Impact of Diabetes, Drug-Induced Liver Injury, and Sepsis on Outcomes in Metabolic Dysfunction Associated Fatty Liver Disease-Related Acute-on-Chronic Liver Failure.

INTRODUCTION: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute-on-chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied. METHODS: Patients with MAFLD-ACLF were recruited from the Asian Pacific Association for the Study of the Liver-ACLF Research Consortium (AARC registry). The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease as MAFLD (or previous nomenclature such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, or non-alcoholic steatohepatitis-cirrhosis). Patients with coexisting other etiologies of chronic liver disease (such as alcohol, hepatitis B virus, hepatitis C virus, etc.) were excluded. Data were randomly split into derivation (n = 258) and validation (n = 111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered. RESULTS: The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27% and hypertension in 29%. The dominant precipitants included viral hepatitis (hepatitis A virus and hepatitis E virus, 32%), drug-induced injury (drug-induced liver injury, 29%), and sepsis (23%). Model for End-Stage Liver Disease-Sodium (MELD-Na) and AARC scores on admission averaged 32 ± 6 and 10.4 ± 1.9. At 90 days, 51% survived. Nonviral precipitant, diabetes, bilirubin, international normalized ratio, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for nonviral precipitant), and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts. DISCUSSION: Almost half of patients with MAFLD-ACLF die within 90 days. Diabetes and nonviral precipitants such as drug-induced liver injury and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for patients with MAFLD-ACLF.

APASL-ACLF Research Consortium-Artificial Intelligence (AARC-AI) model precisely predicts outcomes in acute-on-chronic liver failure patients.

BACKGROUND AND AIMS: We hypothesized that artificial intelligence (AI) models are more precise than standard models for predicting outcomes in acute-on-chronic liver failure (ACLF). METHODS: We recruited ACLF patients between 2009 and 2020 from APASL-ACLF Research Consortium (AARC). Their clinical data, investigations and organ involvement were serially noted for 90-days and utilized for AI modelling. Data were split randomly into train and validation sets. Multiple AI models, MELD and AARC-Model, were created/optimized on train set. Outcome prediction abilities were evaluated on validation sets through area under the curve (AUC), accuracy, sensitivity, specificity and class precision. RESULTS: Among 2481 ACLF patients, 1501 in train set and 980 in validation set, the extreme gradient boost-cross-validated model (XGB-CV) demonstrated the highest AUC in train (0.999), validation (0.907) and overall sets (0.976) for predicting 30-day outcomes. The AUC and accuracy of the XGB-CV model (%Δ) were 7.0% and 6.9% higher than the standard day-7 AARC model (p < .001) and 12.8% and 10.6% higher than the day 7 MELD for 30-day predictions in validation set (p < .001). The XGB model had the highest AUC for 7- and 90-day predictions as well (p < .001). Day-7 creatinine, international normalized ratio (INR), circulatory failure, leucocyte count and day-4 sepsis were top features determining the 30-day outcomes. A simple decision tree incorporating creatinine, INR and circulatory failure was able to classify patients into high (~90%), intermediate (~60%) and low risk (~20%) of mortality. A web-based AARC-AI model was developed and validated twice with optimal performance for 30-day predictions. CONCLUSIONS: The performance of the AARC-AI model exceeds the standard models for outcome predictions in ACLF. An AI-based decision tree can reliably undertake severity-based stratification of patients for timely interventions.

Flare of Autoimmune Hepatitis Causing Acute on Chronic Liver Failure: Diagnosis and Response to Corticosteroid Therapy.

