Pik Eu Chang

Clinical applications, limitations and future role of transient elastography in the management of liver disease.

Transient elastography (TE) is a reliable tool for the non-invasive assessment of liver fibrosis in routine clinical practice. TE is currently approved for use in Europe, Asia and the United States. The widespread adoption of this technology is certain to increase the use of TE worldwide. Although TE has been well validated in chronic viral hepatitis, its clinical role in other liver diseases remains less clear. The advent of new treatment for chronic hepatitis C and emerging prevalence of non-alcoholic steatohepatitis raises new questions on the role of TE in current clinical practice. This review aims to examine the clinical applications, limitations and future role of TE in current clinical practice in light of the changing epidemiology of liver diseases and new clinical management paradigms. In current clinical practice, TE is the most accurate non-invasive method for diagnosis of liver cirrhosis. TE is useful to rule out fibrosis and cirrhosis but does not have sufficient accuracy to discern between various stages of fibrosis. The clinical role of TE has evolved from cross-sectional point-in-time assessment of fibrosis and cirrhosis to the more relevant role of prediction of vital clinical end-points. This provides clinicians with the ability to modify treatment strategies based on the information provided by TE. TE has evolved over the past decade to become an essential tool to assist the clinician in the management of chronic liver disease.

Epidemiology and Prognosis of Paraneoplastic Syndromes in Hepatocellular Carcinoma

Background. Paraneoplastic syndromes (PNS) such as hypercalcaemia, hypercholesterolaemia, and erythrocytosis have been described in hepatocellular carcinoma (HCC). Aims. (1) To examine the prevalence, clinical characteristics, and survival of PNS in HCC patients and (2) to evaluate the extent to which each individual PNS impacts on patient survival. Methods. We prospectively evaluated the prevalence, clinical characteristics, and survival of PNS among 457 consecutive HCC patients seen in our department over a 10-year period and compared them with HCC patients without PNS. Results. PNS were present in 127 patients (27.8%). The prevalence of paraneoplastic hypercholesterolemia, hypercalcemia, and erythrocytosis 24.5%, 5.3%, and 3.9%, respectively. Patients with PNS had significantly higher alpha-fetoprotein levels, more advanced TNM stage, and shorter survival. Among the individual PNS, hypercalcemia and hypercholesterolemia were associated with more advanced disease and reduced survival but not erythrocytosis. On multivariate analysis, the presence of PNS was not found to be an independent prognostic factor for reduced HCC survival. Conclusion. PNS are not uncommon in HCC and are associated with poor prognosis and reduced survival due to their association with increased tumor burden. However, they do not independently predict poor survival. Individual PNS impact differently on HCC outcome; paraneoplastic hypercalcemia in particular is associated with poor outcome.

Acute Abdomen Secondary to Incarcerated Umbilical Hernia after Treatment of Massive Cirrhotic Ascites

Umbilical herniation is common in patients with liver cirrhosis and ascites. Rarely, they suffer from incarceration and strangulation of the umbilical hernia after treatment of ascites. We report 3 cases of umbilical hernia incarceration following removal of massive ascites with different treatment modalities. Physicians managing this group of patients should be aware of this rare and potentially fatal complication.

Application of a standardised protocol for hepatic venous pressure gradient measurement improves quality of readings and facilitates reduction of variceal bleeding in cirrhotics.

