Hepatic Inflammation and Fibrosis

After damage or infection, monocytes and KCs in the area detect the damaged cells or infectious agent and respond with release of primary mediators such as TNFa, IL-1 and some IL-6. These cytokines activate the surrounding cells, that respond with a secondary, amplified release of cytokines. This second wave includes large amounts of IL-6, which induce the synthesis of acute phase proteins in hepatocytes and chemoattractants such as IL-8 and MCP-1. These events will then lead to the typical inflammatory reactions. Both IL-1 and TNFa activate the central regulatory protein of many reactions involved in immunity and inflammation, nuclear factor kappa B (NFkB). These cytokines cause dissociation of NFkB from its inhibitor IkB, which makes translocation of NFkB to the nucleus possible. In the nucleus active NFkB induces the transcription of the second wave cytokines (see also Chapter 7 for the molecular mechanisms of cytokine-mediated cell activation). 

Whether liver regeneration will dominate over scar tissue formation depends on many factors, including the nature and the duration of the injury and the genetic background of the individual. It is still unclear at which point liver regeneration is no longer possible and fibroge- 

4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Cells 

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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. 

Isolated cases of chronic paracetamol toxicity have been reported, such as hepatocellular necrosis, hepatic inflammation and fibrosis. These cases occurred in patients taking 2-6 g of paracetamol daily for months... 

Intrahepatic biliary atresia is characterized by a paucity of intrahepatic bile ducts. Jaundice usually appears within the first few days of life. Serum bilirubin is elevated and serum cholesterol may be very high and lead to the formation of xanthomas. The hepatic histology is nonspecific, showing bile duct paucity, giant cells, inflammation, and fibrosis. Survival into adolescence is common, although growth is usually retarded. 

Because there is no evidence of damage to the bile ducts, it was at first assumed that intrahepatic jaundice was caused by kinking of the connection between hepatic cells and the bile ducts, the cholangioles. Inflammation and fibrosis were believed to cause the kinking. This pathogenic interpretation became untenable when jaundice and cholestasis were observed with drugs such as steroids or chlorpromazine without inflammation. 

A cornerstone of the treatment regimen for chronic hepatitis C infection is an alpha interferon (IFN). IFNs are endogenous glycoproteins produced by a variety of cells, usually in response to a viral infection. The mechanism by which IFN acts against the hepatitis C vims is not completely understood. Possible actions include a direct antiviral effect and to a lesser extent, immune system modulation . Immune system modulation by IFN may be important in that decreases in liver inflammation and fibrosis are considered to be long-term goals in the disease s management. 

Liver biopsy Mild inflammation and minimal fibrosis (grade 1, stage 1 disease) that is consistent with chronic hepatitis C... 

The incidence of liver complications associated with PN ranges from approximately 7% to 84%, and end-stage liver disease develops in as many as 15% to 40% of adult patients on long-term PN.35 Patients often develop a mild increase in liver enzymes within 1 to 2 weeks of initiating PN, but this generally resolves when PN is discontinued. Severe liver complications include hepatic steatosis (fat deposition in liver), steatohepatitis (a severe form of liver disease characterized by hepatic inflammation that may progress rapidly to liver fibrosis and cirrhosis), cholestasis, and cholelithiasis.35... 

Steatohepatitis A severe form of liver disease caused by fat deposition in the liver, characterized by hepatic inflammation that may rapidly progress to liver fibrosis and cirrhosis. 

Another drug that has been found to have anticytokine activity is pentoxifylline. It was initially characterized as a haemorheologic agent for the treatment of peripheral vascular diseases [141]. In addition, it was also found to be capable of inhibiting the pro-inflammatory actions of IL-1 and TNEa on neutrophil function and cytokine production by monocytic cells [142]. Its mechanism of action is the inhibition of phosphodiesterases, leading to increased intracellular levels of cyclic adenosine monophosphate [143]. Besides its effects on the cytokine network, pentoxifylline also exerted an anti-fibrogenic action in cultures of fibroblasts and in animal models of fibrosis [144] and could therefore be an attractive candidate for targeting hepatic inflammation. 

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)... 