Autoimmune hepatitis (AIH) is considered less common in the Asia Pacific region. Due to this, AIH flare as a cause of acute on chronic liver failure (ACLF) is often overlooked and treatment delayed. We aimed at the defining clinical and histopathological spectrum and role of steroid therapy in AIH-ACLF. Patients with AIH-ACLF, prospectively recruited and followed between 2012 and 2017, were analyzed from the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) data base. Diagnosis of AIH was confirmed using International Autoimmune Hepatitis Group score or simplified AIH score with histopathological evidence. Of 2,825 ACLF patients, 82 (2.9%) fulfilled criteria of AIH (age 42.1 ± 18.1 years, 70% female). At baseline, mean bilirubin was 18.6 ± 8.2 mg/dL, Child-Turcotte-Pugh score was 11.7 ± 1.4, and Model for End-Stage Liver Disease (MELD) score was 27.6 ± 6.5. Mean immunoglobulin G was 21.61 ± 7.32 g/dL, and this was elevated ≥1.1 times in 97% of cases; 49% were seronegative. Liver histology was available in 90%, with median histological activity index of 10 (interquartile range, 7-12); 90% with moderate to severe interface activity; 56% showing significant parenchymal necrosis (bridging and confluent necrosis); and cirrhosis in 42%. Twenty-eight (34%) patients received steroid therapy and showed shorter intensive care unit (ICU) stay (median 1.5 versus 4 days, P < 0.001) and improved 90-day survival (75% versus 48.1%, P = 0.02) with comparable incidence of sepsis (P = 0.32) compared to those who did not. Patients of advanced age, more severe liver disease (MELD >27; 83.3% sensitivity, 78.9% specificity, area under the receiver operating characteristic curve 0.86), presence of hepatic encephalopathy, and fibrosis grade ≥F3 had an unfavorable response to corticosteroid therapy. Conclusion: AIH presenting as ACLF is not uncommon in Asian patients; a low threshold for liver biopsy is needed to confirm the diagnosis as nearly half the patients are seronegative; early stratification to steroid therapy or liver transplantation (MELD >27, hepatic encephalopathy in ≥F3) would reduce ICU stay and improve outcomes.

Drug-Induced Acute-on-Chronic Liver Failure in Asian Patients.

OBJECTIVES: Acute insults from viruses, infections, or alcohol are established causes of decompensation leading to acute-on-chronic liver failure (ACLF). Information regarding drugs as triggers of ACLF is lacking. We examined data regarding drugs producing ACLF and analyzed clinical features, laboratory characteristics, outcome, and predictors of mortality in patients with drug-induced ACLF. METHODS: We identified drugs as precipitants of ACLF among prospective cohort of patients with ACLF from the Asian Pacific Association of Study of Liver (APASL) ACLF Research Consortium (AARC) database. Drugs were considered precipitants after exclusion of known causes together with a temporal association between exposure and decompensation. Outcome was defined as death from decompensation. RESULTS: Of the 3,132 patients with ACLF, drugs were implicated as a cause in 329 (10.5%, mean age 47 years, 65% men) and other nondrug causes in 2,803 (89.5%) (group B). Complementary and alternative medications (71.7%) were the commonest insult, followed by combination antituberculosis therapy drugs (27.3%). Alcoholic liver disease (28.6%), cryptogenic liver disease (25.5%), and non-alcoholic steatohepatitis (NASH) (16.7%) were common causes of underlying liver diseases. Patients with drug-induced ACLF had jaundice (100%), ascites (88%), encephalopathy (46.5%), high Model for End-Stage Liver Disease (MELD) (30.2), and Child-Turcotte-Pugh score (12.1). The overall 90-day mortality was higher in drug-induced (46.5%) than in non-drug-induced ACLF (38.8%) (P = 0.007). The Cox regression model identified arterial lactate (P < 0.001) and total bilirubin (P = 0.008) as predictors of mortality. DISCUSSION: Drugs are important identifiable causes of ACLF in Asia-Pacific countries, predominantly from complementary and alternative medications, followed by antituberculosis drugs. Encephalopathy, bilirubin, blood urea, lactate, and international normalized ratio (INR) predict mortality in drug-induced ACLF.

Findings from a large Asian chronic hepatitis C real-life study.

There is a paucity of information on chronic hepatitis C (CHC) patients treated with direct antiviral agents (DAAs) in Asia. We invited Asia-Pacific physicians to collate databases of patients enrolled for CHC treatment, recording baseline clinical, virologic and biochemical characteristics, sustained virologic response at week 12 (SVR12) and virologic failure. SVR12 outcome was based on intention to treat (ITT). Multivariate analysis was used to assess independent risk factors for SVR12 using SPSS version 20. A total of 2171 patients from India (n = 977), Myanmar (n = 552), Pakistan (n = 406), Thailand (n = 139), Singapore (n = 72) and Malaysia (n = 25) were collected. At baseline, mean age was 49 years, 50.2% were males, and 41.8% had cirrhosis. Overall, SVR12 was 89.5% and by genotype (GT) based on ITT and treatment completion, respectively, was 91% and 92% for GT1, 100% and 100% for GT2, 91% and 97% for GT3, 64% and 95% for GT4, 87% and 87% for GT6 and 79% and 91% for GT untested. Patients with cirrhosis had SVR12 of 85% vs 93% for noncirrhosis (P < 0.001) (RR 2.1, 95% CI 1.4-3.1, P = 0.0002). Patients with GT1 and GT3 treated with sofosbuvir/ribavirin (SR) had 88% and 89% SVR12, respectively, but those GT6 treated with sofosbuvir/ledipasvir (SL) had only 77.6% SVR12. Multivariate analysis showed absence of cirrhosis was associated with higher SVR12 (OR 2.0, 95% CI 1.3-3.1, P = 0.002). In conclusion, patients with GT1 and GT3 with/without cirrhosis had surprisingly high efficacy using SR, suggesting that Asians may respond better to some DAAs. However, poor GT6 response to SL suggests this regimen is suboptimal for this genotype.

Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure.

BACKGROUND AND AIM: There is limited data on predictors of acute kidney injury in acute on chronic liver failure. We developed a PIRO model (Predisposition, Injury, Response, Organ failure) for predicting acute kidney injury in a multicentric cohort of acute on chronic liver failure patients. PATIENTS AND METHODS: Data of 2360 patients from APASL-ACLF Research Consortium (AARC) was analysed. Multivariate logistic regression model (PIRO score) was developed from a derivation cohort (n=1363) which was validated in another prospective multicentric cohort of acute on chronic liver failure patients (n=997). RESULTS: Factors significant for P component were serum creatinine[(≥2 mg/dL)OR 4.52, 95% CI (3.67-5.30)], bilirubin [(<12 mg/dL,OR 1) vs (12-30 mg/dL,OR 1.45, 95% 1.1-2.63) vs (≥30 mg/dL,OR 2.6, 95% CI 1.3-5.2)], serum potassium [(<3 mmol/LOR-1) vs (3-4.9 mmol/L,OR 2.7, 95% CI 1.05-1.97) vs (≥5 mmol/L,OR 4.34, 95% CI 1.67-11.3)] and blood urea (OR 3.73, 95% CI 2.5-5.5); for I component nephrotoxic medications (OR-9.86, 95% CI 3.2-30.8); for R component,Systemic Inflammatory Response Syndrome,(OR-2.14, 95% CI 1.4-3.3); for O component, Circulatory failure (OR-3.5, 95% CI 2.2-5.5). The PIRO score predicted acute kidney injury with C-index of 0.95 and 0.96 in the derivation and validation cohort. The increasing PIRO score was also associated with mortality (P<.001) in both the derivation and validation cohorts. CONCLUSIONS: The PIRO model identifies and stratifies acute on chronic liver failure patients at risk of developing acute kidney injury. It reliably predicts mortality in these patients, underscoring the prognostic significance of acute kidney injury in patients with acute on chronic liver failure.

Systemic inflammatory response syndrome in acute-on-chronic liver failure: Relevance of 'golden window': A prospective study.

BACKGROUND AND AIM: Systemic inflammatory response syndrome (SIRS) is an early marker of sepsis and ongoing inflammation and has been reported in large proportion of acute-on-chronic liver failure (ACLF) patients. Whether sepsis is the cause or the result of liver failure is unclear and is vital to know. To address this, the study investigated the course and outcome of ACLF patients without SIRS/sepsis. METHODS: Consecutive ACLF patients were monitored for the development of SIRS/sepsis and associated complications and followed till 90 days, liver transplant or death. RESULTS: Of 561 patients, 201 (35.8%) had no SIRS and 360 (64.2%) had SIRS with or without infection. New onset SIRS and sepsis developed in 74.6% and 8% respectively in a median of 7 (range 4-15) days, at a rate of 11% per day. The cumulative incidence of new SIRS was 29%, 92.8%, and 100% by days 4, 7, and 15. Liver failure, that is, bilirubin > 12 mg/dL (odds ratio [OR] = 2.5 [95% confidence interval {CI} = 1.05-6.19], P = 0.04) at days 0 and 4, and renal failure at day 4 (OR = 6.74 [95%CI = 1.50-13.29], P = 0.01), independently predicted new onset SIRS. Absence of SIRS in the first week was associated with reduced incidence of organ failure (20% vs 39.4%, P = 0.003), as was the 28-day (17.6% vs 36%, P = 0.02) and 90-day (27.5% vs 51%,P = 0.002) mortality. The 90-day mortality was 61.6% in the total cohort and that for those having no SIRS and SIRS at presentation were 42.8% and 65%, respectively (P < 0.001). CONCLUSION: Liver failure predicts the development of SIRS. New onset SIRS in the first week is an important determinant of early sepsis, organ failure, and survival. Prompt interventions in this 'golden window' before development of sepsis may improve the outcome of ACLF.

