The second Mexican consensus on hepatocellular carcinoma. Part II: Treatment.

Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this second part of the document, the topics related to the treatment of HCC are presented.

The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis.

Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this first part of the document, the topics related to epidemiology and diagnosis are presented.

Efficacy of rifaximin in the different clinical scenarios of hepatic encephalopathy. / Eficacia de la rifaximina en los diferentes escenarios clínicos de la encefalopatía hepática.

Hepatic encephalopathy is a frequent complication in patients with cirrhosis of the liver and is associated with a high mortality rate. Costs attributed to the management of patients with cirrhosis are especially high due to complications, such as hepatic encephalopathy, given that they increase the number of days of hospital stay. Different drugs are currently used to treat hepatic encephalopathy, and the main ones are lactulose, L-ornithine L-aspartate (LOLA), and certain antibiotics, especially rifaximin-α (RFX). Even though many of them have been shown to be effective to greater or lesser degrees, it is important to understand the differences between them, so that every patient receives individualized treatment and the best option is chosen, in accordance with the different clinical scenarios. Thus, the aim of the present study was to analyze the evidence on the advantages and disadvantages of the individual or combined use of the 3 main treatments for hepatic encephalopathy, specifically taking into consideration their different degrees of efficacy, their impact on quality of life, prophylaxis, and cost reduction.

The Mexican consensus on nonalcoholic fatty liver disease. / Consenso mexicano de la enfermedad por hígado graso no alcohólico.

Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Mexico is one of the countries whose population has several risk factors for the disease and its prevalence could surpass 50%. If immediate action is not taken to counteract what is now considered a national health problem, the medium-term panorama will be very bleak. This serious situation prompted the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología to produce the Mexican Consensus on Fatty Liver Disease. It is an up-to-date and detailed review of the epidemiology, pathophysiology, clinical forms, diagnosis, and treatment of the disease, whose aim is to provide the Mexican physician with a useful tool for the prevention and management of nonalcoholic fatty liver disease.

Consenso Mexicano para el Tratamiento de la Hepatitis C / The Mexican consensus on the treatment of Hepatitis C

El objetivo del Consenso Mexicano para el Tratamiento de la Hepatitis C fue el de desarrollar un documento como guía en la práctica clínica con aplicabilidad en México. Se tomó en cuenta la opinión de expertos en el tema con especialidad en: gastroenterología, infectología y hepatología. Se realizó una revisión de la bibliografía en MEDLINE, EMBASE y CENTRAL mediante palabras claves referentes al tratamiento de la hepatitis C. Posteriormente se evaluó la calidad de la evidencia mediante el sistema GRADE y se redactaron enunciados, los cuales fueron sometidos a voto mediante un sistema modificado Delphi, y posteriormente se realizó revisión y corrección de los enunciados por un panel de 34 votantes. Finalmente se clasificó el nivel de acuerdo para cada oración. Esta guía busca dar recomendaciones con énfasis en los nuevos antivirales de acción directa y de esta manera facilitar su uso en la práctica clínica. Cada caso debe ser individualizado según sus comorbilidades y el manejo de estos pacientes siempre debe ser multidisciplinario.

The aim of the Mexican Consensus on the Treatment of Hepatitis C was to develop clinical practice guidelines applicable to Mexico. The expert opinion of specialists in the following areas was taken into account: gastroenterology, infectious diseases, and hepatology. A search of the medical literature was carried out on the MEDLINE, EMBASE, and CENTRAL databases through keywords related to hepatitis C treatment. The quality of evidence was subsequently evaluated using the GRADE system and the consensus statements were formulated. The statements were then voted upon, using the modified Delphi system, and reviewed and corrected by a panel of 34 voting participants. Finally, the level of agreement was classified for each statement. The present guidelines provide recommendations with an emphasis on the new direct-acting antivirals, to facilitate their use in clinical practice. Each case must be individualized according to the comorbidities involved and patient management must always be multidisciplinary.

The Mexican consensus on the treatment of hepatitis C. / Consenso Mexicano para el Tratamiento de la Hepatitis C.

