Andri Sanityoso Sulaiman

Significant hepatic histopathology in chronic hepatitis B patients with serum ALT less than twice ULN and high HBV-DNA levels in Indonesia

OBJECTIVE:  To study the prevalence of significant hepatic histopathology in chronic hepatitis B (CHB) patients with alanine aminotransferase (ALT) ≤ twice upper limit of normal (ULN) and its association with age, HBeAg status, hepatitis B virus (HBV)‐DNA level and viral genotype.

Clinical significance of hepatitis B virion and SVP productivity: relationships between intrahepatic and serum markers in chronic hepatitis B patients

Background Clinical use of hepatitis B viral (HBV) quantitative seromarker\s remains questionable since it is not precisely known whether they represent intrahepatic viral replication. Covalently closed circular DNA (cccDNA), relaxed circular DNA (rcDNA), and pregenomic RNA (pgRNA) are more likely to represent active HBV replication and their measurement can be used to derive virion productivity (VP; rcDNA/cccDNA), subviral particle (SVP) productivity (quantitative HBsAg/cccDNA), and replicative activity (RA; pgRNA/cccDNA). These can be used to compare relative HBV replication between HBeAg-negative and -positive patients. Objective To study the clinical significance of intrahepatic HBV replication phenomenon between HBeAg-negative and -positive patients and its correlation with quantitative HBV seromarkers. Method This was a prospective study between January 2010 and December 2011. Study subjects were naive chronic hepatitis B patients from Cipto Mangunkusumo and Medistra Hospitals. All patient samples underwent liver biochemistry and HBV seromarkers testing (HBeAg, quantitative HBsAg and HBV DNA levels), and patients underwent liver biopsy. Stored liver specimens were analysed for intrahepatic rcDNA, cccDNA, and pgRNA with quantification performed by real-time PCR. Comparison of HBV markers between HBsAg-positive and -negative patients was carried out using the Mann–Whitney U-test. Pearson’s correlation test was performed among HBV intrahepatic and seromarkers using their log-transformed values. Results A total of 104 patients were enrolled in this study; 54 (51.9%) were male. Patients’ mean age was 41.9 ± 11.63 years (range 19–70 years). Sixty-one patients (58.7%) were HBeAg-negative. All HBV markers were significantly higher in HBeAg-positive than HBeAg-negative patients, except for SVP productivity and RA. Serum HBV DNA was strongly correlated with intrahepatic total HBV DNA (r = 0.771), cccDNA (r = 0.774), and rcDNA (r = 0.780) while serum quantitative HBsAg showed only moderate correlation with intrahepatic total DNA (r = 0.671), cccDNA (r = 0.632), rcDNA (r = 0.675), and SVP productivity (r = 0.557). Conclusions Serum HBV DNA concentration and quantitative HBsAg might not accurately predict intrahepatic viral activity. Virion and SVP production do not occur in parallel with replicative activity.

Inflammatory Process in Hepatic Encephalopathy: The Role of Interleukin-18

Hepatic encephalopathy (HE) is a spectrum of neuropsychiatric abnormalities associated in patients with liver dysfunction and/or portosystemic shunting. It is one of the most serious complication of cirrhosis. HE is associated with increase hospitalization, increase in health cost, and mortality of cirrhosis patients. Approximately 30-45% of cirrhosis patients will develop HE and it is the most common cause of hospitalization in decompensated cirrhosis patients. Cirrhosis patients who had HE had 1-year survival probability of 42% and 3-year probability of 23%.1 HE comprises a complex, multifactorial, mechanisms resulting in functional impairment of neuronal cell. For many years, ammonia was considered as the main role of the pathogenesis of HE. However, many studies showed that blood ammonia levels may not correlate with the degree of HE suggesting more compounds were involved. In recent years, many agents emerge as a part of HE pathogenesis such as deposition manganese in the basal ganglia, benzodiazepine-like compounds, microbiota, aromatic amino acids, and also inflammatory cytokines.1 Many evidences showed that inflammation plays important role in the development of HE. Astrocytes and microglia are capable to produce proinflammatory cytokines as a response to inflammatory state in cirrhosis patients.2 These cytokines will increase blood-brain barrier permeability for ammonia and its passage into astrocytes.3 It has been long documented that the levels of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukins (ILs) were increase in decompensated cirrhotic patients.4 In 1995, Izumi et al had shown that interleukin (IL)-6 was correlated with fulminant hepatic failure and chronic HE.5 Since then, multiple interleukins were identified to be associated with HE including IL-18.6 IL-18 is a proinflammatory cytokine, previously describe as interferon γ-inducing factor, involved in activation and differentiation of various T cell populations.7 IL-18 show proinflammatory properties such as increase in cell-adhesion molecules, nitric oxide synthesis, and chemokine production.8 Other than induce the inflammatory state, IL-18 may induce HE by disturbed intestinal permeability and mucus production by goblet cells resulted in dysbiosis and increase of plasma endotoxin.7,10 Recent study by Anton et al showed that mean serum of IL-18 levels were higher in the cirrhosis patients compared to healthy controls (688.5 ± 674.3 pg/mL vs. 163.9 ± 100 pg/mL; p = 0.01). In this study, IL-18 was significantly correlated with HE (r = 0.85; p < 0.05). More importantly, IL-18 levels were significantly different between the severity grade of HE.11 These evidences show possibilities to utilize IL-18 for diagnosis and management HE in the future.

