Vol. 6 Issue 4
On the cover: Official Journal of the Mexican Association of Hepatology
The treatment of autoimmune hepatitis is evolving as the natural history of the disease and newer agents become available. This concise review will outline the various treatment options in these patients. Treatment with current corticosteroids and azathioprine works in most patients but issues of intolerance and incomplete response arise. These situations led to the investigation of newer immunosupressants including mycophenolate mofetil, budesonide cyclosporine, tacrolimus and ursodeoxycholic acid. The newer agents have been studied in small patient numbers so they are not first-line treatment yet but do have a clear role in those patients with intolerance of incomplete response to standard corticosteroids and azathioprine.
Intrahepatic hypoxia may occur during the inflammatory and fibrotic processes that characterize several chronic liver diseases of viral and autoimmune origin. As a consequence, new vascular structures are formed to provide oxygen and nutrients. Angiogenesis involves a tightly regulated network of cellular and molecular mechanisms that result in the formation of functional vessels. Of particular importance are growth factors and molecules involved in matrix remodeling and cell migration, as weel as vessel maturation- related factors. In recent years a number of studies have investigated the expression and function of many pro- and antiangiogenic molecules in chronic liver diseases and liver regeneration. This review examines the potential pathogenic role of angiogenesis in the context of viral hepatitis, autoinmmune hepatitis, primary biliary cirrhosis and hepatocellular carcinoma.
Ascites, the most common complication of cirrhosis, is associated with a poor quality of life, an increased risk of infection, and renal failure. Twenty percent of cirrhotic patients have ascites at the time of diagnosis, while 30% and 50% will develop ascites by 5 and 10 years, respectively. There are several factors that contribute to ascites formation in cirrhotic patients, these include splanchnic vasodilatation, arterial hypotension, high cardiac output, and decreased vascular resistance. These factors lead to ineffective intravascular volume (hyperdynamic state), impairment of renal function, and subsequent water and sodium retention, all of which lead to dilutional hyponatremia (serum sodium <130 mEq/L), one of the most important prognostic factors in these patients. In conclusion, the therapeutic objective is to improve sodium balance and circulatory function through non-pharmacological measures, such as dietary sodium and water restriction as well as bed rest. Spironolactone (100-400 mg/day) is the initial drug of choice, while loop diuretics (like furosemide, 40-60 mg/day) are frequently used as adjuvants. Recently, agents that interfere with the renal effects of vasopressin by inhibiting water reabsorption in collecting ducts and producing free water diuresis have been used. These agents are called aquaretics and can be useful in the treatment of ascites unresponsive to conventional therapy.
Background: Insulin resistance plays an important role in the pathogenesis of NAFLD. Pharmacological treatment of patients with NAFLD is still evolving. Insulin sensitizing drugs like metformin may be effective in these patients. Twenty five adult patients with NAFLD who did not achieve normalization of alanine transaminases (ALT) after 6 months of lifestyle interventions and UDCA were treated with metformin 500mg tid for 6 months. Insulin resistance was determined by HOMA- IR. Liver function tests were done monthly and patients were defined having no response, partial response or complete biochemical response depending on the change in ALT. Results were compared with 25 patients with NAFLD from the same cohort treated only with lifestyle interventions (disease controls). Results: Thirteen (52%) patients had class III (n = 5) or class IV (n = 8) disease amounting to histological NASH. Of these 13 patients none had severe inflammation and none had stage 4 fibrosis (cirrhosis). All 25 patients with NAFLD had insulin resistance in comparison to healthy controls. In comparison to disease controls (127.5 ± 41.8 vs. 118 ± 21.6 p = NS), all patients treated with metformin had partial biochemical response (mean ALT 122.2 ± 26.8 vs 74.3 ± 4.2 p < 0.01) and 14 (56%) of them achieved complete normalization of ALT. Conclusions: Metformin is effective to achieve biochemical response in patients with NAFLD who do not respond to lifestyle interventions and UDCA.
