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Background: Portal hypertension is a major complication of cirrhosis that is associated with significant morbidity and mortality. The present gold-standard method to risk stratify and observe cirrhosis patients with portal hypertension is hepatic venous pressure gradient measurement or esophagogastroduodenoscopy. However, these methods are invasive, carry a risk of complications and are associated with significant patient discomfort. Therefore, non-invasive splenic parameters are of clinical interest as potential useful markers in determining the presence of portal hypertension. However, diagnostic accuracy and reproducibility remains unvalidated., Aim: To assess the diagnostic accuracy of spleen stiffness, area and diameter in predicting the presence of portal hypertension., Methods: Of 50 patients with varying liver disease pathologies were prospectively recruited from the St. Mary's Hospital Liver Unit in London; 25 with evidence of portal hypertension and 25 with no evidence of portal hypertension. Liver stiffness, spleen stiffness, spleen diameter and spleen area were measured using the Philips Affiniti 70 elastography point quantification point shear wave elastography system. The aspartate aminotransferase-to-platelet-ratio-index (APRI) score was also calculated. Performance measures, univariate and multivariate logistic regression were used to evaluate demographic, clinical and elastography variables. Interclass correlation coefficient was used to determine the reproducibility of splenic area and diameter., Results: On univariate and individual performance, platelet count [area under the receiver operating characteristic (AUROC) 0.846, P value < 0.001], spleen area (AUROC 0.828, P value = 0.002) and APRI score (AUROC 0.827, P value < 0.001) were the most accurate variables in identifying the presence of portal hypertension. On multivariate logistic regression models constructed, the combination of spleen area greater than 57.90 cm 2 and platelet count less than 126 × 10 9 had 63.2% sensitivity and 100% specificity, 100% positive predictive value and 100% negative predictive value. An alternative combination of spleen stiffness greater than 29.99 kPa and platelet count less than 126 × 10 9 had 88% sensitivity, 75% specificity, 78.6% positive predictive value and 85.7% negative predictive value. An interclass correlation coefficient value of 0.98 (95%CI: 0.94-0.99, P value < 0.001) and 0.96 (95%CI: 0.91-0.99, P value < 0.001) were determined for inter-operator variability for spleen area and diameter respectively., Conclusion: Spleen area, spleen stiffness and platelet count may be useful markers to assess the presence of portal hypertension in patients of various etiologies., Competing Interests: Conflict-of-interest statement: This work was supported by Philips Medical Systems (Seattle, Washington, United States); United Kingdom National Institute for Health Research Biomedical Facility at Imperial College London, London, United Kingdom., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Chronic liver disease is a major cause of morbidity and mortality worldwide and usually develops over many years, as a result of chronic inflammation and scarring, resulting in end-stage liver disease and its complications. The progression of disease is characterised by ongoing inflammation and consequent fibrosis, although hepatic steatosis is increasingly being recognised as an important pathological feature of disease, rather than being simply an innocent bystander. However, the current gold standard method of quantifying and staging liver disease, histological analysis by liver biopsy, has several limitations and can have associated morbidity and even mortality. Therefore, there is a clear need for safe and non-invasive assessment modalities to determine hepatic steatosis, inflammation and fibrosis. This review covers key mechanisms and the importance of fibrosis and steatosis in the progression of liver disease. We address non-invasive imaging and blood biomarker assessments that can be used as an alternative to information gained on liver biopsy., Competing Interests: Conflict-of-interest statement: The authors declare no relevant or potential conflicts of interest.