INTRODUCTION Hepatic venous pressure gradient (HVPG) measurement is recommended for prognostic and therapeutic indications in centres with adequate resources and expertise. Our study aimed to evaluate the quality of HVPG measurements at our centre before and after introduction of a standardised protocol, and the clinical relevance of the HVPG to variceal bleeding in cirrhotics. METHODS HVPG measurements performed at Singapore General Hospital from 2005-2013 were retrospectively reviewed. Criteria for quality HVPG readings were triplicate readings, absence of negative pressure values and variability of ≤ 2 mmHg. The rate of variceal bleeding was compared in cirrhotics who achieved a HVPG response to pharmacotherapy (reduction of the HVPG to < 12 mmHg or by ≥ 20% of baseline) and those who did not. RESULTS 126 HVPG measurements were performed in 105 patients (mean age 54.7 ± 11.4 years; 55.2% men). 80% had liver cirrhosis and 20% had non-cirrhotic portal hypertension (NCPH). The mean overall HVPG was 13.5 ± 7.2 mmHg, with a significant difference between the cirrhosis and NCPH groups (p < 0.001). The proportion of quality readings significantly improved after the protocol was introduced. HVPG response was achieved in 28 (33.3%, n = 84) cirrhotics. Nine had variceal bleeding over a median follow-up of 29 months. The rate of variceal bleeding was significantly lower in HVPG responders compared to nonresponders (p = 0.025). CONCLUSION The quality of HVPG measurements in our centre improved after the introduction of a standardised protocol. A HVPG response can prognosticate the risk of variceal bleeding in cirrhotics.

Low serum albumin and advanced age predict early mortality in Asian patients with extreme elevations of serum aminotransferase.

Extreme elevations of serum aminotransferases (EESAT), defined as alanine transaminase (ALT) or aspartate transaminase (AST) level of above 3000 U/L, reflect severe liver injury and poor outcomes of the patients. This study aimed to evaluate the prevalence, etiology and clinical outcomes of EESAT in Asian patients and to identify the predictors of early mortality.

Translation and cultural adaption of the Chronic Liver Disease Questionnaire for the Mandarin-speaking Chinese population in Singapore through cognitive debriefing:

Background: Patients with chronic liver disease often suffer from poor quality of life. The Chronic Liver Disease Questionnaire (CLDQ) is a validated tool to assess health-related quality of life in these patients. It has been translated and validated for use in many countries and languages globally. Objectives: We aimed to translate Mainland Chinese Mandarin to Singapore Mandarin and perform cross-cultural adaption of CLDQ for the Mandarin-speaking population in Singapore (CLDQ-SG). Methods: This study was conducted based on the International Society for Pharmacoeconomics and Outcomes Research Principles of Good Practice. The study consisted of two parts: part one involved cognitive debriefing and cultural adaption of CLDQ, and part two was a pilot study on the first version of CLDQ-SG among adult patients with chronic liver disease in a tertiary hospital. Results: During the cognitive debriefing process of part one, questions beginning with “recent” (最近) two weeks in Mandarin were changed to “last” (在过去) two weeks. Eighteen patients were recruited for part two of the study (50% male, mean age 49±13 years). Time taken to complete CLDQ-SG was 15±8 minutes, and the mean score was 5.1±0.5. The reliability of measurements for all domains was good, with an intra-class correlation coefficient ≥0.8. Items one and four needed further restructuring. There were no discrepancies between CLDQ and CLDQ-SG. Conclusion: This study showed that CLDQ-SG was culturally acceptable by the Mandarin-speaking population in Singapore. There were only two items that needed revision in the finalized CLDQ-SG.

Second harmonic generation microscopy provides accurate automated staging of liver fibrosis in patients with non-alcoholic fatty liver disease