The aim of the Mexican Consensus on the Treatment of HepatitisC was to develop clinical practice guidelines applicable to Mexico. The expert opinion of specialists in the following areas was taken into account: gastroenterology, infectious diseases, and hepatology. A search of the medical literature was carried out on the MEDLINE, EMBASE, and CENTRAL databases through keywords related to hepatitisC treatment. The quality of evidence was subsequently evaluated using the GRADE system and the consensus statements were formulated. The statements were then voted upon, using the modified Delphi system, and reviewed and corrected by a panel of 34 voting participants. Finally, the level of agreement was classified for each statement. The present guidelines provide recommendations with an emphasis on the new direct-acting antivirals, to facilitate their use in clinical practice. Each case must be individualized according to the comorbidities involved and patient management must always be multidisciplinary.

Strategies to manage hepatitis C virus (HCV) infection disease burden - volume 2.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries, and the relative impact of two scenarios was considered: (i) increased treatment efficacy while holding the treated population constant and (ii) increased treatment efficacy and increased annual treated population. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. In most countries, the annual treated population had to increase several fold to achieve the largest reductions in HCV-related morbidity and mortality. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. In most of the studied countries, the majority of patients were born between 1945 and 1985.

The present and future disease burden of hepatitis C virus (HCV) infections with today's treatment paradigm - volume 2.

Morbidity and mortality attributable to chronic hepatitis C virus (HCV) infection are increasing in many countries as the infected population ages. Models were developed for 15 countries to quantify and characterize the viremic population, as well as estimate the number of new infections and HCV related deaths from 2013 to 2030. Expert consensus was used to determine current treatment levels and outcomes in each country. In most countries, viremic prevalence has already peaked. In every country studied, prevalence begins to decline before 2030, when current treatment levels were held constant. In contrast, cases of advanced liver disease and liver related deaths will continue to increase through 2030 in most countries. The current treatment paradigm is inadequate if large reductions in HCV related morbidity and mortality are to be achieved.

Risk of non-alcoholic fatty liver disease in patients with psoriasis: a systematic review and meta-analysis.

BACKGROUND: Psoriasis has been linked to an increased risk of metabolic syndrome (MetS). Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MetS, is now the commonest liver disease worldwide and can evolve into cirrhosis in a subgroup of patients. Psoriasis has been reported to be associated to NAFLD. AIM: The aim of this study was to evaluate the strength of the association between psoriasis and NAFLD. METHODS: A systematic review of the literature was conducted in six databases (Medline, CINAHL, Scopus, LILACS, Cochrane Library and EMBASE). Data from studies assessing frequency of NAFLD in psoriatic and non-psoriatic patients were extracted and meta-analysed using the Mantel-Haenszel method. Subgroups analysis of patients with psoriatic arthritis and moderate to severe psoriasis was also performed. RESULTS: Seven case-control studies were included, all of them of low or moderate quality. Psoriatic patients exhibited an increased risk of NAFLD compared to non-psoriatic controls (six studies; n = 267,761 patients; odds ratio (OR): 2.15, 95% CI: 1.57-2.94). The association remained significant (OR: 2.07, 95% CI: 1.62-2.64) when only high/moderate quality studies were analysed (three studies; n = 3345 patients). The risk of NAFLD was significantly greater in patients with psoriatic arthritis (three studies; n = 505 patients; OR: 2.25, 95% IC: 1.37-3.71) and in patients with moderate to severe psoriasis compared to those with mild psoriasis (two studies; 51,930 patients, OR: 2.07, 95% CI: 1.59-2.71). LIMITATIONS: Data quality and heterogeneity may restrict the interpretation of the pooled risk estimates. CONCLUSION: Case-control studies support an association between psoriasis and NAFLD. Screening of NAFLD in this group of patients may be warranted.

Role of oxidative stress and molecular changes in liver fibrosis: a review.