Aim: To establish if a distinct urinary metabolic profile could be identified in Bangladeshi hepatitis-B hepatocellular carcinoma (HCC) patients compared to cirrhosis patients and controls., Methods: Urine samples from 42 Bangladeshi patients with HCC (39 patients with hepatitis-B HCC), 47 with cirrhosis on a background of hepatitis B, 46 with chronic hepatitis B, and seven ethnically-matched healthy controls were analyzed using nuclear magnetic resonance (NMR) spectroscopy. A full dietary and medication history was recorded for each subject. The urinary NMR data were analyzed using principal component analysis (PCA) and orthogonal partial least squared discriminant analysis (OPLS-DA) techniques. Differences in relative signal levels of the most discriminatory metabolites identified by PCA and OPLS-DA were compared between subject groups using an independent samples Kruskal-Wallis one-way analysis of variance (ANOVA) test with all pairwise multiple comparisons. Within the patient subgroups, the Mann-Whitney U test was used to compare metabolite levels depending on hepatitis B e-antigen (HBeAg) status and treatment with anti-viral therapy. A Benjamini-Hochberg adjustment was applied to acquire the level of significance for multiple testing, with a declared level of statistical significance of P < 0.05., Results: There were significant differences in age (P < 0.001), weight (P < 0.001), and body mass index (P < 0.001) across the four clinical subgroups. Serum alanine aminotransferase (ALT) was significantly higher in the HCC group compared to controls (P < 0.001); serum α-fetoprotein was generally markedly elevated in HCC compared to controls; and serum creatinine levels were significantly reduced in the HCC group compared to the cirrhosis group (P = 0.004). A three-factor PCA scores plot showed clustering of the urinary NMR spectra from the four subgroups. Metabolites that contributed to the discrimination between the subgroups included acetate, creatine, creatinine, dimethyamine (DMA), formate, glycine, hippurate, and trimethylamine-N-oxide (TMAO). A comparison of relative metabolite levels confirmed that carnitine was significantly increased in HCC; and creatinine, hippurate, and TMAO were significantly reduced in HCC compared to the other subgroups. HBeAg negative patients showed a significant increase in creatinine (P = 0.001) compared to HBeAg positive patients in the chronic hepatitis B subgroup, whilst HBeAg negative patients showed a significant decrease in DMA (P = 0.004) in the cirrhosis subgroup compared to HBeAg positive patients. There were no differences in metabolite levels in HCC patients who did or did not receive antiviral treatment., Conclusion: Urinary NMR changes in Bangladeshi HCC were identified, corroborating previous findings from Egypt and West Africa. These findings could form the basis for the development of a cost-effective HCC dipstick screening test.

Hepatocellular carcinoma (HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the option for curative treatments is limited to early stage cancers, diagnosis in non-symptomatic individuals is crucial. International guidelines advise regular surveillance of high-risk populations but the current tools lack sufficient sensitivity for early stage tumors on the background of a cirrhotic nodular liver. A number of novel biomarkers have now been suggested in the literature, which may reinforce the current surveillance methods. In addition, recent metabonomic and proteomic discoveries have established specific metabolite expressions in HCC, according to Warburg's phenomenon of altered energy metabolism. With clinical validation, a simple and non-invasive test from the serum or urine may be performed to diagnose HCC, particularly benefiting low resource regions where the burden of HCC is highest.

Chronic liver disease has become a global health problem as a result of the increasing incidence of viral hepatitis, obesity and alcohol misuse. Over the past three decades, in the United Kingdom alone, deaths from chronic liver disease have increased both in men and in women. Currently, 2.5% of deaths worldwide are attributed to liver disease and projected figures suggest a doubling in hospitalisation and associated mortality by 2020. Chronic liver diseases vary for clinical manifestations and natural history, with some individuals having relatively indolent disease and others with a rapidly progressive course. About 30% of patients affected by hepatitis C has a progressive disease and develop cirrhosis over a 20 years period from the infection, usually 5-10 years after initial medical presentation. The aim of the current therapeutic strategies is preventing the progression from hepatitis to fibrosis and subsequently, cirrhosis. Hepatic steatosis is a risk factor for chronic liver disease and is affecting about the half of patients who abuse alcohol. Moreover non-alcoholic fatty liver disease is part of the metabolic syndrome, associated with obesity, hypertension, type II diabetes mellitus and dyslipidaemia, and a subgroup of patients develops non-alcoholic steatohepatitis and fibrosis with subsequent cirrhosis. The strengths and pitfalls of liver biopsy are discussed and a variety of new techniques to assess liver damage from transient elastography to experimental techniques, such as in vitro urinary nuclear magnetic resonance spectroscopy. Some of the techniques and tests described are already suitable for more widespread clinical application, as is the case with ultrasound-based liver diagnostics, but others, such as urinary metabonomics, requires a period of critical evaluation or development to take them from the research arena to clinical practice.

