Impact of beta-blockers on cardiopulmonary exercise testing in patients with advanced liver disease.

BACKGROUND: Patients with advanced liver disease may develop portal hypertension that can result in variceal haemorrhage. Beta-blockers reduce portal pressure and minimise haemorrhage risk. These medications may attenuate measures of cardiopulmonary performance, such as the ventilatory threshold and peak oxygen uptake measured via cardiopulmonary exercise testing. AIM: To determine the effect of beta-blockers on cardiopulmonary exercise testing variables in patients with advanced liver disease. METHODS: This was a cross-sectional analysis of 72 participants who completed a cardiopulmonary exercise test before liver transplantation. All participants remained on their usual beta-blocker dose and timing prior to the test. Variables measured during cardiopulmonary exercise testing included the ventilatory threshold, peak oxygen uptake, heart rate, oxygen pulse, the oxygen uptake efficiency slope and the ventilatory equivalents for carbon dioxide slope. RESULTS: Participants taking beta-blockers (n = 28) had a lower ventilatory threshold (P <.01) and peak oxygen uptake (P = .02), compared to participants not taking beta-blockers. After adjusting for age, the model of end-stage liver-disease score, liver-disease aetiology, presence of refractory ascites and ventilatory threshold remained significantly lower in the beta-blocker group (P = .04). The oxygen uptake efficiency slope was not impacted by beta-blocker use. CONCLUSIONS: Ventilatory threshold is reduced in patients with advanced liver disease taking beta-blockers compared to those not taking the medication. This may incorrectly risk stratify patients on beta-blockers and has implications for patient management before and after liver transplantation. The oxygen uptake efficiency slope was not influenced by beta-blockers and may therefore be a better measure of cardiopulmonary performance in this patient population.

Liver-related mortality in countries of the developed world: an ecological study approach to explain the variability.

BACKGROUND: Liver-related mortality varies across developed nations. AIM: To assess the relative role of various risk factors in relation to liver-related mortality in an ecological study approach. METHODS: Data for liver-related mortality, prevalence data for hepatitis B and C, human immunodeficiency virus (HIV), alcohol consumption per capita, Type 2 Diabetes mellitus (T2DM), overweight and obesity were extracted from peer-reviewed publications or WHO databases for different developed countries. As potential other risk-modifying factors, purchase power parity (PPP)-adjusted gross domestic product (GDP) per capita and health expenditure per capita were assessed. As an environmental 'hygiene factor', we also assessed the effect of the prevalence of Helicobacter pylori. Only countries with a PPP-adjusted GDP greater than $20 000 and valid information for at least 8 risk modifiers were included. Univariate and multivariate analyses were utilised to quantify the contribution to the variability in liver-related mortality. RESULTS: The proportion of chronic liver diseases (CLD)-related mortality ranged from 0.73-2.40% [mean 1.56%, 95% CI (1.43-1.69)] of all deaths. Univariately, CLD-related mortality was significantly associated with Hepatitis B prevalence, alcohol consumption, PPP-adjusted GDP (all P < 0.05) and potentially H. pylori prevalence (P = 0.055). Other investigated factors, including hepatitis C, did not yield significance. Backward elimination suggested hepatitis B, alcohol consumption and PPP-adjusted GDP as risk factors (explaining 66.3% of the variability). CONCLUSION: Hepatitis B infection, alcohol consumption and GDP, but not hepatitis C or other factors, explain most of the variance of liver-related mortality.

Leptin and the risk of Barrett's oesophagus.

