National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma.

A consensus meeting of national experts from all major national hepatobiliary centres in the country was held on May 26, 2023, at the Pakistan Kidney and Liver Institute & Research Centre (PKLI & RC) after initial consultations with the experts. The Pakistan Society for the Study of Liver Diseases (PSSLD) and PKLI & RC jointly organised this meeting. This effort was based on a comprehensive literature review to establish national practice guidelines for hilar cholangiocarcinoma (hCCA). The consensus was that hCCA is a complex disease and requires a multidisciplinary team approach to best manage these patients. This coordinated effort can minimise delays and give patients a chance for curative treatment and effective palliation. The diagnostic and staging workup includes high-quality computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography. Brush cytology or biopsy utilizing endoscopic retrograde cholangiopancreatography is a mainstay for diagnosis. However, histopathologic confirmation is not always required before resection. Endoscopic ultrasound with fine needle aspiration of regional lymph nodes and positron emission tomography scan are valuable adjuncts for staging. The only curative treatment is the surgical resection of the biliary tree based on the Bismuth-Corlette classification. Selected patients with unresectable hCCA can be considered for liver transplantation. Adjuvant chemotherapy should be offered to patients with a high risk of recurrence. The use of preoperative biliary drainage and the need for portal vein embolisation should be based on local multidisciplinary discussions. Patients with acute cholangitis can be drained with endoscopic or percutaneous biliary drainage. Palliative chemotherapy with cisplatin and gemcitabine has shown improved survival in patients with irresectable and recurrent hCCA.

Perception of Gastrointestinal Endoscopy Personnel on Society Recommendations on Personal Protective Equipment, Case Selection, and Scope Cleaning During Covid-19 Pandemic: An International Survey Study.

BACKGROUND/AIMS: The Thai Association for Gastrointestinal Endoscopy published recommendations on safe endoscopy during the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to assess the practicality and applicability of the recommendations and the perceptions of endoscopy personnel on them. METHODS: A validated questionnaire was sent to 1290 endoscopy personnel globally. Of these, the data of all 330 responders (25.6%) from 15 countries, related to the current recommendations on proper personal protective equipment (PPE), case selection, scope cleaning, and safety perception, were analyzed. Ordinal logistic regression was used to determine the relationships between the variables. RESULTS: Despite an overwhelming agreement with the recommendations on PPE (94.5%) and case selection (95.5%), their practicality and applicability on PPE recommendations and case selection were significantly lower (p=0.001, p=0.047, p<0.001, and p=0.032, respectively). Factors that were associated with lower sense of safety in endoscopy units were younger age (p=0.004), less working experience (p=0.008), in-training status (p=0.04), and higher national prevalence of COVID-19 (p=0.003). High prevalent countries also had more difficulty implementing the guidelines (p<0.001) and they considered the PPE recommendations less practical and showed lower agreement with them (p<0.001 and p=0.008, respectively). A higher number of in-hospital COVID-19 patients was associated with less agreement with PPE recommendations (p=0.039). CONCLUSION: Using appropriate PPE and case selection in endoscopic practice during a pandemic remains a challenge. Resource availability and local prevalence are critical factors influencing the adoption of the current guidelines.

Risk of Covid-19 infection during endoscopy: Efficacy of personal protective equipment (PPE) in protecting health professionals.

OBJECTIVES: To correlate compliance to personal protective equipment (PPE) protocols and risk of exposure to SARS-COV-2 infection in endoscopy staff. METHODS: We included 85 endoscopic procedures performed at Lahore General Hospital from May to July 2020. Standard operating procedures (SOPs) were implemented for patient selection, risk stratification and personal protective equipment (PPE) use for endoscopy staff. Patient and endoscopy staff were followed for Covid-19 infection. PPE scores for staff and Covid-19 positivity on follow-up were correlated using student's t test. RESULTS: Following 85 procedures included, 2 (2.3%) patients became Covid-19 positive. PPE score was <9 in 5 (5.8%) procedures for endoscopist and Covid-19 developed in 2 (2.3%) of them, PPE score was <9 during 19 (22.3%) procedures in 1st assistant and 9 (10.5%) developed infection and for 2nd assistant PPE score was <9 in 19(22.3%) endoscopies and 5 (5.9%) tested positive for covid-19. Infectivity of endoscopy staff was 6.2%. Association between PPE score and risk of Covid-19 was not significant. (p value 0.51 for endoscopist, 0.10 for 1st assistant and 0.09 for 2nd assistant). CONCLUSION: Compliance of SOPs for infection control reduces risk of acquiring Covid-19 infection during endoscopy. Proper use of PPE is effective for safety of endoscopy staff.

Interferon-λ rs12979860 genotype association with liver fibrosis in chronic hepatitis C (CHC) patients in the Pakistani population.