MORBIDITY AND MORTALITY ASSESSMENT IN ACUTE HEPATITIS-E.

BACKGROUND: Hepatitis-E is an enterically transmitted virus causing acute hepatitis. Mostly it is a self-limiting clinical course, but can be life threatening in certain high risk groups. Pakistan is endemic for Hepatitis-E with limited published literature. The aim of this study is to evaluate the predictors of mortality in patients with acute Hepatitis-E. METHODS: We analyzed the medical records of 369 adult patients with Hepatitis-E infection admitted at Aga khan University Hospital, from January 1996 to December 2010. Details of their laboratory investigations, clinical course and complications such as FHF and mortality were noted. The outcome was compared, and determinants of mortality were evaluated in important patient subgroups. RESULTS: Out of 369 patients with Hepatitis-E, 326 (88.3%) were discharged after full recovery. Out of these 22 (6%) patients had chronic liver disease CLD in this study, of whom 10 (2.7%) expired (p-value <0.001). There were about 67 (18%) pregnant patients, with a mean gestational age of 29.19 +/- 7.68 weeks and 5 (1.4%) pregnant patients died (p-value=0.23). A total of 58 (15.7%) patients were coinfected with other hepatotropic virus, and a comparison did not find an increased risk of mortality in this group. CONCLUSION: This study showed that Hepatitis-E is significantly associated with mortality in patients suffering from pre-existing chronic liver disease. Pregnancy was not a determinant of mortality in Hepatitis-E patients in this study, and neither was coinfection with other Hepatotropic viruses.

Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: a multicentre randomized controlled trial.

BACKGROUND & AIMS: Esophageal variceal bleed is a major problem in patients with cirrhosis. Endoscopic variceal ligation (EVL) has been shown to be equal to or better than propranolol in preventing first bleed. Carvedilol is a non-selective ß blocker with alpha-1 adrenergic blocker activity. Hemodynamic studies have shown carvedilol to be more effective than propranolol at reducing portal pressure. We compared efficacy of carvedilol with EVL for primary prophylaxis of esophageal variceal bleed. METHODS: Cirrhotic patients with esophageal varices were randomized to carvedilol 12.5mg daily or EVL at three university hospitals of Pakistan. End points were esophageal variceal bleeding, death or liver transplant. RESULTS: Two hundred and nine patients were evaluated. Eighty two and eighty six patients were randomized in carvedilol and EVL arms respectively. Mean age was 48 ± 12.2 years; 122 (72.7%) were males; 89.9% had viral cirrhosis; mean Child-Pugh score was 7.3 ± 1.6 and mean follow up was 13.3 ± 12.1 months (range 1-50 months). Both EVL and carvedilol groups had comparable variceal bleeding rates (8.5% vs. 6.9%), bleed related mortality (4.6% vs. 4.9%) and overall mortality (12.8% vs. 19.5%) respectively. Adverse events in carvedilol group were hypotension (n=2), requiring cessation of therapy, while transient nausea (n=18) and dyspnea (n=30) resolved spontaneously. In the EVL arm, post banding ulcer bleed (n=1) and chest pain (n=17), were termed as serious adverse events while transient dysphagia (n=58) resolved without treatment. CONCLUSIONS: Although our study is underpowered, the findings suggest that carvedilol is probably not superior to EVL in preventing first variceal bleed in patients with viral cirrhosis.

Cytokine changes in colonic mucosa associated with Blastocystis spp. subtypes 1 and 3 in diarrhoea-predominant irritable bowel syndrome.