The incidence of hepatocellular carcinoma (HCC) is known to be high in West Africa with an approximate yearly mortality rate of 200000. Several factors are responsible for this. Early acquisition of risk factors; with vertical or horizontal transmission of hepatitis B (HBV), environmental food contaminants (aflatoxins), poor management of predisposing risk factors and poorly-managed strategies for health delivery. There has been a low uptake of childhood immunisation for hepatitis B in many West African countries. Owing to late presentations, most sufferers of HCC die within weeks of their diagnosis. Highlighted reasons for the specific disease pattern of HCC in West Africa include: (1) high rate of risk factors; (2) failure to identify at risk populations; (3) lack of effective treatment; and (4) scarce resources for timely diagnosis. This is contrasted to the developed world, which generally has sufficient resources to detect cases early for curative treatment. Provision of palliative care for HCC patients is limited by availability and affordability of potent analgesics. Regional efforts, as well as collaborative networking activities hold promise that could change the epidemiology of HCC in West Africa.

Aim: To explore recent trends, modes of diagnosis, ethnic distribution and the mortality to incidence ratio of primary liver cancer by subtypes in England and Wales., Methods: We obtained incidence (1979-2008) and mortality (1968-2008) data for primary liver cancer for England and Wales and calculated age-standardised incidence and mortality rates. Trends in age-standardised mortality (ASMR) and incidence (ASIR) rates and basis of diagnosis of primary liver cancer and subcategories: hepatocellular carcinoma, intrahepatic bile duct and unspecified liver tumours, were analysed over the study period. Changes in guidelines for the diagnosis of primary liver cancer (PLC) may impact changing trends in the rates that may be obtained. We thus explored changes in the mode of diagnosis as reported to cancer registries. Furthermore, we examined the distribution of these tumours by ethnicity. Most of the statistical manipulations of these data was carried out in Microsoft excel® (Seattle, Washington, United Sttaes). Additional epidemiological statistics were done in Epi Info software (Atlanta, GA, United Sttaes). To define patterns of change over time, we evaluated trends in ASMR and ASIR of PLC and intrahepatic bile duct carcinoma (IHBD) using a least squares regression line fitted to the natural logarithm of the mortality and incidence rates. We estimated the patterns of survival over subsequent 5 and 10 years using complement of mortality to incidence ratio (1-MIR)., Results: Age-standardised mortality rate of primary liver cancer increased in both sexes: from 2.56 and 1.29/100000 in 1968 to 5.10 and 2.63/100000 in 2008 for men and women respectively. The use of histology for diagnostic confirmation of primary liver cancer increased from 35.7% of registered cases in 1993 to plateau at about 50% during 2005 to 2008. Reliance on cytology as a basis of diagnosis has maintained a downward trend throughout the study period. Although approximately 30% of the PLC registrations had information on ethnicity, there was a relatively higher registration of the major tumour subtypes in patients whose ethnic backgrounds were from high incident regions of the world. Survival from PLC is estimated to get poorer in 10 years (2018) relative to 2008, particularly as a result of IHBD., Conclusion: Incidence and mortality of PLC, and particularly IHBD, have continued to rise in England and Wales. Changes in the modes of diagnosis may be contributing.