Three adolescents taking therapeutic doses of minocycline for 12-20 months met the 1993 International Autoimmune Hepatitis Group criteria for autoimmune hepatitis. All had hypogammaglobulinemia and positive antinuclear antibody and antismooth muscle antibody titers. Two underwent liver biopsy that showed severe chronic lymphoplasmocytic inflammation, necrosis, and fibrosis. All other causes of liver disease were excluded. One patient had resolution of symptoms after withdrawal of the drug, while two required immunosuppressive therapy. 

Liver disease, autoimmune. Diseases caused by autoimmune-mediated inflammation and/or fibrosis autoimmune hepatitis, -primary biliary cirrhosis, and primary sclerosing cholangitis. 

Flisiak et al. (F4) proposed that plasma TIMP-1 and TGF- might also be useful as noninvasive biomarkers of liver fibrosis in patients with chronic hepatitis B and C. Boeker et al. (B8) reported that plasma values of both TIMP-1 and MMP-2 were useful indicators of increasing fibrosis in patients with chronic hepatitis C. Serum TIMP-1 levels correlated with the degree of hepatic fibrosis and inflammation. Serum MMP-1 levels were reported to be decreased in patients with postoperative biliary atresia TIMP-1/-2 levels were not aifected (K6). Koulentaki et al. (KIO) reported that the concentrations of MMP-1,-2,-3, and-9 were significantly decreased in the sera of patients with acute hepatitis B. These authors proposed that the decreased... 

It should also be kept in mind that in many instances (as with viral hepatitis and nonalcoholic steatohepatitis (NASH)), inflammation and/or fibrosis is a predisposing factor and it is feasible that incorporating such facets into xenograft models may result in a closer parallel to human HCC (Bakiri and Wagner, 2013). 

Liver Fibrosis Liver fibrosis is a common end result of inflammation and/or necrosis. While the liver does have considerable regenerative capabilities, cytokine release associated with the inflammatory/necrotic process can lead to fibrosis that can have a deleterious effect on hepatic function, not only from the aspect of decreased hepatic functional mass but also from the standpoint of compromising blood supply. Animal models of hepatic fibrosis would be valuable from the standpoint of facilitating the development of noninvasive biomarkers as well as development of interventional agents. 

Surgical models also exit for evaluation of hepatic fibrosis. The most common method employed is ligation of the common bile duct in rats or mice. The subsequent response involves not only fibrosis but also proliferation of biliary epithelial cells, oval cells, portal inflammation, and, of course, cholestasis. With time, there is progression to biliary cirrhosis and hepatic failure. Relatively high mortality... 

Prealbumin (trans- thyretin) 2-3 Binds triiodothyronine and to a lesser extent thyroxine carrier for retinolbinding protein Kidney dysfunction Cirrhosis, hepatitis, stress, inflammation, surgery, hyperthyroidism, cystic fibrosis, kidney dysfunction, zinc deficiency... 

A 49-year-old woman developed jaundice after taking pioglitazone 30 mg/day for 6 weeks, and after 3 weeks the alanine transaminase was 131 U/l and aspartate transaminase 79 U/l (106). Tests for viral hepatitis were negative. A liver biopsy showed marked portal edema, patchy chronic inflammation, a cellular infiltrate, and marked bile duct proliferation. There was no fibrosis. The laboratory results worsened after pioglitazone was withdrawn, and 1 month after withdrawal the bilirubin reached a peak of 585 pmol/1. Over the next 8 weeks the symptoms and laboratory tests improved, and after 6 months her condition was the same as when she had started to take pioglitazone. 

Injury to the hepatocytes, for example by hepatotoxins or viruses, will result in hepatocellular damage. This generally manifests itself as fatty infiltration (steatosis), inflammation (hepatitis) or cell death (necrosis). If the assault is mild and remits, the liver will recover and overall liver function will remain normal. Snstained injnry causing hepatocyte cell death will, however, nltimately lead to fibrosis and cirrhosis and potentially severe liver dysfimction. 

This occurs typically in alcoholic steatosis. Macrovesicular steatosis has less effect on the function of the hepatocyte and liver function tests are usually only minimally abnormal. The accumulation of fat within the hepatocyte may trigger an inflammatory response this inflammation within the hepatocyte, or hepatitis related to steatosis, is termed steatohepatitis. Continued inflammatory responses further damage hepatocytes, and the liver disease may then progress to fibrosis and cirrhosis. 

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