Hepatic injury in chronic iron overload. Role of lipid peroxidation

In both hereditary hemochromatosis and in the various forms of secondary hemochromatosis, there is a pathologic expansion of body iron stores due mainly to an increase in absorption of dietary iron. Excess deposition of iron in the parenchymal tissues of several organs (e.g. liver, heart, pancreas, joints, endocrine glands) results in cell injury and functional insufficiency. In the liver, the major pathological manifestations of chronic iron overload are fibrosis and ultimately cirrhosis. Evidence for hepatotoxicity due to iron has been provided by several clinical studies, however the specific pathophysiologic mechanisms for hepatocellular injury and hepatic fibrosis in chronic iron overload are poorly understood. The postulated mechanisms of liver injury in chronic iron overload include (a) increased lysosomal membrane fragility, perhaps mediated by iron-induced lipid peroxidation, (b) peroxidative damage to mitochondria and microsomes resulting in organelle dysfunction, (c) a direct effect of iron on collagen biosynthesis and (d) a combination of all of the above.     

Computational experiments reveal plausible mechanisms for changing patterns of hepatic zonation of xenobiotic clearance and hepatotoxicity

No concrete, causal, mechanistic theory is available to explain how different hepatic zonation patterns of P450 isozyme levels and hepatotoxicity emerge following dosing with different compounds. We used the synthetic method of modeling and simulation to discover, explore, and experimentally challenge concrete mechanisms that show how and why biomimetic zonation patterns can emerge and change within agent-based analogues, expecting that those mechanisms may have counterparts in rats. Mobile objects map to compounds. One analogue represents a cross-section through a lobule. It is comprised of 460 identical, quasi-autonomous functional units called sinusoidal segments (SSs). SSs detect and respond to compound-generated response signals and the local level of an endogenous gradient. Each SS adapts by using those signals to adjust (or not) the probability that it will clear a detected compound during the next simulation cycle. The adjustment decision is based on the value of a biomimetic algorithm that is based on an assumed, evolution imposed, genetic mandate that normal hepatocytes resist increasing the cost of their actions. The algorithm estimates the long-term, discounted cost to a given SS of continuing to use its current clearance effort. Upon compound exposure, lobular analogues developed a variety of clearance and hepatotoxicity patterns that were strikingly similar to those reported in the literature. A degree of quantitative validation was achieved against data on hepatic zonation of CYP1A2 mRNA expression caused by three different doses of TCDD (2,3,7,8-tetracholorodibenzo-p-dioxone).     

Toxic hepatitis induced by a herbal medicine: Tinospora crispa

Herbal remedies are becoming increasingly popular in many countries. Tinospora species (Menispermaceae) is commonly used as a herbal medicine in South Asia, but very few toxic effects have been described. We report a case of acute hepatitis associated with chronic use of high doses of Tinospora crispa.A 49-year-old male with chronic low back pain bought a herbal medicine at a market in Vietnam that was supposed to be Tinospora crispa, and started to take 10 pellets per day. He had no medical history and did not take any other drugs or toxins. Four weeks later; he developed dark urine and pale stools, associated with asthenia and right hypochondrial pain. Two months after starting treatment, he was referred to the hepatology department with jaundice. Blood tests showed aspartate aminotransferase: 1.169 IU/l, alanine aminotransferase: 2.029 IU/l, total bilirubin: 20.47 mg/dl, direct bilirubin: 13.29 mg/dl, and γ-glutamyltransferase: 243 IU/l. Viral and autoimmune hepatitis were eliminated. Upper abdominal ultrasound was normal. Histopathological findings were consistent with a toxic reaction. The herbal medicine was stopped on admission and the patient fully recovered without treatment, with normal liver function 2 months after the acute episode. Tinospora crispa was clearly identified in the pellets by microscopic analysis of the botanical characters combined with chromatographic fingerprints.The use of herbal medicines containing Tinospora crispa can induce toxic hepatitis. Recovery can be complete after discontinuation. This case highlights the risk associated with traditional herbal remedies.     

Serum bile acids as a sensitive biological marker for evaluating hepatic effects of organic solvents

Serum bile acids (SBAs) are suggested as a potentially sensitive and specific indicator of liver function which, accordingly, could provide an early indication of hepatobiliary dysfunction. This offers advantages over more traditional parameters of liver integrity/function. Recent studies have shown that occupational exposure to low levels of halogenated aliphatic or non-halogenated aromatic solvents is associated with significant increases in SBA levels. As this has often been evident in the absence of any effect on conventional parameters of hepatobiliary integrity/function, elevated SBA levels may well be regarded as a sensitive biological marker of exposure/effect of these compounds. In addition, it may be considered that they provide an early indicator of solvent-induced changes in hepatobiliary function. Extensive studies with experimental animals have also provided supporting evidence for these observations in solvent-exposed individuals. Investigations of the mechanisms at cellular and subcellular levels by which these increases occur have suggested that these effects are likely to be the result of selective, dose-related and reversible inhibition of bile acid uptake at the sinusoidal domain of the hepatocyte plasma membrane. Increased concentrations of SBA under low levels of exposure to different solvents have been demonstrated to be a short-lived and reversible effect which is not accompanied by any other evidence of liver damage. Therefore, it could be assumed that it is unlikely that there would be pathological sequelae to these effects, although the longer term ramifications of such effects have not been thoroughly investigated. Nevertheless, the available evidence indicates that investigation of SBA in solvent-exposed workers could provide useful indications of exposure and effect.     

Dogma driven science, the need to establish a common base line

This commentary examines hepatotoxicity and drug-drug interactions in terms of quoted epidemiology and, the compounds and concentrations used its relationship to the screen being proposed and asks if we have a common ground for validation.