Aim: To determine the rates and impact of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections on response to long-term highly active antiretroviral therapy (HAART) in a large human immunodeficiency virus (HIV) population in Nigeria., Methods: HBV and HCV as well as HIV infections are endemic in sub Saharan Africa. This was a retrospective cohort study of 19,408 adults who were recruited between June 2004 and December 2010 in the AIDS Prevention Initiative in Nigeria in Nigeria programme at Jos University Teaching Hospital. Serological assays, including HBV surface antigen (HBsAg) and hepatitis C antibody were used to categorise hepatitis status of the patients. HBsAg was determined using enzyme immunoassay (EIA) (Monolisa HBsAg Ultra3; Bio-Rad). HCV antibody was tested using third generation EIA (DIA.PRO Diagnostic, Bioprobes srl, Milan, Italy). HIV RNA levels were measured using Roche COBAS Amplicor HIV-1 monitor test version 1.5 (Roche Diagnostics, GmbH, Mannheim, Germany) with a detection limit of 400 copies/mL. Flow cytometry was used to determine CD4+ cell count (Partec, GmbH Munster, Germany). Comparison of categorical and continuous variables were achieved using Pearson's χ(2) and Kruskal Wallis tests respectively, on MedCalc for Windows, version 9.5.0.0 (MedCalc Software, Mariakerke, Belgium)., Results: With an overall hepatitis screening rate of over 90% for each virus; HBV, HCV and HBV/HCV were detected in 3162 (17.8%), 1983 (11.3%) and 453 (2.5%) HIV infected adults respectively. The rate of liver disease was low, but highest among HIV mono-infected patients (29, 0.11%), followed by HBV co-infected patients (15, 0.08%). Patients with HBV co-infection and triple infection had higher log10 HIV RNA loads (HBV: 4.6 copies/mL vs HIV only: 4.5 copies/mL, P < 0.0001) and more severe immune suppression (HBV: 645, 55.4%; HBV/HCV: 97, 56.7%) prior to initiation of HAART compared to HIV mono-infected patients (1852, 48.6%) (P < 0.0001). Of 3025 patients who were 4.4 years on HAART and whose CD4 cell counts results at baseline and end of follow up were available for analyses, CD4 increase was significantly lower in those with HBV co-infection (HBV: 144 cells/mm(3); HBV/HCV: 105 cells/mm(3)) than in those with HCV co-infection (165 cells/mm(3)) and HIV mono-infection (150 cells/mm(3)) (P = 0.0008)., Conclusion: High rates of HBV and HCV infections were found in this HIV cohort. CD4 recovery was significantly diminished in patients with HBV co-infection.

Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, particularly in parts of the developing world, and is increasing in incidence. This article reviews the current modalities employed for the diagnosis of HCC, including serum markers, radiological techniques and histological evaluation, and summarises international guidelines for the diagnostic approach to HCC.

Improvements in imaging technology allow exploitation of the dual blood supply of the liver to aid in the identification and characterisation of both malignant and benign liver lesions. Imaging techniques available include contrast enhanced ultrasound, computed tomography and magnetic resonance imaging. This review discusses the application of several imaging techniques in the diagnosis and staging of both hepatocellular carcinoma and cholangiocarcinoma and outlines certain characteristics of benign liver lesions. The advantages of each imaging technique are highlighted, while underscoring the potential pitfalls and limitations of each imaging modality.

Hepatocellular carcinoma (HCC) is the commonest primary malignant cancer of the liver in the world. Given that the burden of chronic liver disease is expected to rise owing to increasing rates of alcoholism, hepatitis B and C prevalence and obesity-related fatty liver disease, it is expected that the incidence of HCC will also increase in the foreseeable future. This article summarizes the international epidemiology, the risk factors and the pathogenesis of HCC, including the roles of viral hepatitis, toxins, such as alcohol and aflatoxin, and insulin resistance.

Hepatic steatosis affects 20% to 30% of the general adult population in the western world. Currently, the technique of choice for determining hepatic fat deposition and the stage of fibrosis is liver biopsy. However, it is an invasive procedure and its use is limited, particularly in children. It may also be subject to sampling error. Non-invasive techniques such as ultrasound, computerised tomography (CT), magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ((1)H MRS) can detect hepatic steatosis, but currently cannot distinguish between simple steatosis and steatohepatitis, or stage the degree of fibrosis accurately. Ultrasound is widely used to detect hepatic steatosis, but its sensitivity is reduced in the morbidly obese and also in those with small amounts of fatty infiltration. It has been used to grade hepatic fat content, but this is subjective. CT can detect hepatic steatosis, but exposes subjects to ionising radiation, thus limiting its use in longitudinal studies and in children. Recently, magnetic resonance (MR) techniques using chemical shift imaging have provided a quantitative assessment of the degree of hepatic fatty infiltration, which correlates well with liver biopsy results in the same patients. Similarly, in vivo (1)H MRS is a fast, safe, non-invasive method for the quantification of intrahepatocellular lipid (IHCL) levels. Both techniques will be useful tools in future longitudinal clinical studies, either in examining the natural history of conditions causing hepatic steatosis (e.g. non-alcoholic fatty liver disease), or in testing new treatments for these conditions.