Background Assessment of severity of liver fibrosis is essential in the management of non-alcoholic fatty liver disease (NAFLD). Second Harmonic Generation (SHG) microscopy is a novel optical tissue imaging system that provides automated quantification of fibrosis based on unique architectural features of collagen. This study aims to develop and validate a SHG-based index for automated staging of liver fibrosis in patients with NAFLD. Methods SHG microscopy was performed on archived liver biopsy specimens from 83 patients with NAFLD. A unique algorithm was developed to identify specific SHG parameters that correlated with fibrosis stage. The accuracy of the algorithm was compared against clinical assessment by experienced liver histopathologists using the Brunt fibrosis staging and further validated using the leave-one-out cross-validation method. Results Mean age of the study cohort was 51.8 ± 11.7 years, with 41% males. A fibrosis index (SHG B-index) was developed comprising 14 unique SHG-based collagen parameters that correlated with severity of NAFLD fibrosis in a continuous fashion. The SHG B-index had excellent correlation with Brunt fibrosis stage (Spearman’s correlation 0.820, p<0.001). AUROCs for prediction of Brunt fibrosis stages 1, 2, 3 and 4 were 0.853, 0.967, 0.985 and 0.941 respectively. In the cross-validation analysis, the SHG B-index demonstrated high specificity for diagnosis of all grades of fibrosis. A SHG B-index score of >1.76 had an overall diagnostic accuracy of 98.5% for prediction of presence of bridging fibrosis (Brunt stage ≥3) with sensitivity of 87.5%, specificity 98.0%, positive predictive value 96.6% and negative predictive value 92.6%. Conclusion The SHG B-index is a unique SHG-based index that provides accurate automated assessment of fibrosis stage in NAFLD patients.

Ruxolitinib for the Treatment of Portal Hypertension in a Patient With Primary Myelofibrosis

Figure 1. Liver biopsy from the patient at (A) baseline and (B) month 42. Arrows indicate megakaryocytes and asterisks indicate sinusoidal dilatation. Hematoxylin-eosin 200 . 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 Dear Editors: Primary myelofibrosis is a form of myeloproliferative neoplasm characterized by stem-cell derived clonal proliferation, resulting in bone marrow fibrosis, splenomegaly and extramedullary haematopoiesis, with portal hypertension (PHT) occuring in 10%–20% of patients. Here, we report a patient with primary myelofibrosis whose PHT improved significantly following treatment with ruxolitinib, thereby allowing discontinuation of all drug therapy for PHT. A 54-year-old man was admitted to our hospital with progressive abdominal distension. He had large ascites, moderate hepatomegaly and massive splenomegaly (22cm below left costal margin). Initial laboratory investigations were as follows: hemoglobin 11.5g/dL, leukocyte count 25.5 x 10/L, platelet count 375 x 10/L, blast cell 1.0%, albumin 36 g/L, bilirubin 13mmol/L, alkaline phosphatase 153U/L, alanine aminotransferase 29U/L, aspartate aminotransferase 37U/L and prothrombin time 11.8 seconds. Bone marrow examination revealed a hypocellular marrow with diffuse stromal fibrosis, consistent with primary myelofibrosis. Janus kinase-2 V617F mutation analysis was negative. He was treated with hydroxyurea and spironolactone 50mg/d. One month later, he was readmitted with hematemesis and malena. Urgent esophagogastroduodenoscopy (EGD) was performed and four columns of moderate esophageal varices (EV) were ligated. Six weeks later, there were four residual columns of EV which were not amenable to further ligation. Hepatic venous pressure gradient (HVPG) and transjugular liver biopsy were performed to evaluate the etiology and nature of the PHT. Wedge hepatic venous pressure (WHVP) was 21mmHg and free hepatic venous pressure (FHVP) was 8mmHg, giving rise to HVPG of 13mmHg. Microscopic examination of the liver showed minimal peri-portal inflammation and no fibrosis. There was myeloid metaplasia (MM), with eight to nine megakaryocytes per high-power field (PHF) (200 ) and mild sinusoidal dilatation (Figure 1A). Ultrasound doppler showed a patent splanchnic circulation but blood flow in the main portal vein was increased (1719mL/min, normal 8001200mL/min) and splenic vein was dilated (2.3cm, normal 0.8–1.0cm). He was treated with propranolol 60mg/d, isosorbide mononitrate 60mg/d, spironolactone 150mg/d and furosemide 60mg/d. Six months after diagnosis, he was started on ruxolitinib, an oral inhibitor of Janus kinase-1 and -2. Ten weeks after initiation of ruxolitinib, his ascites