BACKGROUND: Obesity is associated with increased risks of Barrett's oesophagus and oesophageal adenocarcinoma. Alterations in serum leptin and adiponectin, obesity-related cytokines, have been linked with several cancers and have been postulated as potential mediators of obesity-related carcinogenesis; however, the relationship with Barrett's oesophagus remains unexplored. METHODS: Serum leptin and adiponectin concentrations were measured on two subsets of participants within a case-control study conducted in Brisbane, Australia. Cases were people aged 18-79 years with histologically confirmed Barrett's oesophagus newly diagnosed between 2003 and 2006. Population controls, frequency matched by age and sex to cases, were randomly selected from the electoral roll. Phenotype and medical history data were collected through structured, self-completed questionnaires. Odds ratios (OR) and 95% CI were calculated using multivariable logistic regression analysis. RESULTS: In the pilot analysis (51 cases, 67 controls) risks of Barrett's oesophagus were highest among those in the highest quartile of serum leptin (OR 4.6, 95% CI 0.6 to 33.4). No association was seen with adiponectin. In the leptin validation study (306 cases, 309 controls), there was a significant threefold increased risk of Barrett's oesophagus among men in the highest quartile of serum leptin (OR 3.3, 95% CI 1.7 to 6.6) and this persisted after further adjustment for symptoms of gastro-oesophageal reflux (OR 2.4, 95% CI 1.1 to 5.2). In contrast, the risk of Barrett's oesophagus among women decreased with increasing serum leptin concentrations. CONCLUSIONS: High serum leptin is associated with an increased risk of Barrett's oesophagus among men but not women. This association is not explained simply by higher body mass or gastro-oesophageal reflux among cases. The mechanism remains to be determined.

Living with chronic hepatitis C means 'you just haven't got a normal life any more'.

OBJECTIVE: To explore psychosocial factors that impact on quality of life for people living with self-reported chronic hepatitis C. METHODS: A purposeful sample of 70 people who were self-identified as being hepatitis C virus (HCV)-positive was recruited through a variety of institutions and community agencies. Semi-structured interviews were held with 12 groups and 21 individuals. A qualitative grounded-theory methodology was used for data collection and analysis. Experiences of physical and psychological symptoms, stigma and discrimination, and living with an infectious disease, were explored using matrices. RESULTS: Phenomena emerging from the data included previously undocumented illness 'attacks' that were associated with depressive symptoms and a perception of hepatitis C as fatal. Uncertainty related to disease progression and transmission of the virus were common experiences among participants. A universal experience was fear and anxiety about stigma and discrimination. DISCUSSION: The findings of this study indicate that chronic hepatitis C has a pervasive impact on quality of life with a complexity that has not been explored with quantitative research approaches. Primary healthcare professionals need to be alert to the psychological and social impacts of chronic hepatitis C and to avoid behaviours that lead to perceptions of stigma and discrimination. The research indicates a need for further investigation into the relationship between psychosocial factors, disease management and disease progression.

Adiponectin--a key adipokine in the metabolic syndrome.

Adiponectin is a recently described adipokine that has been recognized as a key regulator of insulin sensitivity and tissue inflammation. It is produced by adipose tissue (white and brown) and circulates in the blood at very high concentrations. It has direct actions in liver, skeletal muscle and the vasculature, with prominent roles to improve hepatic insulin sensitivity, increase fuel oxidation [via up-regulation of adenosine monophosphate-activated protein kinase (AMPK) activity] and decrease vascular inflammation. Adiponectin exists in the circulation as varying molecular weight forms, produced by multimerization. Recent data indicate that the high-molecular weight (HMW) complexes have the predominant action in the liver. In contrast to other adipokines, adiponectin secretion and circulating levels are inversely proportional to body fat content. Levels are further reduced in subjects with diabetes and coronary artery disease. Adiponectin antagonizes many effects of tumour necrosis factor-alpha(TNF-alpha) and this, in turn, suppresses adiponectin production. Furthermore, adiponectin secretion from adipocytes is enhanced by thiazolidinediones (which also act to antagonize TNF-alpha effects). Thus, adiponectin may be the common mechanism by which TNF-alpha promotes, and the thiazolidinediones suppress, insulin resistance and inflammation. Two adiponectin receptors, termed AdipoR1 and AdipoR2, have been identified and these are ubiquitously expressed. AdipoR1 is most highly expressed in skeletal muscle and has a prominent action to activate AMPK, and hence promote lipid oxidation. AdipoR2 is most highly expressed in liver, where it enhances insulin sensitivity and reduces steatosis via activation of AMPK and increased peroxisome-proliferator-activated receptor alpha ligand activity. T-cadherin, which is expressed in endothelium and smooth muscle, has been identified as an adiponectin-binding protein with preference for HMW adiponectin multimers. Given the low levels of adiponectin in subjects with the metabolic syndrome, and the beneficial effect of the adipokine in animal studies, there is exciting potential for adiponectin replacement therapy in insulin resistance and related disorders.

Low level microsatellite instability may be associated with reduced cancer specific survival in sporadic stage C colorectal carcinoma.