Lipoproteins are synthesized by the liver and secreted to plasma. Chronic alcoholic intoxication produces frequently cirrhosis and concomitantly alterations in liver metabolism. Thirty patients with alcoholic cirrhosis and 83 healthy controls were selected for this study. Apolipoprotein A1, B100, lecithin cholesterol acyltransferase, responsible for cholesterol esterification and seudocholinesterase enzyme activity not related to lipid metabolism, as a referent of proteins synthesized by the liver were analyzed. In 7 patients serum tiobarbituric acids, catalase, glutathione peroxidase were measured, as exponent of the presence of oxidative stress. Our results showed a significant decrease in lipoproteins, lecithin cholesterol acyltransferase and seudocholinesterase activities. An increase in serum tiobarbituric acids and a decrease in both antioxidant enzymes were found as well. In conclusion, alcohol cirrhotic liver decreases the production of liver proteins including those related to lipid metabolism, allowing the formation of steatosis and/or necrosis. Moreover oxidative stress participate possible as a major mechanism in liver damage.
The aim of this study was to investigate the effects of combinations of pegilated–interferon (PEG–IFN), ribavirin, and danazol on thrombocytopenia and liver injury in rats with fibrosis. Male adult Wistar rats were treated with either mineral oil, danazol (0.83 mg/kg per day), PEG–interferon α-2a (PEG–IFN, 0.3 μg/ week) + ribavirin (12 mg/kg per day), PEG–IFN + ribavirin + danazol, CCl4 (4 g/kg for eight weeks), CCl4 + PEG–IFN + ribavirin, or CCl4 + PEG–IFN + ribavirin + danazol. The following assays were conducted: hematology, clinical chemistry, liver function, liver fibrosis, lymphocyte cytokine mRNA expression, and bone-marrow DNA content. Platelet counts were low in sham-treated animals and animals treated with PEG– IFN + ribavirin (30% and 25% respectively; P < 0.05). PEG–IFN + ribavirin + danazol reduced platelet counts of fibrotic animals by only 9% (P < 0.05). PEG– IFN + ribavirin reduced hepatic collagen content by 50%, whereas danazol + PEG–IFN + ribavirin reduced hepatic collagen content by 60% (P < 0.05). PEG–IFN + ribavirin reduced the total bilirubin concentration by 27%, alanine amino transferase (ALT) activity by 75% and γ-glutamyl transpeptidase (γ-GTP) activity by 74% (P < 0.05). In contrast, danazol + PEG–IFN + ribavirin reduced total bilirubin levels by 61%, alkaline phosphatase activity by 45%, ALT activity by 76%, and γ-GTP activity by 74% (P < 0.05). The only treatment that increased interleukin 10 (IL-10) mRNA in fibrotic rats was PEG–IFN + ribavirin. However, danazol + PEG–IFN + ribavirin reduced the expression of IL-6, IL-10, tumor necrosis factor α and transforming growth factor β. Bone-marrow DNA content was not altered by any treatment. In conclusion, PEG–IFN + ribavirin + danazol could be a new therapeutic option for patients with liver injury, fibrosis, and thrombocytopenia.
Objective(s): Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with unknown etiology. The insulin resistance, immune mechanisms and oxidative stress are the main factors in its pathogenesis. Dipeptidyl peptidase IV (DPPIV) or CD26 is a protein with endocrine and immune functions. This study aimed to elicudate the changes related to DPPIV in NASH patients. Methods: Serum and urinary DPPIV activities were measured in 31 NASH patients and 17 healthy controls. The liver biopsies of 29 patients were immunolabeled for CD26. Results: The mean age of patients were 46 ± 11 years and 14 (45%) of them were female. The serum DPPIV activity was higher in patients (57.3 ± 7.8 U/L) than controls (43.6 ± 10.6 U/L) (p < 0.0001), and correlated with the histopathological grade (p = 0.038, r = 0.373) and hepatosteatosis (p = 0.018, r = 0.423) but not with stage (p = 0.286), class (p = 0.286) or CD26 staining (p = 0.743). The urinary DPPIV activity was similar in patients (1.52 ± 0.94 U/mmol creatinine) and controls (1.37 ± 0.68 U/mmol creatinine) (p = 0.861). Three acinar zones of liver had equal CD26 expression (p = 0.076). The intensity of CD26 immunostaining was correlated with histopathological grade (p = 0.001) and hepatosteatosis (p = 0.003) but no correlation with stage or class could be detected (p = 0.610 and 0.956, respectively). In Conclusions: The serum DPPIV activity and the staining intensity of CD26 in liver are correlated with histopathologic grade of NASH and hepatosteatosis. DPPIV can be proposed as a novel candidate with several potential functions in NASH pathogenesis.