Liver fibrosis represents a health problem with significant morbidity and mortality that affects 100 million people worldwide. It is a final pathway to several chronic liver diseases and is characterized by excess collagen and accumulation of extracellular matrix in response to chronic hepatocellular damage. Clinical and experimental data suggest that oxidative stress (OS) mediates the progression of fibrosis, and that OS-related molecules may act as mediators of molecular and cellular events implicated in liver fibrosis. The generation of reactive oxygen species (ROS) plays an important role in producing liver damage and initiating hepatic fibrogenesis. OS disrupts lipids, proteins and DNA, induces necrosis and apoptosis of hepatocytes and amplifies the inflammatory response. ROS also stimulate the production of profibrogenic mediators from Kupffer cells and circulating inflammatory cells and directly activate hepatic stellate cells, resulting in the initiation of fibrosis. Advances in understanding the mechanisms involved in fibrosis have identified new molecular targets with therapeutic potential for more targeted and personalized control of this disease. This review will highlight recent concepts in OS, antioxidants and the molecular pathways involved in hepatic fibrosis.

Mechanisms involved in the protective effects of metformin against nonalcoholic fatty liver disease.

Metformin is an antidiabetic drug used widely in clinical practice. Its main clinical effect is to reduce blood glucose levels by improving insulin resistance. Nonalcoholic fatty liver disease is characterized by chronic liver damage and can develop into liver cirrhosis. Nonalcoholic fatty liver disease is associated with obesity and contributes to insulin resistance, and metformin is used to treat individuals with these conditions. The mechanisms underlying the clinical effects of metformin in treating nonalcoholic fatty liver disease are unclear. This article summarizes the literature on the mechanisms associated with liver glucose metabolism and the beneficial effects of metformin on this common liver disease.

Meta-analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding - an updated Cochrane review.

BACKGROUND: Antibiotic prophylaxis seems to decrease the incidence of bacterial infections in patients with cirrhosis and upper gastrointestinal bleeding and is considered standard of care. However, there is no updated information regarding the effects of this intervention. AIM: To assess the benefits and harms of antibiotic prophylaxis in cirrhotic patients with gastrointestinal bleeding by performing a systematic review of randomised trials. METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE and Science Citation Index EXPANDED until June 2010. We statistically combined data calculating relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes. RESULTS: Twelve trials (1241 patients) evaluating antibiotic prophylaxis against placebo or no antibiotic prophylaxis were included. Antibiotic prophylaxis was associated with reduced mortality (RR 0.79, 95% CI 0.63-0.98), mortality from bacterial infections (RR 0.43, 95% CI 0.19-0.97), bacterial infections (RR 0.35, 95% CI 0.26-0.47), rebleeding (RR 0.53, 95% CI 0.38-0.74) and days of hospitalisation (MD -1.91, 95% CI -3.80-0.02). Trials analysing rebleeding rate and hospitalisation length are still scarce, thus, caution should be exerted when interpreting the results. CONCLUSIONS: Antibiotic prophylaxis in patients with cirrhosis and upper gastrointestinal bleeding significantly reduced bacterial infections, and reduce all-cause mortality, bacterial infection mortality, rebleeding events and hospitalisation length. Novel clinically significant outcomes were included in this meta-analysis. Some benefits are biased and the risks are not yet properly assessed, this encourages future research in this field.

[Neural pathophysiology of cancer anorexia]. / Observaciones sobre la patogénesis de la anorexia asociada a cáncer y su regulación por el sistema nervioso central.

INTRODUCTION: Approximately two thirds of cancer patients at advanced stages of the disease suffer from anorexia. Defined as the loss of the desire to eat, anorexia lower the energy intake which further exacerbates a progressive deterioration of the patient nutritional status. Malnutrition has a large impact on morbidity and mortality affecting the quality of life. Cancer anorexia etiology is multifactorial including complex interactions among the tumor, host metabolism and antineoplastic treatment. New related theories include peripheral and brain mechanisms affecting hypothalamic pathways; inducing behavioral and metabolic failure of responses to energy balance. The aim of this review is to describe actual concepts involved in the pathogenesis of cancer anorexia with special interest in brain mechanisms. CONCLUSIONS: Anorexia and reduced food intake are important issues in the management of cancer patients, more knowledge about pathogenic mechanism is needed to improve therapeutic options, prognosis and quality of life in cancer patients.

Pyloric gland adenoma: case report.