We determined cytokines (e.g. interleukin-8, 10, 12 and TNF-α) expression by peripheral blood mononuclear cells (PBMCs) and in rectal mucosa in diarrhoea-predominant irritable bowel syndrome (D-IBS) with Blastocystis spp. Eighty patients with D-IBS and Blastocystis spp. infection were classified as 'cases' and 80 with D-IBS without Blastocystis spp. infection were classified as 'control'. Cases were subdivided into D-IBS and Blastocystis sp. defined type 1 (subtype-specific primer SB83) and type 3 (SB227). Stool microscopy and culture were performed. Rectal biopsies were obtained for histology and cytokines by real-time PCR for mRNA expression of cytokines. PBMCs IL-8 was similar in different groups but in type 1, IL-8mRNA was increased compared with type 3 (P = 0·001) and control (P = 0·001). In type 1, IL-10 by PBMCs had a low mean value (14·5±1·6) compared with (16·7±1·5) type 3 and (16±2·3) in controls (P<0·001 and P<0·001, respectively). In Blastocystis sp. type 1, low IL-10 was associated with lymphocyte and plasma cell infiltration (P = 0·015 and P = 0·002, respectively). In Blastocystis sp. type 1 and type 3, IL-12 was associated with goblet cell depletion 23 (85%) (P<0·001) and 8 (29%) (P = 0·037), respectively. In Blastocystis sp. type 1, low IL-10 was associated with a proinflammatory response characterized by IL-8.

Age and site of Colonic Neoplastic Lesions: Implications of screening in South Asia.

UNLABELLED: Objective : To evaluate the Age of patients and the site of Colonic Neoplastic Lesions (CNL) and to determine the appropriate screening strategy for Colorectal Carcinoma (CRC) (sigmoidoscopy versus colonoscopy) in our population. Methods : This is a cross sectional study. Data of all patients more than 16 years of age who underwent full colonoscopic examination at the Aga Khan University hospital between January 2011 till December 2013 and were diagnosed to have CRC or advanced adenomas (defined as polyp more than 1 cm and/or having villous morphology on histology) was recorded. Lesions found distal to the splenic flexure were characterized as distal lesions and while lesions found between the splenic flexure and the cecum were characterized as proximal lesions. RESULTS: During the study period colonic neoplastic lesions were found in 217 patients; 186 (85.7%) patients had CRC and 31(14.3%) patients had advanced adenomatous polyps. Mean age was 55.8±14 years and amongst them 72 (33.2%) patients were less than 50 years of age while 145 (66.8%) were more than 50 years. In 144 (66.4%) patients lesions were located in the distal colon, 65 (30%) had lesions in the proximal colon while in 8 (3.7%) patients the neoplastic lesions were found both in the proximal and distal colon. The predominant symptoms were bleeding per rectum in 39.6% of patients followed by weight loss in 31.8% of patients. Only 3 patients had familial syndromes with multiple polyps. When patients younger than 50 years of age were compared with patients more than 50 years there was no statistically significant difference between the site of neoplastic lesion as well as the presenting symptoms. (p value 0.85). CONCLUSION: Colonic Neoplastic Lesions presented at younger age in our study population and one third of the lesions were found in the right sided colon. Hence screening for CNLs should be implied at an earlier age preferably with colonoscopy. More population based data is required to further validate our results.

Expert consensus on the diagnosis and treatment of end-stage liver disease complicated by infections.

End-stage liver disease (ESLD) is a life-threatening clinical syndrome and when complicated with infection the mortality is markedly increased. In patients with ESLD, bacterial or fungal infection can induce or aggravate the occurrence or progression of liver decompensation. Consequently, infections are among the most common complications of disease deterioration. There is an overwhelming need for standardized protocols for early diagnosis and appropriate management for patients with ESLD complicated by infections. Asia Pacific region has the largest number of ESLD patients, due to hepatitis B and the growing population of alcohol and NAFLD. Concomitant infections not only add to organ failure and high mortality but also to financial and healthcare burdens. This consensus document assembled up-to-date knowledge and experience from colleagues across the Asia-Pacific region, providing data on the principles as well as evidence-based current working protocols and practices for the diagnosis and treatment of patients with ESLD complicated by infections.

Ammonia is associated with liver-related complications and predicts mortality in acute-on-chronic liver failure patients.

