Lucy Lim

Hepatitis B virus splicing is enhanced prior to development of hepatocellular carcinoma

BACKGROUND & AIMS The hepatitis B virus (HBV) genome encodes specific sequence elements which promote splicing of viral DNA. It has been previously suggested that spliced HBV (spHBV) variants promote viral replication and protein production, leading to hepatocellular carcinoma (HCC). In this study, we have analysed changes in spHBV over time; providing the first longitudinal analysis of spHBV in relation to the development of HCC. METHODS Serial serum samples were collected from 165 patients with chronic HBV monoinfection, including 58 patients who later developed HCC. Real-time PCR was used to amplify and quantify wt and sp DNA loads. RESULTS spHBV was detected in over 80% of patients with chronic HBV infection. Median serum spHBV levels were significantly higher in HCC patients than HCC-free control patients (p<0.001). Univariate analysis revealed a strong correlation between time to HCC diagnosis and spHBV DNA levels (τ=0.203; p=0.016). Asian HBV genotype (p=0.025) and increased viral load (p<0.001) were also significantly associated with increased spHBV DNA levels. Multiple regression analysis revealed time to diagnosis of HCC, Asian HBV genotypes, and viral load to be associated with increased spHBV DNA (model p<0.001; R(2)=0.189). CONCLUSIONS HBV splicing is a common event during chronic infection and increases prior to diagnosis of HCC. Measurement of HBV splicing may prove a valuable adjunct to be used in the identification of chronically infected patients who are at increased risk of developing HCC.

Hepatic macrophage activation predicts clinical decompensation in chronic liver disease

Hepatic macrophages (Kupffer cells) play important roles in inflammation and portal hypertension in patients with chronic liver disease (CLD).1 We recently showed that plasma soluble CD163 (sCD163), a specific marker for macrophage activation, is produced within and released from the liver with a direct relationship to the portal venous pressure gradient.2 ,3 We hypothesised that: (1) sCD163 is elevated in patients with CLD with previous clinical decompensation; and (2) sCD163 is a marker for CLD progression and clinical deterioration. We measured sCD163 in 52 controls and 116 consecutive patients with CLD (89% cirrhosis) caused by chronic hepatitis C (36%), alcohol (30%), non-alcoholic fatty liver disease (11%), chronic hepatitis B (10%); other liver diseases (12%) accounted for the remainder of the cases. Cirrhosis was diagnosed by consistent examination and radiological findings, or by liver biopsy. All controls had no history or clinical examination signs of CLD, and normal liver function tests. They were followed for a median of …

Vitamin B12 and its binding proteins in hepatocellular carcinoma and chronic liver diseases

Abstract Background. The vitamin B12 (B12)-binding protein haptocorrin (HC) has proven to be a potentially useful biomarker in patients with fibrolamellar hepatocellular carcinoma (HCC). Little is known concerning the level of HC and other B12-related proteins in patients with HCC as compared to patients with other chronic liver diseases (CLDs) and healthy controls. We hypothesized that HC could be a biomarker of HCC. Aims. To investigate levels of HC and B12-related proteins in HCC compared to CLDs and healthy controls. Methods. We investigated two patient populations: A cross-sectional cohort of HCC patients (n = 130), CLD patients (n = 102) and healthy controls (n = 46) and a cohort of 38 HCC patients studied at baseline and 1, 4, and 12 weeks following ablative treatment. Patients were evaluated by standard biochemistry, Child–Pugh-score and Barcelona Clinic Liver Cancer (BCLC) classification. We analyzed total B12 by routine methods and HC, transcobalamin (TC), B12 saturated TC (holoTC), and the soluble cell surface receptor for holoTC (sCD320) by in-house enzyme-linked immunosorbent assay. Results. HC showed higher median (range) levels for both HCC (590 [290–5860]) and CLD patients (620 [310–4010]) compared to controls (460 [250–2020]) (p < 0.01). Total B12, TC, holoTC, and sCD320 showed elevated levels in both HCC and CLD compared to controls. Only holoTC changed following treatment, without a concurrent change in TC. Conclusion. B12 and B12-related proteins (total B12, HC, TC, holoTC, and sCD320) show elevations in both HCC and CLD patients compared to controls, suggesting a relation to CLD in general rather than to primary liver cancer. Thus, HC is not useful as a biomarker for HCC.