BACKGROUND: Colorectal cancers (CRCs) may be categorised according to the degree of microsatellite instability (MSI) exhibited, as MSI-high (MSI-H), MSI-low (MSI-L), or microsatellite stable (MSS). MSI-H status confers a survival advantage to patients with sporadic CRC. AIMS: To determine if low levels of MSI are related to the clinicopathological features and prognosis of sporadic stage C CRC. PATIENTS: A total of 255 patients who underwent resection for sporadic stage C CRC were studied. No patient received chemotherapy. Minimum follow up was five years. METHODS: DNA extracted from archival malignant and non-malignant tissue was amplified by polymerase chain reaction using a panel of 11 microsatellites. MSI-H was defined as instability at > or =40% of markers, MSS as no instability, and MSI-L as instability at >0% but <40% of markers. Patients with MSI-H CRC were excluded from analysis as they have previously been shown to have better survival. RESULTS: Thirty three MSI-L and 176 MSS CRCs were identified. There was no difference in biological characteristics or overall survival of MSI-L compared with MSS CRC but MSI-L was associated with poorer cancer specific survival (hazard ratio 2.0 (95% confidence interval 1.1-3.6)). CONCLUSIONS: Sporadic MSI-L and MSS CRCs have comparable clinicopathological features. Further studies are required to assess the impact of MSI-L on prognosis.

Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C.

BACKGROUND: Steatosis occurs in more than 50% of patients with chronic hepatitis C and is associated with increased hepatic fibrosis. In many of these patients the pathogenesis of steatosis appears to be the same as for patients with non-alcoholic fatty liver disease-that is, related to visceral adiposity and obesity. METHODS: The effect of a three month weight reduction programme on liver biochemistry and metabolic parameters was examined in 19 subjects with steatosis and chronic hepatitis C. Paired liver biopsies were performed in 10 subjects, prior to and 3-6 months following the intervention, to determine the effect of weight loss on liver histology. RESULTS: There was a mean weight loss of 5.9 (3.2) kg and a mean reduction in waist circumference of 9.0 (5.0) cm. In 16 of the 19 patients, serum alanine aminotransferase levels fell progressively with weight loss. Mean fasting insulin fell from 16 (7) to 11 (4) mmol/l (p<0.002). Nine of 10 patients with paired liver biopsies had a reduction in steatosis irrespective of viral genotype. In these subjects the median modified Knodell fibrosis score decreased from 3 to 1 (p=0.04) and activated stellate cells significantly decreased (p<0.004). CONCLUSIONS: Weight loss in patients with chronic hepatitis C may be associated with a reduction in steatosis and abnormal liver enzymes and an improvement in fibrosis, despite the persistence of the virus. Weight reduction may provide an important adjunct treatment strategy for patients with chronic hepatitis C.

Cooked sausage batter cohesiveness as affected by sarcoplasmic proteins.

In the first trial, m. semitendinosus and m. biceps femoris were held at 0, 10 and 35 °C until they entered rigor, and in the second trial, minced m. semitendinosus was washed in water for 15, 30, 45 or 60 min. The samples from both the trials were then used to make a finely comminuted sausage batter. Soluble sarcoplasmic protein (SSP) levels decreased with increasing rigor temperature (P < 0.05) or washing (P < 0.01). Cooked batter shear stress was not affected by SSP level, but batter shear strain decreased with the decreasing SSP level associated with an increasing rigor temperature (P < 0.05) or washing (P < 0.01). Reducing the SSP content lowered the cook yield (P < 0.05) and emulsion stability (P < 0.01) of the batter from the washed samples compared to that of controls. The results suggest that sarcoplasmic proteins are important in determining the strain values (cohesiveness) of cooked sausage batter.

Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3.