The relationship between ammonia and liver-related complications (LRCs) in acute-on-chronic liver failure (ACLF) patients is not clearly established. This study aimed to evaluate the association between ammonia levels and LRCs in patients with ACLF. The study also evaluated the ability of ammonia in predicting mortality and progression of LRCs. The study prospectively recruited ACLF patients based on the APASL definition from the ACLF Research Consortium (AARC) from 2009 to 2019. LRCs were a composite endpoint of bacterial infection, overt hepatic encephalopathy (HE), and ascites. A total of 3871 cases were screened. Of these, 701 ACLF patients were enrolled. Patients with LRCs had significantly higher ammonia levels than those without. Ammonia was significantly higher in patients with overt HE and ascites, but not in those with bacterial infection. Multivariate analysis found that ammonia was associated with LRCs. Additionally, baseline arterial ammonia was an independent predictor of 30-day mortality, but it was not associated with the development of new LRCs within 30 days. In summary, baseline arterial ammonia levels are associated with 30-day mortality and LRCs, mainly overt HE and ascites in ACLF patients.

Low rate of recurrence of Helicobacter pylori infection in spite of high clarithromycin resistance in Pakistan.

BACKGROUND: The aim was to investigate the reinfection rate of H. pylori during a follow-up period of 12 months in adults who had undergone eradication therapy. METHODS: One hundred-twenty patients; 116 with gastritis, 3 with duodenal ulcer and 1 gastric ulcer, were studied. Their mean age was 41±13 years (range 18-77) and male: female ratio of 2:1. H. pylori were cultured and antibiotic sensitivity was determined by Epsilometer test (E-test) for clarithromycin (CLR) and amoxicillin (AMX). Primers of urease C gene of H. pylori and Sau-3 and Hha I restriction enzymes were used for polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). 14C urea breath test (14C-UBT) was performed 4 weeks after the eradication therapy. The successfully treated patients were observed for 12 months with 14C-UBT to assess H. pylori status. If 14C-UBT was negative, it was repeated after every 12 weeks. If 14C-UBT was positive, endoscopy was repeated with biopsies. RESULT: The eradication therapy was successful in 102(85%) patients. Out of forty-seven H. pylori isolates cultured, clarithromycin sensitivity was present in 30(64%) and amoxicillin in 45(98%), respectively. Follow-up 14C-urea breath tests of all 102 patients who eradicated H. pylori remained negative up to 9 months. However, in 6 patients, the 14C-UBT confirmed recurrence at 12 months. The recurrence rate was 6%. CONCLUSION: A low rate of recurrence of H. pylori infection was found in patients with dyspeptic symptoms. H. pylori isolates demonstrated a high invitro clarithromycin resistance.

Changing trends of hepatitis B seromarkers amongst Pakistani population: a laboratory-based review.

OBJECTIVE: To study the changing trends of hepatitis B markers tested at Aga Khan University Hospital clinical laboratory according to the internationally recognised classification of hepatitis B profile. METHODS: The retrospective study involved analysis of laboratory records of hepatitis B profiles of all patients collected from January 2001 to December 2008 at the Aga Khan University Hospital's clinical laboratory. Patients with complete profile tested were categorised according to the Centre for Diseases Control classification of hepatitis B profile. SPSS 16 was used for statistical analysis. RESULTS: A total of 185,825 patients had serological markers for hepatitis B tested. Mean-age of reactive hepatitis B surface antigen (HBsAg) patients was 30+/-12.5 years. HBsAg reactivity was significantly higher in males than females (34% vs 12%; p <0.0001). HBsAg showed a slight decline in the percentage reactivity during the 8-year study period, while a gradual increase in hepatitis B surface antibody (HBsAb) reactivity was observed. Of the total, 23% patients belonged to the 'susceptible to infection' category; 39% patients were classified as 'chronically-ill'; 12% patients were categorised as 'immune due to hepatitis B vaccination. 3% patients were classed as 'acutely infected'. Overall, samples received from Peshawar, Quetta and Larkana showed very high reactivity rates. CONCLUSION: The study substantiated the general perception that levels of HBsAg is showing a decreasing trend, while levels of HBsAb are increasing perhaps due to better vaccination of population.

Short course adjuvant terlipressin in acute variceal bleeding: a randomized double blind dummy controlled trial.

