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 cholangiopancreato-graphy.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.

Is there a need for universal double reflex testing of HBsAg-positive individuals for hepatitis D infection?

Hepatitis D virus(HDV)can infect HBsAg-positive individuals,causing rapid fibrosis progression,early decompensation,increased hepatocellular carcinoma risk,and higher mortality than hepatitis B virus(HBV)mono-infection.Most countries lack high-quality HDV prevalence data,and the collection techniques employed often bias published data.In recent meta-analyses,HDV prevalence in HBsAg-positive patients reaches 5%-15%and is even significantly higher in endemic areas.Since HBV vaccination programs were implemented,HDV prevalence has decreased among younger populations.However,owing to immigrant influx,it has increased in some Western countries.The current practice of HDV screening in HBsAg-positive individuals is stepwise,based on physician’s discretion,and limited to at-risk populations and may require numerous visits.Double reflex testing,which includes anti-HDV testing in all HBsAg-positive individuals and then HDV RNA testing for anti-HDV-positive ones,is uncommon.Reflex testing can identify more HDV infection cases and link identified patients to further care and follow-up.Moreover,laboratory-based double reflex screening is less biased than physician-led testing.Therefore,health-care providers should learn about reflex testing,and federal and provincial hepatitis control programs should implement laboratory-based double reflex testing to obtain reliable HDV prevalence estimates.The test’s cost-effectiveness depends on the number of HBV-positive patients screened to identify one HDV-positive patient.Such testing may be viable in areas with low HBsAg but high HDV prevalence.However,its economic impact on areas with low HDV prevalence needs further study.

Des-gamma-carboxy prothrombin and alpha-fetoprotein levels as biomarkers for hepatocellular carcinoma and their correlation with radiological characteristics

BACKGROUND Alpha-fetoprotein(AFP),a commonly used biomarker for hepatocellular carcinoma(HCC),is normal in up to one-third of patients.AIM To evaluate the diagnostic performance of des-gamma-carboxy-prothrombin(DCP)alone and in combination with AFP.METHODS In this study,202 patients with radiologically proven HCC were enrolled,and their DCP and AFP levels were evaluated for their diagnostic performance.RESULTS The mean age of the enrolled patients was 58.5 years;72.0%were male.DCP was elevated in 86.6%(n=175)of all patients,100.0%(n=74)of patients with portal vein thrombus,and 87.4%(n=111)of patients with multicentric HCC.AFP was elevated in 64.3%(n=130)of all the patients,74%(n=55)of the patients with portal vein thrombus,and 71.6%(n=91)of the patients with multicentric HCC(P=0.030,0.001,and 0.015,respectively).In tumors less than 2 cm in size(n=46),DCP was increased in 32(69.5%)patients,and AFP was increased in 25(54.3%)patients(P=0.801).There was good pairing between DCP and AFP for HCCs of 2 cm size or larger(P<0.001);however,the pairing among tumors<2 cm size was not significant(P=0.210).In 69 of the patients(34.1%),only one of the tumor markers was positive;DCP was elevated alone in 57/202(28.2%)of all patients,and AFP alone was elevated in 12/202(5.9%)of the patients.The areas under receiver operating characteristic curves(AUROC)for tumors>2 cm was 0.74 for DCP and 0.59 for AFP;combining both markers resulted in an AUROC of 0.73.For tumors<2 cm,the AUROC was 0.25 for DCP and 0.40 for AFP.CONCLUSION DCP,as an individual marker,had a better diagnostic performance in many cases of HCC.Hence,DCP may replace AFP as the primary HCC biomarker.

Co-treatment with pegylated interferon alfa-2a and entecavir for hepatitis D: a randomized trial