BACKGROUND AND AIMS: Hepatic steatosis has been shown to be associated with lipid peroxidation and hepatic fibrosis in a variety of liver diseases including non-alcoholic fatty liver disease. However, the lobular distribution of lipid peroxidation associated with hepatic steatosis, and the influence of hepatic iron stores on this are unknown. The aim of this study was to assess the distribution of lipid peroxidation in association with these factors, and the relationship of this to the fibrogenic cascade. METHODS: Liver biopsies from 39 patients with varying degrees of hepatic steatosis were assessed for evidence of lipid peroxidation (malondialdehyde adducts), hepatic iron, inflammation, fibrosis, hepatic stellate cell activation (alpha-smooth muscle actin and TGF-beta expression) and collagen type I synthesis (procollagen alpha1 (I) mRNA). RESULTS: Lipid peroxidation occurred in and adjacent to fat-laden hepatocytes and was maximal in acinar zone 3. Fibrosis was associated with steatosis (P < 0.04), lipid peroxidation (P < 0.05) and hepatic iron stores (P < 0.02). Multivariate logistic regression analysis confirmed the association between steatosis and lipid peroxidation within zone 3 hepatocytes (P < 0.05), while for hepatic iron, lipid peroxidation was seen within sinusoidal cells (P < 0.05), particularly in zone 1 (P < 0.02). Steatosis was also associated with acinar inflammation (P < 0.005). alpha-Smooth muscle actin expression was present in association with both lipid peroxidation and fibrosis. Although the effects of steatosis and iron on lipid peroxidation and fibrosis were additive, there was no evidence of a specific synergistic interaction between them. CONCLUSIONS: These observations support a model where steatosis exerts an effect on fibrosis through lipid peroxidation, particularly in zone 3 hepatocytes.

Steatosis and chronic hepatitis C: analysis of fibrosis and stellate cell activation.

BACKGROUND/AIMS: Steatosis is a frequent histological finding in chronic hepatitis C and is associated with increased hepatic fibrosis. METHODS: We studied 80 patients with untreated chronic hepatitis C to determine whether steatosis contributes to fibrosis through a steatohepatitis-like pathway. RESULTS: Fine sinusoidal and/or central vein fibrosis was present in 52 patients (65%). This was typically located in acinar zone 3 and had a chicken-wire appearance similar to that seen in steatohepatitis. A statistically significant relationship was found between subsinusoidal fibrosis and age (r(s) = 0.33, P = 0.003) and grade of steatosis (r(s) = 0.35, P = 0.001). Mean body mass index was higher in patients with focal (28.4 +/- 4.7 kg/m2) or extensive (29.6 +/- 5.9 kg/m2) subsinusoidal fibrosis than in those patients with no subsinusoidal fibrosis (25.5 +/- 3.7 kg/m2). The extent of alpha-smooth muscle actin staining (as a marker of stellate cell activation) correlated with the degree of portal inflammation and the stage of portal fibrosis, but not with the grade of hepatic steatosis. CONCLUSIONS: These findings suggest that in hepatitis C infection, host factors, particularly adiposity, contribute to both steatosis and acinar fibrosis. The implication of these observations is that weight reduction may provide an important therapeutic strategy for patients with chronic hepatitis C.

Pathogenesis of hepatocellular carcinoma.

The pathogenesis of HCC is poorly understood at present. There is insufficient understanding to propose a robust general model of hepatic carcinogenesis, partly because pathogenic host and environmental factors show significant regional variation, making such generalization difficult. Figure 4 is a model based on data presented in this article. Multiple risk factors for HCC have been identified, including cirrhosis, male gender, increasing patient age, toxins, chronic viral hepatitis, and other specific liver diseases. The understanding of how the individual risk factors result in genetic changes is rudimentary, and there is even less understanding about interactions between risk factors. Future studies should acknowledge the geographic origin of the HCCs studied and consider the effects of cirrhosis, gender, and age. A more rigorous approach to these factors may help explicate the interaction with specific liver diseases so that a comprehensive model of hepatic carcinogenesis can be developed.

Detection of male DNA in the liver of female patients with primary biliary cirrhosis.

BACKGROUND/AIMS: Primary biliary cirrhosis is a chronic cholestatic liver disease characterized by progressive inflammatory destruction of bile ducts, with eventual hepatic fibrosis and cirrhosis. Since primary biliary cirrhosis affects predominantly middle-aged women and has pathological similarities to hepatic graft-versus-host-disease, we investigated whether fetal cell microchimerism might be involved in the development of this disease. METHODS: The presence of Y-chromosome-specific sequences was analyzed by polymerase chain reaction using peripheral blood mononuclear cells from women with primary biliary cirrhosis (n=18) and healthy (control) women (n=18), and by in situ hybridization of liver biopsy sections from women with primary biliary cirrhosis (n=19) and women with chronic hepatitis C or alcoholic liver disease (n=20). RESULTS: Male cells were detected in liver biopsy specimens of 8 of 19 patients (42%) with primary biliary cirrhosis. Y-chromosome-containing cells were not seen in any of the liver biopsy specimens from women with chronic hepatitis C or alcoholic liver disease. Male cells were detected in peripheral blood mononuclear cells from one healthy control at a level of 1 male cell per 10(6) female cells, but were not detected in peripheral blood mononuclear cells of women with primary biliary cirrhosis. CONCLUSIONS: The presence of male cells in the liver of women with primary biliary cirrhosis raises the possibility that fetal cell microchimerism may be involved in the pathogenesis of this chronic liver disease.

