In hepatic fibrosis

One of the most unusual mechanisms claimed for milk thistle involves an increase in RNA polymerase I activity in nonmalignant hepatocytes but not in hepatoma or other malignant cell lines. By increasing this enzyme s activity, enhanced protein synthesis and cellular regeneration may occur in diseased but not malignant cells. Milk thistle may have a role in hepatic fibrosis. In an animal model of cirrhosis, it reduced collagen accumulation, and in an in vitro model it reduced expression of the profibrogenic cytokine TGF-13. 

C. A. Kawser, J. P. Iredale, P. J. Winwood, and M. J. P. Arthur, Rat hepatic stellate cell expression of alpha 2-macroglobulin is a feature of cellular activation implications for matrix remodelling in hepatic fibrosis, Clin. Sci. 95 179-186 (1998). 

The hepatic stellate (or Ito) cells are fat-storing cells found in the perisinusoidal spaces between the hepatocytes and sinusoids these cells can later become involved in hepatic fibrosis. When hepatic lipid is increased by greater than 5% by weight, the histological changes are described as steatosis, or fatty changes. 

IFN-y exhibits antiviral activity against HBV in vitro (Parvez et al. 2006). In addition, IFN-y was fonnd to rednce hepatic fibrosis by 63% after 9 months, compared to 24% in nntreated controls (Weng et al. 2005). 

Hereditary hemochromatosis is an autosomal recessive disease of increased intestinal iron absorption and deposition in hepatic, cardiac, and pancreatic tissue. Hepatic iron overload results in the development of fibrosis, hepatic scarring, cirrhosis, and hepatocellular carcinoma. Hemochromatosis can also be caused by repeated blood transfusions, but this mechanism rarely leads to cirrhosis. 

Wilson s disease is another autosomal recessive disease leading to cirrhosis. Protein abnormalities result in excessive copper deposition in body tissues. The faulty protein is responsible for facilitating copper excretion in the bile, so copper accumulates in hepatic tissue. High copper levels within hepatocytes are toxic, and fibrosis and cirrhosis may develop in untreated patients. Those with Wilson s disease usually present with symptoms of liver or neurologic disease while still in their teens. 

Kanno K, Tazuma S, Nishioka T, Hyogo H, Chayama K. Angiotensin II participates in hepatic inflammation and fibrosis through MCP-1 expression. Dig Dis Sci 2005 50(5) 942-948. 

Fernandez-Salguero, P., et. al., Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor, Science, 268, 722, 1995. 

When the receptor binding domain is encoded in a small peptide sequence, the peptide hg-and can also be synthesized and conjugated chemically to the carrier protein. This approach was followed in our laboratory by Beljaars et al. for the development of carriers aimed at the hepatic stellate cell, a cell type involved in liver fibrosis [33] (see also Chapter 4). A peptide sequence derived from the receptor binding domains of collagen VI was incorporated into a cyclic peptide homing device, and subsequently conjugated to lysine residues of HSA. This carrier bound selectively to activated hepatic stellate cells and rapidly accumulated in the livers of fibrotic rats. 

Phenolic and antioxidant substances have usually studied in red wines, however, recently, interest has increased in the study of bioactive phenolics in white wines Frega et al. [374] isolated and measured concentration of ethyl caffeoate in Verdicchio white wine by HPLC-tandem-mass spectrometry (HPLC-ESI-MS/MS) and they also determined its effects on hepatic stellate cells and intracellular peroxidation. The resnlts were interesting in the light of other studies demonstrating the relationship between reactive oxygen species, chronic liver injury, and hepatic fibrosis. 

Hall P dela M, Plummer JL, lisley AH, et al. 1990. Hepatic fibrosis and cirrhosis after chronic administration of alcohol and "low-dose" carbon tetrachloride vapor in the rat. Hepatology 13 815-819. 

Intravenous silymarin has been demonstrated to lower mortality from Amanita mushroom poisonings, but this formulation is available only in Europe. Animal studies have demonstrated hepatic protection against alcohol, acetaminophen, and mushroom toxins and protection against hepatic fibrosis with bile duct occlusion. There is also evidence of silybin protecting against cis-platin-induced nephrotoxicity in rats. It is not yet clear whether milk thistle extract offers any renal protection to humans. 

Dessein, A.J., Hillaire, D., Elwali, N.E., Marquet, S., Mohamed-Ali, Q., Mirghani, A., Henri, S., Abdelhameed, A.A., Saeed, O.K., Magzoub, M.M. and Abel, L. (1 999) Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene. American journal of Human Genetics 65, 709-721. 

Possible mechanisms of fenofibrate-induced liver injury include activation of peroxisome proliferation-activator receptors, a hypersensitivity reaction, and immune -mediated injury from cross-reactivity of the drug with autoantigens. The authors referred to six reported cases of hepatic fibrosis attributed to fenofibrate. Raised transaminase activities occur commonly with fenofibrate but are generally transient, reverse on withdrawal, and do not result in long-term injury. Fenofibrate should be withdrawn if higher than normal enzyme activities persist, and a liver biopsy should be considered if liver enzymes do not normalize after withdrawal. 

J. J. Maher and R. F. McGuire, Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo, J. Clin. Invest. 86 1641-1688 (1990). 

M. Ohata, M. Lin, M. Satre, and H. Tsukamoto, Diminished retinoic acid signaling in hepatic stellate cells in cholestatic liver fibrosis, Am. J. Physiol. 272 G589-596... 

Hepatic fibrosis is seen with chronic exposure to hepatoxicants that cause increasing damage to hepatocytes and is part of the wound healing response. Chronic fibrosis leads to severe disruption of the liver architecture by the deposition of extracellular matrix (ECM). Advanced fibrosis disrupts the proper blood flow and results in scarring of the liver that can lead to irreversible liver damage known as cirrhosis. Chronic exposure to the hepatoxins CCI4, monocrotaline, and alcohol are examples of compounds that cause excessive fibrosis. 

It is known that the first aldehyde metabolite of alcohol, acetaldehyde, stimulates collagen transcription in vitro in hepatic fibroblasts and lipocytes [85,86], suggesting a link with alcoholic liver fibrosis in vivo. Chojkier et al. [84] have shown that the lipid-peroxidation product malondialdehyde also increases collagen production 2-3-fold in cultured foetal fibroblasts. The way in which... 

Hepato toxicity Liver, bile duct, and gall bladder. The liver is particularly susceptible to xenobiotics due to its large blood supply and its role in metabolism Steatosis (lipid accumulation in hepatocytes) Chemical hepatitis (inflammation of the liver) Hepatic necrosis (death of the hepatocytes) Hepatic cancer (cancer of the liver) Hepatic cirrhosis (chronic fibrosis) Hypersensitivity (immune reaction resulting in hepatic necrosis)... 

Hepatic stellate cells (HSC) are star-shaped cells with long cytoplasmic extrusions. They were first described over 150 years ago hy von Kupffer, but for many years their function remained a mystery. They are found in the space of Disse adjacent to the overlying endothelium and hepato-cytes, and in the normal liver they represent 5-8% of all liver cells. Under resting conditions HSC store retinoids in numerous vitamin A-rich lipid droplets and are thought to regulate sinusoidal blood flow via contractile intracellular filaments. HSC are the principal cells involved in liver fibrosis, remodelling extracellular matrix and synthesising scar tissue in response to liver injury. 

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