positive for Giardia comprised 10 (67%) of the 15 found smear-positive for the same parasite but only nine (5%) of the 163 found smear-negative (k=0.545; P<0.001). Similarly, the 12 patients found PCR-positive for Cryptosporidium comprised all 11 (100%) patients found smear-positive for the same parasite but only one (0.6%) of the 167 found smear-negative (k=0.954; P<0.001). Although C. parvum was associated with chronic diarrhoea in the present study, the carriage of G. lamblia often appeared asymptomatic.

Helicobacter pylori infection in children: population-based age-specific prevalence and risk factors in a developing country.

AIM: We estimated the prevalence, age of acquisition and risk factors for Helicobacter pylori (H. pylori) seroprevalence in children aged 1-15 years. METHODS: Exposure was assessed using ELISA. Parents responded to a questionnaire regarding number of individuals sharing house, rooms, water source, latrines, housing and assessment of socioeconomic status (SES) by Hollingshead Index. RESULTS: Serum of 1976 children was tested. Helicobacter pylori seropositivity in children aged 11-15 years was 53.5% (OR: 2.0, 95% CI: 1.58-2.5). It increased with moderate crowding index (CRI) of 2-4 to 45.9% (OR: 1.23, 95% CI: 0.92-1.63) and to 51.2% with CRI >4 (OR: 1.52, 95% CI: 1.12-2.06). In middle SES, seropositivity was 50.5% (331/655) (OR: 1.7, 95% CI: 1.29-2.35), whereas in lower SES, it was 47.1% (500/1062) (OR: 1.5, 95% CI: 1.1-2.0). Multivariate analysis showed that Helicobacter pylori seroprevalence was high in children aged 6-10 and 11-15 years (OR: 1.5, 95% CI: 1.2-1.9 and OR: 1.9, 95% CI: 1.56-2.47 respectively), in lower-middle SES (OR: 1.6, 95% CI: 1.2-2.1 and OR: 1.5, 95% CI: 1.10-2.0 respectively) and in uneducated fathers (OR: 1.58, 95% CI: 1.27-1.95). CONCLUSION: Helicobacter pylori seropositivity increases with age, in low-middle SES and is related to father's educational status. Reducing H. pylori seroprevalence will require improvement in sanitary conditions and educational status of the population.

Health care risk factors among women and personal behaviours among men explain the high prevalence of hepatitis C virus infection in Karachi, Pakistan.

To estimate the prevalence and identify factors associated with hepatitis C virus (HCV) infection among men and women in Karachi, Pakistan. We conducted a cross-sectional study of adult men and women in a peri-urban community of Karachi (Jam Kandah). Households were selected through systematic sampling from within all villages in the study area. All available adults within each household were interviewed about potential HCV risk factors. A blood specimen was collected to test for anti-HCV antibodies by enzyme immunoassay. We used generalized estimating equations while accounting for correlation of responses within villages to identify the factors associated with HCV infection. Of 1997 participants, 476 (23.8%) were anti-HCV positive. Overall, HCV infection was significantly associated with increasing age, ethnicity, and having received > or =2 blood transfusions, > or =3 hospitalizations, dental treatment and >5 injections among women. Among women, > or =2 blood transfusions [adjusted odds ratio (aOR) = 2.32], >5 injections during the past 6 months (aORs = 1.47), dental treatment (aOR = 1.31) and increasing age(aOR = 1.49), while among men, extramarital sexual intercourse (aOR = 2.77), at least once a week shave from barber (aOR = 5.04), > or =3 hospitalizations (aOR = 2.50) and increasing age (aOR = 1.28) were associated with HCV infection. A very high prevalence of HCV was found in the study population. Among women, unsafe health care practices, while among men extramarital sex, shaving from a barber and hospitalizations were associated with HCV infection. Efforts are needed to improve the safety of medical procedures to reduce the transmission of HCV in Pakistan [Corrections made in Summary after initial online publication.].

Low prevalence of the intact cag pathogenicity island in clinical isolates of Helicobacter pylori in Karachi, Pakistan.

Clinical diseases that follow Helicobacter pylori infection are associated with expression of the cagA gene, a part of cytotoxin-associated gene pathogenicity island (cag-PAI). This study aims to determined whether or not the presence of cagA is associated with the presence of complete cag-PAI and to evaluate inflammatory changes associated with the five loci in the cag-PAI of H. pylori comprising cagA, cagA promoter region (cagAP), cagE, cagT and the left end of the cagA gene (LEC). H. pylori isolates were obtained from patients with dyspeptic symptoms. Clinical strains of H. pylori were screened by the polymerase chain reaction (PCR) for respective genes of the cag-PAI. Of 115 H. pylori isolates, 31 (28%) were positive for the five cag-PAI loci. H. pylori isolates with intact cag-PAI were associated with gastric carcinoma (GC; n=9 [60%]) and gastric ulcer (GU; n=5 [45%]) compared to non-ulcer dyspepsia (NUD; n=14 [18%]) (P=0.001 and P=0.049, respectively). In patients with intact cag-PAI, acute on chronic inflammation was present in 25 (81%) and was more common than chronic inflammation (P=0.013). The cagE and cagAP had deletions in 25 (37%) and 23 (35%) cases, respectively. The cagAP region was significantly associated with GC (n=12 [80%], P<0.001) and GU (n=9 [82%], P=0.001) compared to NUD (n=24 [30%] and with significant acute on chronic inflammation (n=40 [80%], P=0.007). The distribution of vacAs1a with intact cag-PAI in GC was 9 (60%) and in NUD was 10 (13%) (P<0.001). The presence of the cagA gene does not signify presence of an intact cag-PAI. Most of the H. pylori isolates studied had partial cag-PAI with missing cagE and cagA promoter regions.

Medical mortality in Pakistan: experience at a tertiary care hospital.

AIM: To acquire systematic data on the causes of hospital mortality in Pakistan, a developing country with scant mortality records. STUDY DESIGN: Retrospective review of death certificates and hospital charts of patients dying on general and specialty medical services at our hospital during one calendar year. RESULTS: Of a total 10,590 admissions, 657 (6.2%) died in hospital. The deceased included 357 (54.4%) males and 299 (45.6%) females, with a collective median age of 63 years and mean length of stay 6.71 days (median 4 days, range 1-56 days). Primary cause of death was categorised as infectious (21.2%), pulmonary (17.2%), cancer related (15.7%), cardiovascular (12.6%), gastrointestinal and hepatic (10.8%), neurological (11.4%) and miscellaneous (11.1%). Within each category, the most common diagnoses were septicaemia (76.9% of infectious cases), pneumonia (55.7% of pulmonary cases), myocardial infarction (40.9% of cardiovascular), intracranial haemorrhage (37.3% of neurological), and cirrhosis (45.0% of gastrointestinal). There were multiple causes among malignant disorders with no single cause dominating. Patients with cardiovascular and pulmonary deaths tended to be older than the median age (p = 0.001), while patients with gastrointestinal and cancer related deaths tended to be younger than the median age (p = 0.001). Length of stay did not differ significantly among the various subgroups. About a quarter (26.4%) deaths occurred within 24 h of admission. CONCLUSIONS: Infections, including septicaemia and pneumonia, are the leading causes of hospital mortality in our setting, followed by malignancy and cardiovascular causes. The overall mortality rate is comparable to published mortality data from other hospital settings.