Magnetic resonance imaging (MRI) and diseases of the liver and biliary tract. Part 1. Basic principles, MRI in the assessment of diffuse and focal hepatic disease.

Magnetic resonance imaging (MRI) relies on the physical properties of unpaired protons in tissues to generate images. Unpaired protons behave like tiny bar magnets and will align themselves in a magnetic field. Radiofrequency pulses will excite these aligned protons to higher energy states. As they return to their original state, they will release this energy as radio waves. The frequency of the radio waves depends on the local magnetic field and by varying this over a subject, it is possible to build the images we are familiar with. In general, MRI has not been sufficiently sensitive or specific in the assessment of diffuse liver disease for clinical use. However, because of the specific characteristics of fat and iron, it may be useful in the assessment of hepatic steatosis and iron overload. Magnetic resonance imaging is useful in the assessment of focal liver disease, particularly in conjunction with contrast agents. Haemangiomas have a characteristic bright appearance on T2 weighted images because of the slow flowing blood in dilated sinusoids. Focal nodular hyperplasia (FNH) has a homogenous appearance, and enhances early in the arterial phase after gadolinium injection, while the central scar typically enhances late. Hepatic adenomas have a more heterogenous appearance and also enhance in the arterial phase, but less briskly than FNH. Hepatocellular carcinoma is similar to an adenoma, but typically occurs in a cirrhotic liver and has earlier washout of contrast. The appearance of metastases depends on the underlying primary malignancy. Overall, MRI appears more sensitive and specific than computed tomography with contrast for the detection and evaluation of malignant lesions.

Magnetic resonance imaging and diseases of the liver and biliary tract. Part 2. Magnetic resonance cholangiography and angiography and conclusions.

Magnetic resonance cholangiography (MRC) relies on the strong T2 signal from stationary liquids, in this case bile, to generate images. No contrast agents are required, and the failure rate and risk of serious complications is lower than with endoscopic retrograde cholangiopancreatography (ERCP). Data from MRC can be summated to produce an image much like the cholangiogram obtained by using ERCP. In addition, MRC and conventional MRI can provide information about the biliary and other anatomy above and below a biliary obstruction. This provides information for therapeutic intervention that is probably most useful for hilar and intrahepatic biliary obstruction. Magnetic resonance cholangiography appears to be similar to ERCP with respect to sensitivity and specificity in detecting lesions causing biliary obstruction, and in the diagnosis of choledocholithiasis. It is also suited to the assessment of biliary anatomy (including the assessment of surgical bile-duct injuries) and intrahepatic biliary pathology. However, ERCP can be therapeutic as well as diagnostic, and MRC should be limited to situations where intervention is unlikely, where intrahepatic or hilar pathology is suspected, to delineate the biliary anatomy prior to other interventions, or after failed or inadequate ERCP. Magnetic resonance angiography (MRA) relies on the properties of flowing liquids to generate images. It is particularly suited to assessment of the hepatic vasculature and appears as good as conventional angiography. It has been shown to be useful in delineating vascular anatomy prior to liver transplantation or insertion of a transjugular intrahepatic portasystemic shunt. Magnetic resonance angiography may also be useful in predicting subsequent variceal haemorrhage in patients with oesophageal varices.

Sertraline treatment of interferon-alfa-induced depressive disorder.

Interferon alfa therapy for chronic hepatitis C infection is commonly associated with neuropsychiatric symptoms, including depression. These side effects may necessitate reduction or even cessation of interferon alfa, but there is little information regarding the management of this important problem. We report 10 cases of interferon-alfa-induced depressive disorder treated with the selective serotonin reuptake inhibitor sertraline. All patients obtained rapid symptom relief without the need for reduction or cessation of interferon alfa.

Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer.

BACKGROUND: Colorectal cancers exhibiting microsatellite instability (MSI) appear to have unique biological behaviour. This study analyses the association between extensive MSI (MSI-H), clinicopathological features and survival in an unselected group of patients with sporadic Australian Clinico-Pathological Stage (ACPS) C (tumour node metastasis stage III) colorectal cancer. METHODS: Some 255 patients who underwent resection for sporadic ACPS C colorectal cancer between 1986 and 1992 were studied. No patient had received chemotherapy. Minimum follow-up for all patients was 5 years. Archival normal and tumour DNA was extracted and amplified by polymerase chain reaction using a radioactive labelling technique. MSI-H was defined as instability in 40 per cent or more of seven markers. RESULTS: Twenty-one patients showed MSI-H. No association was found between MSI and age or sex. Tumours exhibiting MSI-H were more commonly right sided (P<0.00001), larger (P = 0.002) and more likely to be high grade (P = 0.049). After adjustment for age, sex and other pathological variables, patients whose cancers exhibited MSI-H had improved survival (P = 0.015). CONCLUSION: Recognition of MSI-H in sporadic ACPS C tumours identifies a subset of cancers with improved prognosis. Such stratification should be considered in trials of adjuvant therapy and may be relevant to therapeutic decision making.

p73 is up-regulated in a subset of hepatocellular carcinomas.

Loss of heterozygosity (LOH) at 1p36 occurs in a number of solid tumors including hepatocellular carcinoma (HCC). Recently, a novel gene, p73, has been identified at 1p36.33. p73 is structurally and functionally related to p53 located at 17p13.1, which is a target for inactivation in HCCs. p73 produces at least two splicing variants, p73alpha and beta, and a polymorphism in exon 2 results in two alleles, GC or AT. Initially, only the AT allele and p73alpha transcripts were identified in malignant cell lines, suggesting a role for these in the malignant phenotype. The aims of this study were to determine the extent of LOH at 1p36 and 17p13.1 in HCCs from Australia and South Africa, and to identify patterns of p73 mRNA and p73 and p53 protein expression. LOH at 1p36 was found in 8 of 25 Australian and 6 of 10 South African cases. p73 mRNA expression occurred in 8 HCCs, but not in nonmalignant liver tissue. Two of these 8 HCCs had LOH of 1p36. Both alpha and beta transcripts were observed in GC/GC homozygotes and GC/AT heterozygotes. No p73 protein expression was observed by immunohistochemistry in nonmalignant liver tissue or in HCC. p53 inactivation appeared to be associated with up-regulation of p73 expression, suggesting a compensatory role for p73 in this situation. The LOH at 1p36 implies a liver-specific tumor suppressor gene is in this region. However, the up-regulation of p73 mRNA suggests p73 is not the target of this loss.

Hepatocellular carcinoma.

The incidence of hepatocellular carcinoma (HCC) appears to be declining in Taiwan and potentially in other high-prevalence areas as a consequence of vaccination for hepatitis B virus (HBV). However, there is evidence that the incidence of HCC is increasing in North America and Europe. This appears to be related to the increasing prevalence and duration of hepatitis C virus (HCV) infection in these countries. There is also growing evidence to support an increase in the risk of HCC in patients with HCV who are coinfected with occult HBV (patients who have lost HBV surface antigen but still have detectable HBV DNA either in blood or liver). Occult HBV infection in patients with HCV may be more common than previously thought, and HCC that occurs in this setting appears to have a worse prognosis. There is continuing interest in the effect of interferon therapy on the incidence of HCC in patients with HCV. Several studies from Japan have shown a benefit in patients without cirrhosis, although there are a number of potentially confounding variables that may partly explain these results. Prospective randomized studies are needed to investigate this important question. The molecular biology of HCC and the events of malignant transformation in the liver continue to be areas of intense study. Recently, there has been considerable interest in telomeres, the repeat units on the ends of chromosomes, and the enzyme that maintains these, telomerase. Telomeres shorten with each cell division and can be used to determine the number of divisions a cell has undergone. Eventually they reach a critical length, with further loss resulting in cellular senescence. Telomerase restores telomere length and may help malignant cells escape senescence. Nearly all HCCs have telomerase activity and assessments of telomeres and telomerase may be clinically useful.