Pyloric gland adenoma (PGA), also called adenoma with gastric differentiation, is a rare neoplasm of the gastric mucosa that can appear as gastric heterotopia in several organs. A 49-year-old woman presented with gastric reflux and chronic elevation of liver enzymes. She had a history of type 2 diabetes mellitus, hypothyroidism and an unspecified allergy treated with deflazacor, and a family history of autoimmune diseases. A liver biopsy showed macro- and microvesicular steatohepatitis. Hepatitis B and virus serum tests were negative. Autoimmune hepatitis was suspected and investigated. As an evaluation for dyspeptic symptoms an upper gastrointestinal endoscopy was performed, showing diffuse gastroduodenitis. A few polyps were found and resected from the gastric fundus; histopathology revealed a pyloric gland adenoma. There is very few clinical data on this tumor type because it is frequently underdiagnosed and reported as dysplasia. Further research is needed on the pathophysiology of this disease.

Ulcerative colitis in husband and wife. First report in Mexico.

The prevalence of inflammatory bowel disease in Mexico is low. The occurrence in familial cases has been attributed to genetic influences. We described the first report of inflammatory bowel diseases in one pairs of husband-wife in Mexico. According with characteristics of this case, we can speculate that the environmental and infectious etiology might play some role in the development of IBD.

Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease.

BACKGROUND AND AIM: Fatty infiltration and fibrosis are major issues in chronic liver disease. Recent reports suggest a role for the endocannabinoid system in these processes. AIM: To characterize localization and expression of CB2 in normal liver and nonalcoholic fatty liver. METHODS: We studied 64 liver biopsies: eight were considered normal; 56 had a diagnosis of nonalcoholic fatty liver disease (NAFLD); 32 with nonalcoholic steatosis and 24 nonalcoholic steatohepatitis (NASH). CB2 immunolocalization was studied in 38 samples in paraffin blocks using immunohistochemistry, and a computerized semiquantitative analysis was carried out. CB2 mRNA expression was assessed through RT-PCR in 26 frozen liver samples and the ratio CB2/beta-actin was used to evaluate differences between groups. Statistical analysis was performed with central tendency measures and the Mann-Whitney U-test. We considered as significant differences those with a P-value <0.05. RESULTS: Neither parenchymal nor nonparenchymal cells in normal liver tissue react towards anti-CB2 antibodies. All the samples from patients with steatosis and nonalcoholic steatohepatitis showed hepatocellular immunoreactivity. Cholangiocytes were positive only in the NAFLD group. Normal liver tissue showed a normalized CB2/beta-actin ratio of 0.001+/-0.01, steatosis 6.52+/-17.3 (P=0.05 vs normal) and NASH 6.49+/-12.2 (P=0.06 vs normal and P=0.6 vs steatosis). CONCLUSION: CB2 receptors are expressed by hepatocytes in nonalcoholic fatty liver disease but not in normal liver.

Adiponectin, structure, function and pathophysiological implications in non-alcoholic fatty liver disease.

Obesity is a major risk factor for the development of the metabolic syndrome, a cluster of diseases including insulin resistance, type 2 diabetes, dyslipidemia, hypertension, microalbuminuria, atherosclerosis, and non-alcoholic steatohepatitis. On the other hand, it is now generally accepted that adipose tissue acts as an endocrine organ producing a number of substances with an important role in the regulation of food intake, energy expenditure and a series of metabolic processes. Adiponectin is a recently discovered hormone produced exclusively by adipocytes. In fact, adiponectin is considered currently as a major factor in obesity-related insulin resistance and atherosclerosis. This new hormone differs from other adipocytokines in that its production and concentrations are actually decreased in insulin resistant subjects. The aim of this review is to summarize the current knowledge about the chemistry and physiology of adiponectin and to discuss its implications in the pathophysiology and potential treatment of insulin resistance and non-alcoholic fatty liver disease.

Zinc salts precipitate unconjugated bilirubin in vitro and inhibit enterohepatic cycling of bilirubin in hamsters.