Factors Associated with Surveillance for Early Detection of Hepatocellular Carcinoma in Liver Cirrhosis Patients

Background: The minimal number of hepatocellular carcinoma (HCC) patients diagnosed through surveillance is proposed as the cause of persistently low number of survival. It is important to identify the proportion of surveillance for early detection of HCC in patients with liver cirrhosis and related factors. This study aimed to determine the proportion of surveillance for early detection of HCC in patients with liver cirrhosis and related factors. Method: A cross-sectional study of patients with liver cirrhosis at RSCM from January to December 2013. The data was obtained from medical records and confirmed by telephone. Surveillance was required for abdominal ultrasound with or without AFP at least once a year within 3 years after that period. Factors studied were gender, ethnicity, education level, income level, availability of medical insurance, location of residence, surveillance education, cirrhosis aetiology, and severity of cirrhosis. Then, logistic regression test was used in the multivariate analysis. Results: From 200 patients, 50 patients (25,0%) underwent surveillance, 150 patients (75,0%) did not. Bivariate analysis revealed 4 variables with p < 0.25, gender (p = 0,056), ethnicity (p = 0, 231), surveillance education (p = 0,005), and severity of cirrhosis (p = 0, 005). Multivariate analysis showed that the risk factors for surveillance were surveillance education (OR = 2,598; CI 95% (1,325 - 5,094), p = 0,005) and severity of cirrhosis (OR = 1.815; CI 95% = 1,210-2,724; p = 0,004). Conclusion: Surveillance education and severity of cirrhosis were the factors associated with surveillance for early detection of HCC in liver cirrhosis patients.

Complete Remission after Sequential Therapy of Drug Eluting Beads Transarterial Chemoembolization and Liver Resection in Large Solitary Nodule Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the fifth most prevalent and the second highest cause of death among cancer. The treatment of large solitary nodule HCC is still challenging. Transarterial chemoembolization (TACE) and liver resection are two modalities of therapy in HCC management. However, recurrence rate from each therapy is relatively high. We report a case of 46-year-old man diagnosed with large solitary nodule HCC, who was treated with drug eluting bead TACE (DEB-TACE) prior to liver resection. Studies about this combination are still limited and showed various results.

Therapeutic Interventional Endoscopic Ultrasound Based on Rare Cases in Indonesia: A Single-Center Experience in Unselected Patients

Background: Endoscopic ultrasound (EUS) is still not widely available and has a barrier in most Southeast Asian countries due to lack of training program, high cost, and hospital investment. In this study, we would like to show the impact of therapeutic interventional EUS procedures in gastroenterology practice in Indonesia, which represents the biggest Southeast Asian country. Methods: Patients who underwent interventional EUS procedure in Medistra Hospital were prospectively recruited within 1 year. Results: Of 147 patients who underwent EUS procedures, 39 patients underwent fine needle aspiration. Most of the cases suffered from pancreatic cancer (47.5%) followed by ampullary cancer (20%), gastric subepithelial mass (10%), and other conditions. There were 4 rare cases that underwent therapeutic interventional EUS procedures. Patients with large mesenteric cyst attached to the gastric wall and large left liver lobe cyst with gastric compression who were previously suspected with gastrointestinal stromal tumor were successfully managed by cyst aspiration. One patient with a large pseudocyst due to chronic pancreatitis was successfully managed by plastic stent placement. Another patient with duodenal duplication cyst causing duodenal obstruction was managed by inserting a plastic stent through the cyst. No complications were observed during and after the therapeutic EUS procedures. Conclusions: Innovation in interventional EUS has a high impact in gastroenterology practice as well as in a developing country like Indonesia, which represents the biggest Southeast Asian country. Further developments are needed regarding the cost, investment, and especially the necessary training curriculum to make this technology available in tertiary referral centers.

The Association Among Serum Quantitative Hepatitis B Surface Antigen (Qhbsag), Intrahepatic HBV Markers and Liver Fibrosis in Chronic Hepatitis B (Chb) Patients

