Misael Uribe

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.

Current concepts in the pathogenesis of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of chronic liver disease, representing the leading cause of hepatology referral in some centres. However, its pathophysiology is not completely understood. Insulin resistance is one of the major mechanisms involved in disease prevalence and progression. Owing to the lack of an effective pharmacological therapy, recommendations on treatment are scarce and are based mainly on lifestyle changes, including diet and exercise. A review of the current literature on pathogenesis of NAFLD is presented in this article.

The nutritional management of hepatic encephalopathy in patients with cirrhosis: International society for hepatic encephalopathy and nitrogen metabolism consensus

Nitrogen metabolism plays a major role in the development of hepatic encephalopathy (HE) in patients with cirrhosis. Modulation of this relationship is key to the management of HE, but is not the only nutritional issue that needs to be addressed. The assessment of nutritional status in patients with cirrhosis is problematic. In addition, there are significant sex‐related differences in body composition and in the characteristics of tissue loss, which limit the usefulness of techniques based on measures of muscle mass and function in women. Techniques that combine subjective and objective variables provide reasonably accurate information and are recommended. Energy and nitrogen requirements in patients with HE are unlikely to differ substantially from those recommended in patients with cirrhosis per se viz. 35‐45 kcal/g and 1.2‐1.5g/kg protein daily. Small meals evenly distributed throughout the day and a late‐night snack of complex carbohydrates will help minimize protein utilization. Compliance is, however, likely to be a problem. Diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the staple diet. Branched chain amino acid supplements may be of value in the occasional patient intolerant of dietary protein. Increasing dietary fiber may be of value, but the utility of probiotics is, as yet, unclear. Short‐term multivitamin supplementation should be considered in patients admitted with decompensated cirrhosis. Hyponatremia may worsen HE; it should be prevented as far as possible and should always be corrected slowly. Conclusion: Effective management of these patients requires an integrated multidimensional approach. However, further research is needed to fill the gaps in the current evidence base to optimize the nutritional management of patients with cirrhosis and HE. (Hepatology 2013)

Effect of Ezetimibe on the Prevention and Dissolution of Cholesterol Gallstones

BACKGROUND & AIMS Cholesterol cholelithiasis is one of the most prevalent and most costly digestive diseases in developed countries and its incidence has increased markedly in Asian countries owing to the adoption of Western-type dietary habits. Because animal experiments showed that high efficiency of intestinal cholesterol absorption contributes to gallstone formation, we explored whether the potent cholesterol absorption inhibitor ezetimibe could prevent gallstones and promote gallstone dissolution in mice and reduce biliary cholesterol content in human beings. METHODS Male gallstone-susceptible C57L mice were fed a lithogenic diet and concomitantly administered with ezetimibe at 0, 0.8, 4, or 8 mg/kg/day for 8 or 12 weeks. Gallbladder biles and gallstones were examined by microscopy. Gallbladder emptying in response to cholecystokinin octapeptide was measured gravimetrically. Biliary lipid outputs were analyzed by physical-chemical methods. Cholesterol absorption efficiency was determined by fecal dual-isotope ratio and mass balance methods. Lipid changes in gallbladder biles of gallstone patients vs overweight subjects without gallstones were examined before (day 0) and at 30 days after ezetimibe treatment (20 mg/day). RESULTS Ezetimibe prevented gallstones by effectively reducing intestinal cholesterol absorption and biliary cholesterol secretion, and protected gallbladder motility function by desaturating bile in mice. Treatment with ezetimibe promoted the dissolution of gallstones by forming an abundance of unsaturated micelles. Furthermore, ezetimibe significantly reduced biliary cholesterol saturation and retarded cholesterol crystallization in biles of patients with gallstones. CONCLUSIONS Ezetimibe is a novel approach to reduce biliary cholesterol content and a promising strategy for preventing or treating cholesterol gallstones by inhibiting intestinal cholesterol absorption.

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.

Strong Association between Gallstones and Cardiovascular Disease

BACKGROUND AND AIM:Obesity is closely associated with the increased morbidity and mortality of many common diseases in the Western world, including coronary heart disease (CHD) and gallstone diseases (GD). We have investigated the association between GD and CHD in a cross-sectional study.METHODS AND RESULTS:Subjects who had gallstones visible by ultrasound were considered as cases and subjects negative for gallstones were classified as controls. Positive CHD was defined when the stress test was positive. Body mass index (BMI), waist circumference, blood pressure, serum lipid concentrations, and insulin resistance were measured. The association was estimated by odds ratios using logistic regression models adjusted for confounders. Four hundred and seventy-three subjects (292 males and 181 females) were included, comprising 354 controls and 119 cases. Subjects with GD had higher prevalence of CHD (15.96%) than controls (4.52%) (p < 0.0001). In univariate unconditional logistic regression analysis CHD, BMI ≥ 30 kg/m2, waist circumference, high blood pressure, and HOMA-IR > 2.5 were the most important risk factors for GD. In multivariate analysis (adjusted for age and gender, and BMI) the risk for GD in subjects with CHD was higher (OR 2.84, 95% CI: 1.33–6.07, p < 0.007).CONCLUSIONS:Subjects with CHD have an increased risk to have GD, both diseases are strongly associated and the main characteristics of these subjects are those frequently involved as part of the metabolic syndrome.

