Vol. 2 Issue 4
On the cover: Official Journal of the Mexican Association of Hepatology
Cholestasis may result from a failure in bile secretion in hepatocytes or ductular cells, or from a blockade to the free bile flow. Human cholestasis may be induced by many drugs, being antibiotics the more common. Other types of cholestasis seen in humans are a group of familial cholestatic disorders, obstructive cholestasis, primary biliary cirrhosis, extrahepatic biliary atresia, primary sclerosing cholangitis, cholestasis of pregnancy, oral contraceptive-induced cholestasis, and sepsis-induced cholestasis. Experimental animal models allow the understanding of pathophysiological mechanisms involved and their clinical correlates. The most common experimental models of intrahepatic cholestasis are estrogen-induced, endotoxin-induced and drug-induced cholestasis. A well known model of extrahepatic biliary obstruction is common bile duct ligation. Drug-induced cholestasis were described using different drugs. On this regard, alpha naphthylisothiocyanate treatment has been extensively used, permitting to describe not only cholestatic alterations but also compensatory mechanisms. Congenital defficiency of transport proteins also were studied in natural rat models of cholestasis. The experimental animal models allow to define down-regulated alterations of hepatocyte transport proteins, and up-regulated ones acting as compensatory mechanisms. In conclusion, animal model and transport protein studies are necessary for the progressive understanding of congenital and acquired human cholestasis, and regulatory mechanisms that operate on liver cells.
Hepatic fibrosis, is a wound healing process characterized by accumulation of extracellular matrix proteins (ECM) especially collagen types I and III, as well as an increase in other extracellular matrix constituents such as proteoglycans, fibronectin and laminin in response to liver injury. Recruitment of leukocytes takes place after the insult and requires several adhesion molecules. Monocytes and macrophages are involved in inflammatory actions by producing nitric oxide and inflammatory cytokines. As a consequence of chronic tissue damage stellate cells (SC) as well as extracellular matrix producting cells, undergo a process of activation characterized by proliferation, motility, contractility, and synthesis of extracellular matrix. Activation of SC is regulated by several soluble factors, including cytokines, chemokines, growth factors, and products of oxidative stress. TGF - b and IL- 6 are the two main fibrogenic cytokines. Potential regulatory factors of the activation of SC are important targets for future antifibrogenic treatments.
Therapy of chronic HCV infection has greatly improved in recent years with the addition of ribavirin to alpha interferon and has further improved more with the use of PEG-interferons. However, more than half of patients do not achieve lasting benefits from these therapies. The future therapeutic developments may include one or more of the following approaches: understanding the HCV genomic organization, elucidating the viral life cycle and HCV replication strategy and understanding the immune mechanisms required for viral propagation or infectivity. The development of novel antiviral strategies and a preventive vaccine against HCV infection remains a major challenge for the future, and will depend on progress on both molecular biology as well as clinical studies. Unfortunately, the low replication of the virus in culture, the lack of convenient animal models, and the high genome variability present mayor challenges for drug development.
FAP is an autosomal dominant inherited disease, characterized by systemic deposition of amyloid fibrils in various tissues. The purpose of this study is to describe the gross and microscopic findings of the explanted livers for FAP. 10 patients were transplanted for FAP at our institution. Diagnosis was supported by positive familiar history, clinical data and detection of mutated TTR by electrospray ionization mass spectrometry with Val30Met mutation verified by PCR. All the explanted livers were photographed, fixed in formol and processed according to protocol. Later they were examined with HyE, reticulin, PAS diastasa, Masson trichromic, Congo red with polarised light and immunoreactivity against TTR. The gross aspect was normal. We obtained multiple samples representative of the organ and the hepatic hilium. All of the patients presented with deposits of amyloid substance in the lymph nodes and the nerves of the hepatic hilium These deposits were Congo red positive with a greenish birefringence to polarized light Deposits show immunoreactivity with antihuman TTR. Whereas liver transplantation restores hepatic function in patients with cirrhosis, liver transplantation cures the FAP patient of their genetic defect. Domino transplantation is a procedure in which the index patient receives an organ, while the explanted organ is reused for transplantation into another patient. In conclusion, exclusion of hepatic amyloid deposits which can cause functional alterations in the FAP liver is vital; and is important to study the explanted livers of patients with FAP to confirm the results of the scarce published series.
The purpose of the present work was to study the pharmacokinetics of ketorolac, a poorly metabolized drug, in experimental cirrhosis. Cirrhosis was induced by bile duct ligation (BDL) for four weeks in male Wistar rats. Ketorolac was given intravenously (1 mg/ kg ) or orally (3.2 mg/kg) to control (sham-operated) and BDL-rats. Determination of ketorolac in plasma was carried out by HPLC and estimation of pharmacokinetic parameters was performed by non-compartmental analysis. Indicators of liver damage and liver fibrosis were significantly increased (p < 0.05) in BDL compared to control rats. Experimental cirrhosis did not induce any significant alteration in intravenous ketorolac pharmacokinetics. Volume of distribution, clearance, AUC and t1/2 were similar in BDL and control animals. Notwithstanding, oral ketorolac bioavailability was significantly altered in BDL rats. AUC and Cmax were reduced, while tmax was prolonged, suggesting that both, the extent and the rate of ketorolac absorption were decreased. Results show that liver cirrhosis may result in significant pharmacokinetic alterations, even for poorly bio-transformed drugs, but that alterations may vary with the route of administration. In conclusion, uncritical generalizations on the effect of liver damage on drug kinetics should be avoided and systematic studies for every drug and every route of administration are thus recommended.
Nonalcoholic fatty liver disease (NAFLD) is a medical condition that may progress to end-stage liver disease. The spectrum of NAFLD is wide and ranges from simple fat accumulation in hepatocytes (steatosis), to fat accumulation plus necroinflammatory activity with or without fibrosis (steatohepatitis). In addition, NAFLD is the most common cause of abnormal liver-test results among adults with a prevalence of 13%-23%. This case report is an example of a patient with asymptomatic hypertransaminasemia and severe hepatic steatosis without inflammation in which the diagnosis was made by liver biopsy.