Background: Recently, quantitative HBsAg has been used as a predictor for successful antiviral therapy in chronic hepatitis B (CHB) patients. Intrahepatic HBV-DNA levels have also been tested to know their relevance with clinical manifestation. However, their associations with liver fibrosis are still debatable. Objective: This study was aimed to evaluate the association between serum qHBsAg, serum HBV-DNA, intrahepatic HBV markers and hepatic fibrosis in CHB patients. Method: A cross-sectional study was done on naive CHB patients from September 2009 to June 2011. Quantitative serum HBsAg measurement was performed using the automated chemiluminescent microparticle immunoassay (Architect HBsAg QT assay, Abbott Laboratories, IL, USA). Serum qHBsAg was measured using the automated chemiluminescent microparticle immunoassay (Architect HBsAg QT assay, Abbott Laboratories, IL, USA). Intrahepatic cccDNA was measured quantitatively from biopsy specimen (QiAmp DNA Mini Kit, Qiagen, Germany). Values were log-transformed before being analyzed. Biopsy specimens should include at least 5 portal systems and 1.5 cm length to be eligible for evaluation using the METAVIR score. Results: 103 patients enrolled; 53 (51.9%) of them were men. Mean age was 42+11.6 (range 19-70) years old. There were 60 (58.3%) patients with HbeAg negative. Mean of log serum quantitative HBsAg was 2.54 for F0-F1 patients vs. 3.48 for F2-F4 patients (p < 0.001, student t test). The mean log serum HBV-DNA was 4.65 for F0-F1 vs. 6.69 for F2-F4 patients (p < 0.001; student t test). Intrahepatic rcDNA levels was higher in F2-F4 (median 14.37; range 0-3258.4 copies/GEq) than F0-F1 patients (median 0.50; range 0-514.4 copies/GEq); p < 0.001 (Mann-Whitney U test). In contrast, virion productivity was not differed statistically between the two groups (p 0.096). Conclusion: Quantitative serum HbsAg, HBV-DNA serum, and intrahepatic cccDNA are associated with fibrosis stage in chronic hepatitis B patients. HBV seromarkers might be used to predict disease severity.

Role of Lamivudine as Preemptive Therapy in Cancer Patients with Hepatitis B undergoing Chemotherapy

Patients diagnosed with hematology malignancy and solid tumor who underwent chemotherapy, frequently encountered hepatitis B reactivation. Patients with blood cancer, including lymphoma, had higher risk of reactivation compared to those with solid tumor. Steroid and immunosuppressant drugs contained in chemotherapy regimens were responsible for those events. Hepatitis B reactivation during chemotherapy treatment could contribute to acute liver failure and increase mortality. Administration of analog nucleoside therapy in this group of patient prior to the initiation of chemotherapy could prevent reactivation of hepatitis B. A 43 year-old male patient were diagnosed with diffuse large B cell non-Hodgkin lymphoma stadium II BE (oropharynx) under chemotherapy and had hepatitis B. In this evidence based case report, we reported a critical appraisal of the role of lamivudine as preemptive therapy in blood cancer and solid tumor. Keywords : chemotherapy, hepatitis B reactivation, malignancy

Selecting Treatment Modality for Small Hepatocellular Carcinoma: Radiofrequency Ablation, Percutaneous Alcohol and Acetic Acid Injection

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy worldwide and is the leading cause of death in patients with cirrhosis. In early-stage tumors, potential curative therapies have been used including ablative therapies using percutaneous ethanol injection (PEI), percutaneous acetic acid injection (PAI) or radiofrequency ablation (RFA); surgical resection and liver transplantation. RFA is more effective and safer than other local ablative therapy modalities. RFA should be considered as the first-line treatment for patients with small HCC, i.e. sized less than 5 cm; preferably less than or equal to 3 cm since they are not suitable for liver resection or liver transplantation. RFA should also be compared with transarterial embolization, which currently has been considered as the standard HCC therapy in some countries. It has been reported that the combination of RFA and embolization treatment may reduce the early and late recurrence rate. Keywords: hepatocellular carcinoma, percutaneous ethanol injection, acetic acid injection, radiofrequency ablation

Cardiac Tamponade Due to Liver Amebiasis Rupture

Amebiasis is common cases in Asia, Africa, and South Africa. Liver amebiasis has become a serious problem worldwide especially in health and social aspect. The protozoa named Entamoeba histolytica was easily found in area with poor sanitation, low socioeconomic status, and poor nutrition status. The incidence of amebiasis in several hospitals in Indonesia is 5-15% per year. Epidemiological observation showed the comparison of incidence among male and female population and it was approximately 3 : 1 until 22 : 1 with male predominance. The potential age suffered from amebiasis is around 20 - 50 years old. The route of infection spread to oral-fecal and oral-anal-fecal. The most common complication is abscess rupture (5-15.6%). Rupture may be located in pleural cavity, pericardial cavity, lung, bowel, intraperitoneal, and skin. Rupture of liver amebias spread to pleural and pericardial cavity is a rare case and frequently under reported. This case report illustrates a 40-year-old male with cardiac tamponade due to rupture of liver amebiasis. Patient’s was admitted with chief complaint of shortness of breath, positive Beck’s triad, hepatomegaly, pleural effusion, liver abscess on sonography and swinging of heart on echocardiography. This patient was treated with metronidazole as a drug of choice, and pericardiocentesis for the cardiac tamponade. Keywords: cardiac tamponade, Entamoeba histolytica, oral-anal-fecal, metronidazole, pericardiocentesis