Treatment of chronic portal—Systemic encephalopathy with vegetable and animal protein diets

A controlled crossover clinical comparison of 40-g/day and 80-g/day vegetable protein diets vs a 40g/day meat protein diet plus neomycin-milk of magnesia (as control therapy) was performed on 10 cirrhotic patients with mild chronic portal-systemic encephalopathy. The 40-g vegetable protein diet had a high fiber volume and contained low methionine and low aromatic amino acids. The 80-g vegetable protein diet was rich in branched-chain amino acids and fiber, with a similar content of sulfur-containing amino acids as compared to the 40-g meat protein diet. Serial semiquantitative assessments were done, including mental state, asterixis, number connection tests electroencephalograms and blood ammonia levels. No patient developed deep coma while ingesting either vegetable protein diet or neomycin-milk of magnesia plus 40-g meat protein diet. A significant improvement in the number connection test times was observed during the 40-g vegetable protein diet (P<0.05) and during the 80-g vegetable protein diet (P<0.05) as compared to their previous 40-g meat protein-neomycin periods. In addition, during the period of 80-g vegetable protein diet, the patients showed a significant improvement in their electroencephalograms (P<0.05). The frequency of bowel movements significantly increased (P<0.05) during the 80-g vegetable protein diet period. During the 40-g vegetable protein diet, two cirrhotic-diabetic patients experienced hypoglycemia. Three patients complained of the voluminous 80-g vegetable protein diet. Patients with mild portal-systemic encephalopathy may be adequately controlled with vegetable protein diets as a single therapy.

Beneficial Effect of Vegetable Protein Diet Supplemented With Psyllium Plantago in Patients With Hepatic Encephalopathy and Diabetes Mellitus

A controlled crossover study was performed in 8 diabetic patients with chronic portal-systemic encephalopathy. After a basal period the patients were treated during periods A and B. During period A, a meat protein diet (0.8 g/kg body wt, approximately 1800 kcal/day) was consumed and neomycin plus laxatives were given. During period B patients received vegetable protein (0.8 g/kg body wt, 1800 kcal/day). This diet was supplemented with psyllium fiber to reach 35 g of fiber per day. Four patients were randomly assigned to receive the treatments in the order A-B and the other 4 patients in the order B-A. At the end of the first experimental period, fasting glucose levels were 204 +/- 86 mg% in the meat protein diet group and 127 +/- 8 mg% in the vegetable protein diet group (p less than 0.014). The patients were receiving 2.5 +/- 0.2 g/day and 2.1 +/- 0.5 g/day of tolbutamide at the end of the meat protein diet and vegetable protein diet, respectively. In all cases, fasting glucose levels decreased at the end of the vegetable diet period regardless of the previous treatment. An improvement of greater than or equal to 25 mg% of fasting glucose levels was observed in 7 of the 8 patients after the vegetable protein diet and in no case after the meat protein diet (p less than 0.0078). The parameters of encephalopathy were comparable at the end of both the meat protein diet and the vegetable protein diet. A significant increase in the number of bowel movements was noticed after the vegetable diet plus fiber (p less than 0.01). We propose the use of vegetable diet plus fiber to facilitate the treatment of patients with both diabetes and hepatic encephalopathy.

In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty liver disease: Correlation with biochemical method and morphometry

BACKGROUND & AIMS The clinical application of liver fat quantification has increased in recent years, paralleling the epidemic increase in nonalcoholic fatty liver disease. The aim of this study was to perform a diagnostic evaluation of spectroscopy by comparing its measurement of total lipid content with that from liver biopsies and morphometry in normal subjects and patients with nonalcoholic fatty liver disease. METHODS Patients with symptomatic cholelithiasis underwent 3T MR cholangiography with spectroscopic quantification of TLC. A laparoscopic cholecystectomy was performed on the day of admission, with liver samples taken during surgery. Microcolorimetric assessment quantified lipid content in liver samples and morphometric evaluation in stained slides. Statistical analysis included bivariate correlation, regression, and ROC analysis. RESULTS The study was conducted in 18 patients, 5 men (mean age, 35.2+/-11.03 years; range, 27-54 years) and 13 women (mean age, 46.77+/-11.77 years; range, 21-61 years). Using a cut-off value >5% for fat content, 8 patients presented with steatosis and 10 patients presented with normal liver fat content. A significant correlation was observed between fat spectroscopy and lipid content (r=0.876, p<0.001). A lower and non-significant correlation was observed between lipid content and morphometry (r=0.190, p>0.05). CONCLUSIONS The accuracy of spectroscopy in assessing fat concentration with a cut-off level of 7.48% was 100%. Spectroscopy showed a strong and significant correlation with lipid content. It may reliably replace liver biopsy for the assessment of liver fat content.

Eosinophilic Gastroenteritis: A Review

Eosinophilic gastroenteritis is a rare benign disease characterized by tissue eosinophilic infiltration that may involve several digestive tract layers. Also known as allergic, or eosinophilic allergic, gastroenteropathy, it usually involves the stomach and small intestine: rarely the colon. It may or may not be accompanied by higher counts of eosinophils in the peripheral blood. The main clinical manifestations depend on the site affected. It has been classified according to clinical and pathological features, and the symptoms depend on the patient’s immunological response to several cytokines released by eosinophils. Because of lack of understanding of the etiology and triggering factors, treatment is based mainly on corticosteroids; although other drugs acting on the immune system have been tested, the results are not always satisfactory. This review focuses on the epidemiology, pathophysiology, clinical features, and treatment of this hitherto under-diagnosed disease.