BACKGROUND & AIMS: Terlipressin is recommended for 3-5 days as adjuvant to endoscopic variceal band ligation (EVBL) in esophageal variceal bleeding (EVB). We assessed whether terlipressin can be administered for a shorter period of time to patients with EVB. METHODS: All eligible EVB patients received 24h of open label terlipressin at presentation. After successful EVBL, patients were randomized to receive active or dummy terlipressin for the next 48 h. We excluded patients with failure to achieve initial hemostasis, bleeding gastric varices, known hepatoma, and/or portal vein thrombosis, advanced cirrhosis (Child-Pugh score ≥12), and patients on a ventilator. The primary outcome was failure to control EVB. The secondary outcomes were 30-day mortality; re-bleeding and composite outcome of failure to control EVB. RESULTS: A total of 130 eligible patients were randomized to receive terlipressin for a total of 24 (short course or SC) or 72 h (usual course or UC). Baseline patient characteristics were comparable; the majority of patients were HCV-infected and male. There was one failure to control EVB (1.5%) in UC and none in SC terlipressin (p=0.50). The 30-day re-bleeding rate was 1.5% and 3.1% in UC, and SC terlipressin, respectively (p=0.50). The 30-day mortality was 12, 6 (9.2%) patients in each group (p=0.50). The 30-day failure to control bleeding was observed in 14 patients; seven in each group (p=0.494). CONCLUSIONS: In patients with esophageal variceal bleeding, a 24-h course of terlipressin is as effective as a 72-h course when used as an adjunctive therapy to successful EVBL.

The clinical, endoscopic and histological spectrum of the solitary rectal ulcer syndrome: a single-center experience of 116 cases.

BACKGROUND: Solitary rectal ulcer syndrome (SRUS) is an uncommon although benign defecation disorder. The aim of this study was to evaluate the variable endoscopic manifestations of SRUS and its association with other diseases. METHODS: All the patients diagnosed with SRUS histologically from January 1990 to February 2011 at The Aga Khan University, Karachi were included in the study. The medical records were reviewed retrospectively to evaluate the clinical spectrum of the patients along with the endoscopic and histological findings. RESULTS: A total of 116 patients were evaluated. The mean age was 37.4 ± 16.6 (range: 13-80) years, 61 (53%) of the patients were male. Bleeding per rectum was present in 82%, abdominal pain in 49%, constipation in 23% and diarrhea in 22%. Endoscopically, solitary and multiple lesions were present in 79 (68%) and 33 (28%) patients respectively; ulcerative lesions in 90 (78%), polypoidal in 29 (25%), erythematous patches in 3 (2.5%) and petechial spots in one patient. Associated underlying conditions were hemorrhoids in 7 (6%), hyperplastic polyps in 4 (3.5%), adenomatous polyps in 2(2%), history of ulcerative colitis in 3 (2.5%) while adenocarcinoma of colon was observed in two patients. One patient had previous surgery for colonic carcinoma. CONCLUSION: SRUS may manifest on endoscopy as multiple ulcers, polypoidal growth and erythematous patches and has shown to share clinicopathological features with rectal prolapse, proctitis cystica profunda (PCP) and inflammatory cloacogenic polyp; therefore collectively grouped as mucosal prolapse syndrome. This may be associated with underlying conditions such as polyps, ulcerative colitis, hemorrhoids and malignancy. High index of suspicion is required to diagnose potentially serious disease by repeated endoscopies with biopsies to look for potentially serious underlying conditions associated with SRUS.

Prevalence of non Helicobacter pylori species in patients presenting with dyspepsia.

BACKGROUND: Helicobacter species associated with human infection include Helicobacter pylori, Helicobacter heilmannii and Helicobacter felis among others. In this study we determined the prevalence of H. pylori and non-Helicobacter pylori organisms H. felis and H. heilmannii and analyzed the association between coinfection with these organisms and gastric pathology in patients presenting with dyspepsia. Biopsy specimens were obtained from patients with dyspepsia on esophagogastroduodenoscopy (EGD) for rapid urease test, histology and PCR examination for Helicobacter genus specific 16S rDNA, H. pylori phosphoglucosamine mutase (glmM) and urease B (ureB) gene of H. heilmannii and H. felis. Sequencing of PCR products of H. heilmannii and H. felis was done. RESULTS: Two hundred-fifty patients with dyspepsia were enrolled in the study. The mean age was 39 ± 12 years with males 162(65%). Twenty-six percent (66 out of 250) were exposed to cats or dogs. PCR for Helicobacter genus specific 16S rDNA was positive in 167/250 (67%), H. pylori glmM in 142/250 (57%), H. heilmannii in 17/250 (6%) and H. felis in 10/250 (4%), respectively. All the H. heilmannii and H. felis PCR positive patients were also positive for H. pylori PCR amplification. The occurrence of coinfection of H. pylori and H. heilmannii was 17(6%) and with H. felis was 10(4%), respectively. Only one out of 66 exposed to pets were positive for H. heilmannii and two for H. felis. Histopathology was carried out in 160(64%) of 250 cases. Chronic active inflammation was observed in 53(56%) (p = 0.001) of the patients with H. pylori infection alone as compared to 3(37%) (p = 0.73) coinfected with H. heilmannii and H. pylori and 3(60%) coinfected with H. felis and H. pylori (p = 0.66). Intestinal metaplasia was observed in 3(3%)(p = 1.0) of the patients with H. pylori infection alone as compared to 2(25%) (p = 0.02) coinfected with H. heilmannii and H. pylori and 1(20%) coinfected with H. felis and H. pylori (p = 0.15). CONCLUSION: The prevalence of H. heilmannii and H. felis was low in our patients with dyspepsia. Exposure to pets did not increase the risk of H. heilmannii or H. felis infection. The coinfection of H. pylori with H. heilmannii was seen associated with intestinal metaplasia, however this need further confirmation.