Many hepatoprotective herbal preparations have been recommended in alternative systems of medicine for the treatment of hepatic disorders. No systematic study has been done on protective efficacy of Leucophyllum frutescens to treat hepatic diseases. Protective action of L. frutescens methanol extract (obtained by maceration) was evaluated in an animal model of hepatotoxicity induced by carbon tetrachloride (CCl4). Wistar albino rats were divided into five groups. Group I was normal control group; Groups II-V received CCl4. After inducing hepatic damage, Group II served as control CCl4; Group III was given silymarin as reference hepatoprotective; and Groups IV and V received different doses of plant extract. Liver marker enzymes were assayed in serum. Samples of livers were observed under microscope for the histopathological changes. Levels of marker enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased significantly in CCl4 treated rats (Group II). Groups IV and V intoxicated with CCl4 and treated with L. frutescens methanol extract significant decreased the activities of these two enzymes. Also these groups resulted in less pronounced destruction of the liver architecture, there is not fibrosis and have moderate inflammation compared with Group II. The present study scientifically validated the traditional use of L. frutescens for liver disorders. In conclusion the methanol extract of L. frutescens aerial parts could be an important source of hepatoprotective compounds.
The worldwide obesity epidemic contributes to the increasing incidence of a number of diseases, as nonalcoholic fatty-liver disease (NAFLD) and its most severe form, the nonalcoholic steatohepatitis (NASH). Data on the prevalence of NASH has varied from 18.5%5 to 69%43 in obesity, an unacceptable wide range. The aim of our study was to evaluate how prevalence of NASH is influenced by the different diagnostic histological criteria. Consecutive assessment of 325 obese patients referred for bariatric surgery (BMI ≥ 35 kg/m2), 146 of whose were submitted to histological analysis of the liver allowed the evaluation of the prevalence of NAFLD. Steatohepatitis was diagnosed histologically using 3 types of criteria: a) broad criteria, where steatosis was associated with at least 2 of the following parameters: any degree of lobular inflammatory infiltrate, hepatocellular ballooning and perisinusoidal/ perivenular fibrosis; b) restricted criteria, where the hepatocellular ballooning was of moderate or severe intensity; c) ultrarestricted criteria, which required perisinusoidal and/or perivenular fibrosis. NAFLD was present in 111 (76%) of the patients, and the prevalence of NASH was 25.3% when ultrarestricted criteria were used, 41.1% with restricted criteria and 55.5% with broad criteria. In conclusion, more accurate definition of the criteria for histological diagnosis of NASH should be required, so that further clinicopathological studies may define the long-term progression of the disease and evaluate therapeutic strategies.
Both phytic acid (PA) and catechin (CA) are well known antioxidants of natural origin. They were frequently tried on experimental level as hepatoprotectants, relying only on their antioxidant properties. The present study was conducted mainly to outline the other biochemical pathways underlying the hepatotherapeutic potential of both drugs and to check a possible synergistic action if prescribed concomitantly. As both materials are frequently taken on a daily basis in food and drinks, it will be helpful to pursue their possible utility and/or to check if their value is really of medical importance. For this purpose, CCl4 was used as a hepatotoxin, we evaluated plasma total sialic acid (TSA), serum ascorbic acid (AA) levels, liver tissue thiobarbituric acid reactive species (TBARS) as a marker for lipid peroxidation and total protein (TP) content as a rough marker to measure hepatic synthetic capability in 80 male Wistar rats as experimental models. Animals were classified into 8 groups (10 rats each), the first as control, the second as PA treated (0.3 mg kg -1), orally, the third as CA treated (30 mg kg -1), intraperitoneally, the fourth given both drugs, as a single daily dose for 2 weeks. The same design was repeated 24 hours after CCl4-intoxication (1mL kg -1), intraperitoneally, as a single dose. The results revealed that both PA and CA when used individually, significantly down-regulated TSA in both physiologic (no CCl4 treatment) and pathologic (CCl4- intoxication) states accompanied by significant decrease in lipoperoxidation. The therapeutic action against TSA and the antioxidant power were abolished by co-administration of both drugs . AA was only decreased by PA and the combination in the physiologic state. Both PA and CA showed significant therapeutic effect for protein synthesis against CCl4-intoxication, but the combination abolished this effect. We conclude that both drugs can be considered as a chemotherapeutic against hepatopathies and we for the first time contraindicate the concomitant use of both drugs.