AIM: To investigate the efficacy of pegylated interferon alfa(PEG-IFNα) therapy with and without entecavir in patients with chronic hepatitis D. METHODS: Forty hepatitis D virus(HDV) RNA positive patients were randomized to receive either PEG-IFNα-2a 180 μg weekly in combination with entecavir 0.5 mg daily(n = 21) or PEG-IFNα alone(n =19). Patients who failed to show 2 log reduction in HDV RNA level at 24 wk of treatment, or had detectable HDV RNA at 48 wk of therapy were considered as treatment failure. Treatment was continued for 72 wk in the rest of the patients. All the patients were followed for 24 wk post treatment. Intention to treat analysis was performed.RESULTS: The mean age of the patients was 26.7 ± 6.8 years, 31 were male. Two log reduction in HDV RNA levels at 24 wk of therapy was achieved in 9(43%) patients receiving combination therapy and 12(63%) patients receiving PEG-IFNα alone(P = 0.199). Decline in hepatitis B surface antigen(HBs Ag) levels was insignificant. At the end of treatment, HDV RNA was negative in 8 patients(38%) receiving combination therapy and 10 patients(53%) receiving PEG-IFNα-2a alone. Virological response persisted in 7(33%) and 8(42%) patients, respectively at the end of the 24 wk follow-up period. One responder patient in the combination arm lost HBs Ag and became hepatitis B surface antibody positive. Six out of 14 baseline hepatitis B e antigen reactive patients seroconverted and four of these seroconverted patients had persistent HDV RNA clearance.CONCLUSION: Administration of PEG-IFNα-2a with or without entecavir, resulted in persistent HDV RNA clearance in 37% of patients. The addition of entecavir did not improve the overall response.

Comparison of Shisha Smoking Behavior among Medical and Pharmacy Students

Background: Health care workers are respected in every society and have a strong influence on the behaviour of the community. In order to reduce the shisha dependence in the Pakistani population, it is necessary to evaluate the perspective of future doctors and pharmacists regarding this addiction as they become role models for the future generations. Objective: The aim is to compare the knowledge, attitudes, and practices of shisha use among medical students and pharmacy students in order to assess their support in the anti-shisha campaigns of Pakistan. Methodology: Cross sectional study was performed in four major medical universities of Karachi, Pakistan through a modification of the WHO global health survey questionnaire. Result: 398 medical students and 470 pharmacy students were included in the study which showed that currently 9.6% pharmacy students and 4.8% medical students used shisha daily (p = 0.000). Pharmacy students started shisha use in less than 15 years of age while this number was 29.5% among medical students (P = 0.000). Moreover, 44.6% pharmacy students and 50% medical students were not planning to quit this addiction within the next six months. 14% of pharmacy students and 20.4% in medical students (P = 0.002) were unaware that passive smoking caused lung cancer, while 23.4% pharmacy students and 33.5% medical students rejected it as cause of heart diseases (p = 0.006). Conclusion: A significant number of medical and pharmacy students were unaware about some of the serious consequences of shisha smoking. Therefore, both groups of students need to be educated about the health hazards of shisha use, in order to control this growing menace.

<i>In-Vitro</i>Comparison of Antifungal Activity of Herbs (Darehald and Pomegranate) with Azoles

Aim: Candida, an opportunistic organism is one of the commonest causes of hospital acquired infections among fungi. Currently available antifungal drugs have numerous adverse effects and drug-drug interactions (DDIs) along with increase in resistance over the time. Therefore, it is highly emergent to consider alternative treatments for candidal infections, having fewer adverse effects and is cost-effective. The current in-vitro study is undertaken to assess and compare the antifungal effects of the herbs, Berberis aristata (B. aristata, Darehald/Darhald) and Punica granatum (P. granatum, Pomegranate) with fluconazole and voriconazole, based on culture and sensitivity of candidal isolates. Materials and Methods: Ethanolic extracts of herbs (Berberis aristata and Punica granatum) and concentrations were formulated as per standard procedure. 130 samples were obtained for the study from in and out patients reported in clinical subsets of Ziauddin Hospital, Karachi from March to May, 2018. Samples were collected and grown according to the standard procedures like, wet mount test and gram’s staining. Species were identified by CHROM agar candida and API 20 C AUX methods. Sensitivity tests were performed by Kirby Bauer’s disc diffusion method according to CLSI guide lines M-44 A2, 2009. Data analysis was done by one-way ANOVA to compare the antifungal activities of drugs and herbs. Results: Mean inhibitory zones of herbs, B. aristata and P. granatum were highly significant against clinical candidal isolates with respective p-values of 0.00 and 0.02. Both of the herbs, B. aristata and P. granatum were found to be more sensitive, 98.5% and 97.7% respectively in comparison to fluconazole showing 42.3% and voriconazole showing 29.2% sensitivity against candidal isolates. The most resistant candidal specie was C. tropicalis that showed resistance against both fluconazole and voriconazole, contrary to that, this specie was highly sensitive to both of the herbs, showing sensitivity of 100% respective for Darehald and Pomegranate. Conclusion: In comparison to azoles: Culture sensitivity of both herbs (B. aristata and P. granatum) displayed more sensitivity against candidal isolates of patients having non-invasive and invasive candidiasis. These herbs can be considered as substitute or alternative antifungal agents to the conventional antifungal therapy, particularly in cases of treating candidemia patients, which is a life threating condition.