Peptic Ulcer Disease in Older People

Peptic ulcer disease is a common disorder that affects millions of people worldwide. Peptic ulcer disease has a major impact on quality of life and on the utilisation of the health system when complications occur. Understanding the causative roles of Helicobacter pylori and non‐steroidal anti‐inflammatory drugs has led to changes in management of the disease. Comorbidities in older people add further complexity to treatment. This article summarises the clinical aspects of peptic ulcer disease and outlines principles which enable effective treatment.

Macrophage activation marker soluble CD163 may predict disease progression in hepatocellular carcinoma.

Abstract Background: Tumor associated macrophages are present in hepatocellular carcinoma (HCC) and associated with a poor prognosis. The aim of the present study was to investigate the levels and dynamics of soluble (s)CD163, a specific macrophage activation marker, in patients with HCC. Methods: In a cohort from Australia, we studied 109 HCC patients, 116 patients with chronic liver disease (CLD), and 52 healthy controls. We examined associations between baseline sCD163 and parameters of HCC severity as well as overall and progression-free survival. In a cohort of 42 Danish HCC patients, we measured sCD163 at baseline and 1, 4 and 12 weeks after ablative treatment. Results: In the Australian cohort, median sCD163 was similarly increased in HCC (5.6[interquartile range 3.5–8.0] mg/L) and CLD (6.1[3.6–9.6] mg/L) patients as compared to controls (2.0[1.5–2.7] mg/L, p < 0.001). sCD163 correlated with Child-Pugh and MELD scores in both HCC and CLD patients. Patients with high sCD163 levels had shorter progression-free survival (p < 0.001), but not overall survival (p = 0.15). In the Danish cohort, patients with HCC progression at 12 weeks had an increase in sCD163. There was no association between sCD163 and HCC size, number, vascular invasion or metastasis in any of the cohorts. Conclusions: We confirmed increased sCD163 levels in CLD and HCC patients associated with Child-Pugh and MELD scores and portal hypertension, but not with HCC size and number, or metastasis. As a novel finding, baseline sCD163 appeared to predict a rapid HCC progression, as sCD163 increased during follow-up in HCC patients who showed progression.

Circulating CD147 predicts mortality in advanced hepatocellular carcinoma

The glycoprotein CD147 has a role in tumor progression, is readily detectable in the circulation, and is abundantly expressed in hepatocellular carcinoma (HCC). Advanced HCC patients are a heterogeneous group with some individuals having dismal survival. The aim of this study was to examine circulating soluble CD147 levels as a prognostic marker in HCC patients.

Five-year efficacy and safety of tenofovir-based salvage therapy for patients with chronic hepatitis B who previously failed LAM/ADV therapy

Multidrug‐resistant HBV continues to be an important clinical problem. The TDF‐109 study demonstrated that TDF±LAM is an effective salvage therapy through 96 weeks for LAM‐resistant patients who previously failed ADV add‐on or switch therapy. We evaluated the 5‐year efficacy and safety outcomes in patients receiving long‐term TDF±LAM in the TDF‐109 study.

To TOE or not to TOE? That is the question in patients with portal hypertension and varices

We read with interest your recently published review by Cardenas and Gines on patients with cirrhosis, awaiting liver transplantation,1 with an emphasis on the high morbidity and mortality with variceal bleeding. Such patients may require a transoesophageal echocardiogram (TOE) to assess cardiorespiratory abnormalities potentially precluding a transplant, as well as for intraoperative haemodynamic monitoring and for investigation for endocarditis. However, the safety of performing a TOE in such patients is debated by clinicians due to the perceived risk of postprocedural bleeding.2 Three small studies have analysed post-TOE bleeding complications in patients with varices, having reported no bleeding in 26, 14 and 23 patients.3–5 We hypothesised that direct external trauma by the echocardiographic probe is unlikely to cause significant bleeding, as variceal bleeding is primarily caused by wall tension, a function of increasing variceal diameter and internal pressure.6 We therefore audited post-TOE bleeding rates at an Australian liver transplant referral centre in patients who had both varices or portal hypertension and a TOE based on International Classification of Diseases 10 coding from 1995 …