BACKGROUND: We have evidence for enterohepatic cycling of bilirubin experimentally and in vivo in humans. This study was designed to investigate whether Zn salts might inhibit such cycling of bilirubin. MATERIALS AND METHODS: Micellar bile salt solutions with unconjugated bilirubin were prepared, appropriate concentrations of Zn salts were added, and unconjugated bilirubin precipitation was measured. Hamsters and Wistar rats were fed a chow diet or a chow diet enriched with 1% ZnSO4, and bilirubin secretion rates were monitored. RESULTS: Unconjugated bilirubin was precipitated maximally (90%) after a 10-min incubation with 5 mM Zn salts in the pH range of 6.8-9.0. In control hamsters, total bilirubin secretion rates into bile were 36.0 +/- 2.8 nmol h(-1) 100g(-1) body weight, whereas they were 25.0 +/- 3.3 nmol h-1 100(-1) g in the ZnSO4 group (P < 0.05). CONCLUSIONS: Zn salts that flocculate at physiological pH adsorb unconjugated bilirubin almost completely from unsaturated micellar BS solutions. In addition, Zn salts administered orally suppress biliary bilirubin secretion rates in hamsters. These findings suggest that the administration of Zn salts may inhibit the enterohepatic cycling of unconjugated bilirubin in humans who are predisposed to pigment gallstone formation due to diet, disease or drugs.

Fish oil (n-3) polyunsaturated fatty acids beneficially affect biliary cholesterol nucleation time in obese women losing weight.

It has been reported that intake of (n-3) polyunsaturated fatty acids (PUFA) reduces the risk of coronary heart disease and decreases biliary cholesterol saturation in the bile of gallstone patients. We investigated the effect of n-3 PUFA on cholesterol saturation index (CSI) and nucleation time (NT) in obese subjects who were losing weight. This was a double-blind, placebo-controlled clinical trial. Obese women (n = 35) with a body mass index (BMI) > or = 30 kg/m(2), with no prior history of gallstones or cholecystectomy by ultrasound were first studied to ensure absence of stones or biliary sludge. The women were then assigned to a hypocaloric regimen [5.02 MJ (1200 kcal)/d] and to receive 1200 mg/d of ursodeoxycholic acid (UDCA), 11.3 g/d of (n-3) PUFA or a placebo for 6 wk. BMI, CSI and NT were recorded at baseline and at the end of the experimental period. BMI decreased 5.75 +/- 2.7%/mo (range, 1.5-12.42%/mo) during the experiment. The CSI did not change in any of the groups. Cholesterol NT decreased significantly in the UDCA and placebo groups, but not in the (n-3) PUFA group. None of the women had developed gallstones at 6 wk. These results suggest that (n-3) PUFA maintain the CSI and NT in obese women during rapid weight loss, which probably results in the prevention of cholesterol gallstone formation.

Delayed gastric emptying in subjects with Gilbert's syndrome.

BACKGROUND/AIMS: Recently, it has been proposed that decreased intestinal motility in fasting-induced hyperbilirubinemic rats probably results in an increase in the enterohepatic cycling of unconjugated bilirubin. We investigated the association among gastric emptying, intestinal transit time, and serum unconjugated levels in subjects with Gilbert's syndrome. METHODOLOGY: Ten subjects with Gilbert's syndrome were included in this study according to the following criteria: fasting hyperbilirubinemia; no hemolysis or gastrointestinal disorders and free of any medication. Five normal, healthy volunteers acted as controls. Gastric emptying and intestinal transit time were evaluated after overnight fasting by administration of a standard meal mixed with 1-2ci of 99Tc-labeled diethylene-triamine-pentacetic acid. Serum unconjugated bilirubin levels were determined by high-performance liquid chromatography. RESULTS: The gastric emptying in Gilbert's syndrome subjects was 134.1 +/- 38.9 and 90.9 +/- 6.5 min in controls, P < 0.03. It was a tendency to have a shorter intestinal transit time in subjects with Gilbert's syndrome, 138.3 +/- 59.0, than in control subjects, 183.8 +/- 11.3 min. Serum unconjugated bilirubin levels (mg/dL) were 2.6 +/- 1.04 and 0.95 +/- 0.34, P < 0.01. CONCLUSIONS: Gastric emptying is delayed significantly in Gilbert's syndrome, and intestinal transit time differences between Gilbert's syndrome subjects and controls were not significantly different.