Abdominal actinomycosis is a rare condition caused by actinomyces species found in the normal flora of the oral cavity, gastrointestinal and genital tract. All cases reported describe localized forms demonstrating masses, pseudotumors or abscess during surgery or radiology studies and there are no reports about spontaneous peritonitis caused by actinomycetes. We report a case in which this disease present as symptomatic ascitic fluid infection refractory to antimicrobial therapy for intra- abdominal sepsis and detected during unsuspected cytology test. The case was successfully treated with a penicillin regimen. As a spontaneous peritonitis variety, the microbiology diagnosis remains difficult as we don't think in this form of abdominal actinomycosis not described previously in the literature. The present illustrative case strength the usefulness of cytology test in patients with suspected ascitic fluid infection refractory to a medical therapy.
Hepatic artery thrombosis (HAT) is the most common vascular complication of orthotopic liver transplantation (OLT) and constitutes a potential emergency during the postoperative period. Surgical revascularization and retransplantation are the treatments of choice for this condition. The aim of this report is to present long-term follow-up on survival and graft function of three patients with paclitaxel-coated hepatic artery stents placed percutaneously after earlyonset HAT. Three patients developed early onset HAT after cadaveric-donor OLT in a tertiary care center in Mexico. These patients were treated percutaneously with balloon angioplasty and paclitaxel-coated stents. After 24 months or more of follow-up, 2 patients present total occlusion of the stent and one patient, intra-stent stenosis; interestingly, all patients have normal graft function and excellent quality of life. In conclusion, although balloon angioplasty and stent placement may be a therapeutic option for suitable patients with early-onset HAT after OLT, longterm patency is unlikely even with the use of paclitaxel- coated materials.
Background: To our knowledge, no detailed analysis exists of the incidence and mortality of hepatocellular carcinoma (HCC) among Hispanics in the United States. In previous studies, the rates for Hispanics have not been reported separately from other racial or ethnic groups. Methods: We used information on patients diagnosed as having HCC from 13 registries in the Surveillance Epidemiology and End Results (SEER) database of the National Cancer Institute to calculate race-specific, age-adjusted incidence rates (AIR) between 1992 and 2002. We also used California and Texas state death records from between 1979 and 2001 to calculate race-specific, age-adjusted mortality rates for liver cancer excluding intrahepatic cholangiocarcinoma. For Hispanics and Asians/Pacific Islanders, the rates were calculated for native-born subjects and immigrants separately. Results: In SEER, the yearly AIRs were higher by 1.2-fold in Hispanics than in blacks (6.3 vs 5.0 per 100 000 person-years of the underlying US population) and by 2.7-fold than in non- Hispanic whites (2.4 per 100 000 person-years) but lower than in Asians/Pacific Islanders (10.8 per 100 000 person-years). The median age at HCC diagnosis in Hispanics (64 years) was intermediate between whites (the oldest) and blacks (the youngest). Between the periods 1992-1995 and 2000-2002, there was a 31% increase in the incidence of HCC in Hispanic men and a 63% increase in Hispanic women. The race-specific, age-adjusted mortality rates were remarkably similar in California and Texas and were highest in immigrant Asian/Pacific Islanders followed by native Hispanics. The rates for native Hispanic men were more than twice as high as those for immigrant Hispanic men. For Texas, the rates for native Hispanic men were 65% higher than those for immigrant Hispanic men. Conclusion: Hispanics in the United States have high rates of HCC that are second only to Asians/Pacific Islanders. Abstract published under the permission of the editor of Archives of Internal Medicine.
Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 ± 58 U/l vs. 103 ± 16 U/l in the control group; p < 0.01) and AST (637 ± 37 U/l vs. 175 ± 13 U/l in the control group; p < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1β, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF- α; and an increase in α1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet. Abstract published under the permission of the editor of Am J Physiol Gastrointest Liver Physiol.