Prevalence and Sensitivity Patterns of Candidal Infections in Various Tertiary Care Health Subunits of Karachi

Mostly candida resides as an opportunistic organism on epithelial surfaces of human being. However, under auspicious conditions can cause infections including serious life threatening invasive candidiasis with subsequent mortality particularly in immune deficit and hospitalized patients having co-morbids. Limited data are published on the prevalence of candidiasis, based on the researches conducted at few tertiary care settings which are not representing the overall disease burden in our country, Pakistan. Therefore, this study was conducted to evaluate the frequency and sensitivity patterns of candidiasis in our community. Methods: Out of total 1020 specimens, 130 clinical samples were identified as candidal positive, obtained from March to May 2018. These samples were isolated from vagina, oropharynx, urine, tracheal aspirates, pus, blood, tips of the intubations, wounds and fluids of the body cavities. Identification of candida, its species and antifungal sensitivity screening was done by Kirby Bauer’s disk diffusion method according to CLSI guide lines’ (M - 44 A2 series, 2009). Results: A significant majority, 80 (61.5%) of candidal strains were isolated from females with female to male ratio 8:5 and most of these isolates were obtained from high vaginal swabs (43.75%). Four candidal species (Candida albicans 80%, Candida tropicalis 10%, Candida glabrata 9.2% and Candida ciferrii 0.8%) were isolated from all positive specimens. Maximum number of the positive samples 52 (40%) were obtained from ICU patients. Sensitivity test of candidal positive samples revealed that commonly used azole antifungal drugs, fluconazole and voriconazole were highly resistant, with respective 57.7% and 70.8% resistance. Conclusion: Candidiasis is highly prevalent in our clinical set up and more frequently infecting females in comparison to males as most of the positive isolates were retrieved from HVS (high vaginal swabs). Still, C. albicans was found to be the most prevalent specie isolated among all candida samples. Our study also demonstrated that the resistance of most commonly prescribed antifungals, azoles have shown a rapid rise. Therefore, it is recommended that before prescription of antifungal drugs the clinicians should routinely recommend culture and sensitivity testing of samples taken from candida infected individuals.

Penicillium marneffei infection involving liver

Penicillium marneffei(P.marneffei)is a pathogenic fungus that can cause fatal infections in humans,particularly immunocompromised hosts.It is prevalent only in the Southeast Asian region.A 5-year-old boy was presented with diagnosed Acute Lymphoblastic Leukemia undergoing chemotherapy and suffering from high-grade fever for 15 days positively responded to antibiotics on the initial day,but later he became unresponsive.He was found negative for blood cultures of bacterial growth.Ultrasound of the abdomen showed a borderline enlarged liver with multiple small hypoechoic areas of variable sizes seen scattered in both lobes of the liver.Morphological and microscopic analyses of liver tissues showed multiple septate hyphae of P.marneffei.Amphotericin B was found to be effective in treating the child.Appropriate identification is essential to treat the pathogen-causing disease,especially in immuno-compromised conditions like a leukemic patient,and determine underlying mechanisms behind the pathogenesis.

Factors predicting hepatocellular carcinoma in hepatitis C infection

Hepatitis C virus (HCV) has emerged as a leading cause of hepatocellular carcinoma (HCC). In most cases, the virus causes HCC in the presence of chronic hepatic inflammation, advanced fibrosis, and cirrhosis. A combination of viral, environmental, and genetic factors are likely to determine the host immune response to the infection as well as the progression to HCC. Clinical and epidemiologic studies have identified many of the risk factors associated with HCC development in patients with chronic hepatitis C. Male sex and older age are considered as independent risk factors for HCC, while alcohol consumption accelerates fibrosis, increasing the risk for progression to HCC. Obesity, diabetes mellitus, nonalcoholic fatty liver disease, aflatoxin exposure and occult hepatitis B infection, all contribute to a higher HCC risk. HCV patients infected with HCV genotype 3 are also more likely to develop HCC and genetic variations such as single nucleotide polymorphisms, which may also alter the risk. Sustained virological response to the antiviral therapy results in significantly more favorable long-term outcomes. The incidence of HCC after HCV eradication is similar between patients treated with peginterferon plus ribavirin and direct-acting antiviral therapy.