Risk and progression of liver fibrosis and cirrhosis in chronic hepatitis C (CHC) patients is significantly influenced by host genetic factors in a polygenic manner. The rs12979860 genetic polymorphism in the interferon-λ3-interferon-λ4 (IFNL3-IFNL4) region has been found to be a major determinant of hepatic inflammatory and fibrotic progression in CHC patients of mainly Caucasian origin; however, it is not known if this association applies to other ethnicities, including Pakistani CHC patients. Here, we genotyped IFNL3-IFNL4 rs12979860 genetic variants in a sample set of 502 Pakistani patients with CHC and used logistic regression analysis to determine its association with the risk and progression of HCV-related fibrosis and cirrhosis. We demonstrate that the rs12979860 major (CC) genotype, despite not determining the risk of stage-specific hepatic fibrosis independently, is associated with a marginally significant risk of liver cirrhosis (OR: 1.64, p = 0.049) after an adjustment for age, gender, body mass index, HCV viral load, and liver enzymes. In a subgroup of CHC patients with sustained ALT levels of <60 IU/L, a more pronounced impact of the IFNL3-IFNL4 rs12979860 major (CC) genotype on advanced liver fibrosis (OR: 4.99, p = 0.017) and cirrhosis (OR: 3.34, p = 0.005) was seen. The present study suggests that IFNL3-IFNL4 rs12979860 polymorphism may also be a significant predictor of hepatic fibrosis and cirrhosis in Pakistani CHC patients, especially in those with normal or near-normal liver enzyme levels.

Hepatocellular carcinoma occurs frequently and early after treatment in HCV genotype 3 infected persons treated with DAA regimens.

BACKGROUND: There are conflicting data regarding the risk of hepatocellular carcinoma (HCC) after direct-acting antiviral agent (DAA) treatment. Risk of HCC in HCV genotype-3 infected persons after DAA therapy is not well known. METHODS: We prospectively studied HCV infected persons initiated on a DAA regimen between October 2014 and March 2017 at two centers in Pakistan. All persons were free of HCC at study initiation. HCC was confirmed based on characteristic CT scan findings. Patients were followed for 12 months after the completion of therapy. RESULTS: A total of 662 persons initiated treatment. Median age (IQR) was 50 (41, 57) years and 48.8% were male. At baseline, 49.4% were cirrhotic, 91% were genotype 3 and 91.9% attained SVR. Treatment regimens used were: Sofosbuvir (SOF)/ribavirin (RBV)/pegylated interferon (PEG-IFN), 25.2%; SOF/RBV, 62.4%; SOF/RBV/daclatasavir (DCV), 10.6%; SOF/DCV, 2.0%. Incident HCC was detected in 42 patients (12.8%) in the 12-month period after treatment completion and was exclusively observed in those with cirrhosis. In multivariable Cox regression analysis, SVR was associated with a reduction in HCC risk (HR, 95% CI: 0.35, 0.14,0.85). In Kaplan-Meier plots by treatment regimen, those treated with SOF/RBV, SOF/RBV/DCV, or SOF/DCV regimens had a shorter HCC-free survival compared with those treated with a SOF/RBV/PEG-IFN regimen. CONCLUSION: In a predominantly genotype 3 cohort, incident HCC occurred frequently and early after treatment completion, and exclusively in those with pre-treatment cirrhosis. SVR reduced the risk of HCC. Treating HCV infected persons before development of cirrhosis may reduce risk of HCC.

Post-transplantation lymphoproliferative disorder with gastrointestinal involvement.

Post-transplantation lymphoproliferative disorders (PTLDs) are lymphoid proliferations or lymphomas that are the second most common tumors in adult transplant recipients. Most cases of PTLD are attributed to Epstein-Barr virus, which induces B-cell proliferation and occurs in the setting of severe immunosuppression after solid organ or bone marrow transplantation. The disorder is seen in 1-3% of liver transplant recipients and has a variable presentation chronology. Herein, we chronicle a case of aggressive B-cell lymphoma (PTLD WHO class-3) presenting with isolated gastrointestinal involvement in an Epstein-Barr virus-negative patient with living-donor liver transplantation, 4 years after receiving the transplant. While typical symptoms may be elusive in the immunocompromised setting, clinicians should be vigilant for underlying PTLD with isolated gastrointestinal involvement. Prompt detection and characterization by endoscopic evaluation with biopsy should be particularly stressed in such patients.

Parallel expression profiling of hepatic and serum microRNA-122 associated with clinical features and treatment responses in chronic hepatitis C patients.

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate a variety of biological processes. Recently, human liver-specific miRNA miR-122 has been reported to facilitate hepatitis C virus (HCV) replication in liver cells. HCV is one of the leading causes of liver diseases worldwide. In Pakistan, the estimated prevalence is up to 10%. Here, we report hepatic and serum miR-122 expression profiling from paired liver and serum samples from treatment-naive chronic hepatitis C (CHC) patients and controls. We aimed to elucidate the biomarker potential of serum miR-122 for monitoring disease progression and predicting end treatment response (ETR). Hepatic miR-122 levels were significantly down-regulated in CHC patients. A significant inverse correlation was observed between hepatic and serum miR-122 levels, indicating that serum miR-122 levels reflect HCV-associated disease progression. Both hepatic and serum miR-122 were significantly correlated (P < 0.05) with several clinicopathological features of CHC. Receiver operator curve analysis showed that serum miR-122 had superior discriminatory ability even in patients with normal alanine transaminase levels. Multivariate logistic regression analysis highlighted pre-treatment serum miR-122 levels as independent predictors of ETR. In conclusion, serum miR-122 holds the potential to serve as a promising biomarker of disease progression and ETR in CHC patients.