Aim: To assess the effectiveness of the current UK clinical practice in reducing hepatic fat (IHCL)., Methods: Whole body MRI and (1)H MRS were obtained, before and after 6 mo nutritional counselling, from liver, soleus and tibialis muscles in 10 subjects with non-alcoholic fatty liver disease (NAFLD)., Results: A 500 Kcal-restricted diet resulted in an average weight loss of 4% (-3.4 kg,) accompanied by significant reductions in most adipose tissue (AT) depots, including subcutaneous (-9.9%), abdominal subcutaneous (-10.2%) and intra-abdominal-AT (-11.4%). Intramyocellular lipids (IMCL) were significantly reduced in the tibialis muscle (-28.2%). Decreases in both IHCL (-39.9%) and soleus IMCL (-12.2%) content were also observed, although these were not significant. Several individuals showed dramatic decreases in IHCL, while others paradoxically showed increases in IHCL content. Changes in body composition were accompanied by improvements in certain liver function tests: serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Significant correlations were found between decreases in IHCL and reductions in both intra-abdominal and abdominal subcutaneous AT. Improvements in liver function tests were associated with reductions in intra-abdominal AT, but not with changes in IHCL., Conclusion: This study shows that even a very modest reduction in body weight achieved through lifestyle modification can result in changes in body fat depots and improvements in LFTs.

Nuclear magnetic resonance spectroscopy allows the study of cellular biochemistry and metabolism, both in the whole body in vivo and at higher magnetic field strengths in vitro. Since the technique is non-invasive and non-selective, magnetic resonance spectroscopy methodologies have been widely applied in biochemistry and medicine. In vitro magnetic resonance spectroscopy studies of cells, body fluids and tissues have been used in medical biochemistry to investigate pathophysiological processes and more recently, the technique has been used by physicians to determine disease abnormalities in vivo. This highlighted topic illustrates the potential of in vitro magnetic resonance spectroscopy in studying the hepatobiliary system. The role of in vitro proton and phosphorus magnetic resonance spectroscopy in the study of malignant and non-malignant liver disease and bile composition studies are discussed, particularly with reference to correlative in vivo whole-body magnetic resonance spectroscopy applications. In summary, magnetic resonance spectroscopy techniques can provide non-invasive biochemical information on disease severity and pointers to underlying pathophysiological processes. Magnetic resonance spectroscopy holds potential promise as a screening tool for disease biomarkers, as well as assessing therapeutic response.

Hepatic encephalopathy (HE) is a common neuro-psychiatric abnormality, which complicates the course of patients with liver disease and results from hepatocellular failure and/or portosystemic shunting. The manifestations of HE are widely variable and involve a spectrum from mild subclinical disturbance to deep coma. Research interest has focused on the role of circulating gut-derived toxins, particularly ammonia, the development of brain swelling and changes in cerebral neurotransmitter systems that lead to global CNS depression and disordered function. Until recently the direct investigation of cerebral function has been difficult in man. However, new magnetic resonance imaging (MRI) techniques provide a non-invasive means of assessment of changes in brain volume (coregistered MRI) and impaired brain function (fMRI), while proton magnetic resonance spectroscopy (1H MRS) detects changes in brain biochemistry, including direct measurement of cerebral osmolytes, such as myoinositol, glutamate and glutamine which govern processes intrinsic to cellular homeostasis, including the accumulation of intracellular water. The concentrations of these intracellular osmolytes alter with hyperammonaemia. MRS-detected metabolite abnormalities correlate with the severity of neuropsychiatric impairment and since MR spectra return towards normal after treatment, the technique may be of use in objective patient monitoring and in assessing the effectiveness of various treatment regimens.