Randomized controlled trial of interferon gamma versus amantadine in combination with interferon alpha and ribavirin for hepatitis C genotype 3 non-responders and relapsers.

OBJECTIVES: To evaluate the efficacy and safety of triple combination regimens comprising of interferon alpha-2b (IFN-alpha) and ribavirin plus either IFN-gamma or amantadine in genotype 3 patients, responders or relapsers to interferon plus ribavirin combination. METHODS: Patients were randomized to receive IFN-alpha 3MU thrice a week, ribavirin 800-1200 mg per day with either IFN-gamma 2 MU thrice a week or amantadine 100 mg twice daily. Treatment was continued for 48 weeks in patients showing complete or partial (2 log reduction) early virological response (EVR) at 12 weeks and negative PCR at 24 weeks. RESULTS: Total enrollments were 44; 25 were previously non-responders out of them 12 were in the IFN-gamma arm. Nineteen were relapsers, out of them 10 received IFN-Gamma. Overall EVR with triple regimens was 61.4% (27/44). The EVR for IFN-gamma arm was 72.7% (16/22) and for amantadine arm 50% (11/22) (p=0.089). Sustained virological response (SVR) was 50% (11/22) in the gamma arm and 27.3% (6/22) in the amantadine arm (p=0.122). This figure was 60% (6/10) and 44% (5/9) for relapsers (p=0.845), and 41.6% (5/12) and 7.7% (1/13) for non-responders (p = 0.046).Treatment was well tolerated by most of the patients in both arms. CONCLUSIONS: About one third of patients responded to the triple regimens. However IFN-gamma was a better option. Its combination with pegylated interferon and ribavirin needs further evaluation. ( TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00538811).

Investigating an outbreak of acute viral hepatitis caused by hepatitis E virus variants in Karachi, South Pakistan.

Hepatitis E is a classic water-borne disease in developing countries. Detection of anti-HEV IgM and IgG antibodies, in addition to HEV RNA are useful epidemiological markers in diagnosis of hepatitis E. This study was conducted to investigate an outbreak of acute viral hepatitis in South-Pakistan. Anti-HEV IgM and IgG were assessed comparatively with serological kits manufactured by Abbott, Cosmic, TGH, and Wantai, selecting HEV RNA as reference assay. Molecular evolutionary analysis was performed by phylogeny and HEV spread time analysis by Bayesian Coalescent Theory approach. Of the 89 patients, 24 (26.9%) did not have acute hepatitis viral marker. Of the remaining 65 cases, 4 (6.1%) were positive for anti-HAV IgM, one (1.5%) for anti-HBc IgM, 2 (3%) for HCV, 53 (81.5%) for anti-HEV IgM, and 5 (7.7%) were hepatitis-negative. The Wantai test was 100% sensitive and specific followed by Cosmic (98.1% and 100%), TGH (98.1% and 97.2%) and Abbott (79.2% and 83.3%). Two HEV variant strains were detected by phylogeny responsible for this acute hepatitis outbreak. Estimates on demographic history of HEV showed that HEV in Pakistan has remained at a steady nonexpanding phase from around 1970 to the year 2005, in which it expanded explosively with the emergence of new HEV variants. In conclusion, the limited sensitivity of available assay (Abbott anti-HEV EIA) may be a concern in HEV diagnosis in Pakistan. This study cautions that the dissemination of the variant strains to other areas of Pakistan may lead to explosive HEV outbreaks.