Hypothyroidism In Hepatitis C Patients On Pegylated Interferon Therapy.

BACKGROUND: Chronic hepatitis has become a major health problem all over the world especially in the third world countries. The most common cause of chronic hepatitis in Pakistan is hepatitis C which can lead Toliver cirrhosis and hepatocellular carcinoma. In Pakistan Pegylated Interferon Alpha is still corner stone of therapy for chronic hepatitis C. One of the major side effects of this therapy is the development of thyroid dysfunction, i.e., hypothyroidism and hyperthyroidism. This study was done to assess the frequency of hypothyroidism in hepatitis C patients after three months of pegylated interferon therapy. METHODS: This study was conducted from 1st October 2013 to 31st march 2014 at outpatients department (OPD) of Gastroenterology and Hepatology, Lahore General Hospital Lahore. Descriptive case series study design was used. The sample of 200 patients was taken from the patients who visited OPD and fulfil the inclusion criteria of the study. Serum thyroid stimulating hormone level (TSH) was done before and after completion of three months therapy at centre for Nuclear Medicine (CENUM) laboratory, Mayo Hospital, Lahore by immune-radiometric assay (IRMA) and patients having TSH>4.0 mIU/L (normal range: 0.2-4.0 mIU/L) were considered hypothyroid. RESULTS: The mean age of the patients was 36.29±8.5 years. One hundred and twenty-three (61.5%) were male and 77 (38.5%) were female. After 3 months of interferon therapy, 163 (81.5%) patients were euthyroid and 37(18.5%) patients were having thyroid dysfunction. There were total 29 (14.5%) hypothyroid patients; 8 (27.6%) were male and 21 (72.4%) female. CONCLUSIONS: It is concluded from this study that frequency of hypothyroidism in patients with chronic hepatitis C was 14.5% after treatment with pegylated interferon therapy for 3 months. Female patients were more prone to develop hypothyroidism as compared to male patients.

Structured endoscopic ultrasonography (EUS) training program improved knowledge and skills of trainees: Results from the Asian EUS Group.

BACKGROUND AND AIM: A major reason impeding the growth of endoscopic ultrasound (EUS) in Asia is the lack of training availability. We aimed to prospectively evaluate the effectiveness of a short-term structured EUS training program in improving the knowledge and skill of EUS among trainees. METHODS: The study was conducted in six workshops in six countries including Sri Lanka, Pakistan, Thailand, Vietnam, Singapore and Philippines, within a year. Trainees were evaluated using written and skill tests before and after completion of the training. RESULTS: Pre- and post-workshop written tests from a total of 62 trainees were analyzed. Compared with pre-training, the trainees improved significantly in the overall mean (± SD) scores after the training (66.0 ± 0.3% to 77.5 ± 0.2%, P < 0.0001). Thirty-one trainees were randomly selected to undergo a skill test before and after the course. Compared with pre-training, the proportions of trainees who succeeded in locating each structure post-training were: celiac axis (36-80.5%), pancreatic body (51.5-80.5%), pancreatic body and tail (42-77.5%), splenic vein and artery (48.5-84%), left kidney (60-83%), and spleen (47-83%). Overall, there was a significant improvement in the proportion of trainees' successful localization of structures post-training compared to before training (P < 0.0001). CONCLUSION: Following a structured training program, trainees' knowledge and skills in EUS improved significantly. Structured training courses appear to be an effective way of imparting EUS knowledge and skills to aspiring endosonographers in the Asian region.

Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy.

BACKGROUND & AIMS: Thrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-alfa (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and ENABLE-2, investigated the ability of eltrombopag to increase the number of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV. METHODS: Patients with HCV infection and thrombocytopenia (platelet count <75,000/µL) who participated in ENABLE-1 (n = 715) or ENABLE-2 (n = 805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg/day) for 9 weeks or fewer. Patients whose platelet counts reached the predefined minimal threshold for the initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were assigned randomly (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary end point was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy. RESULTS: More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag, 23%; placebo, 14%; P = .0064; ENABLE-2: eltrombopag, 19%; placebo, 13%; P = .0202). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelet counts of 50,000/µL or higher throughout antiviral treatment (ENABLE-1, 69% vs 15%; ENABLE-2, 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2. CONCLUSIONS: Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV and advanced fibrosis and cirrhosis, allowing otherwise ineligible or marginal patients to begin and maintain antiviral therapy, leading to significantly increased rates of SVR. Clinical trial no: NCT00516321, NCT00529568.