الفهرس 
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Abstract
The liver is localized in the abdominal cavity between the digestive tract and the spleen. The organ receives double blood supply: most of the total blood is provided by the portal vein bringing nutrient-rich blood from the digestive tract while the hepatic artery delivers blood supplemented with oxygen. Within the liver, the blood passes through a network of micro-vessels, called sinusoids, after which it is collected in the hepatic central veins and finally drained by the inferior vena cava (Wisse et al., 1985). Sinusoids are lined by specialized fenestrated endothelial cells, controlling the flow of materials to and from the space between hepatocytes and endothelial cells (space of Disse) (Braet and Wisse, 2002).
figure (1.1) liver structure and histology
The liver plays a central role in the metabolism of carbohydrates, proteins and fats, besides other substances such as vitamins, and is thereby important for maintaining homeostasis in the body. The liver synthesizes most of the plasma proteins, such as albumin and globulins. Another function of the liver is detoxification of xenobiotic compounds such as pollutants and drugs into water-soluble compounds which then can be excreted either in bile or in urine. Importantly, the liver also eliminates particulate substances such as bacteria and viruses and different kinds of macromolecules from the blood stream (Wisse et al., 1985).
Figure (1.2) lobule cell types
At the microscopic level the liver is anatomically organized in functional units called lobules, built up from the three major liver cell types, the parenchymal cells or hepatocytes, the sinusoidal endothelial cells lining the sinusoids and a fixed macrophage population, called Kupffer cells Figure (1.2). The metabolic functions of the liver are maintained mainly by the parenchymal cells, which represent the major population of cells in the liver. The lobules have a hexagonal shape with the terminal hepatic vein in the centre and the portal triads Figure (1.3) at the corners of the hexagon. Each portal triad consists of a portal vein, a hepatic artery and a common hepatic bile duct. The parenchymal cells are structured in cords that are symmetrically distributed around the central vein and separated by liver sinusoids in which blood flows from portal triads towards the central vein (Wisse et al., 1985).
Figure (1.3) Portal triad
In the space of Disse, a fourth population of cells is localized, the hepatic stellate cells. This population of non-parenchymal cells normally stores vitamin A and is involved in the production of extracellular matrix proteins. Other non-parenchymal cells that can be found in the liver are lymphocytes, including natural killer cells and biliary epithelial cells that line the bile ducts (Wisse et al., 1985).
1.2.Hepatic disorders
1.2.1.Autoimmune liver diseases
Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the three major forms of autoimmune liver disease. The three forms can be classified according to the focus of autoimmune injury, the pattern of inflammation and the clinical phenotype. In AIH, the autoimmune injury affects the hepatocytes, leading to the histological picture of interface hepatitis. In PBC, the autoimmune injury affects the small, interlobular bile ducts, causing the typical appearance of non-suppurative, destructive cholangitis. In PSC, autoimmune or immune-mediated injury affects the medium-sized intra- and extrahepatic bile ducts, causing concentric and obliterative fibrosis and multifocal bile duct structuring. The autoimmune diseases are attributed to the loss of immune tolerance to one self-antigen (such as Cytochrome P4502D6 (CYP2D6) in the case of some models of AIH or Pyruvate dehydrogenase complex (PDC-E2) in PBC) (Carbone et al., 2014).
1.2.2.Alcoholic liver disease
Alcoholic liver disease (ALD) is one of the major chronic liver diseases worldwide. The clinical and histological phases of ALD include alcoholic fatty liver (AFL), alcoholic hepatitis (AH) and alcoholic cirrhosis (AC). Although 90%-95% of heavy drinkers suffer from AFL, only 20%-40% of them develop AH and 8%-20% eventually progress to AC. The amount and duration of alcohol consumption are the two important factors and the risk thresholds vary widely among different races. Patients with AC have a poor prognosis (Xie et al., 2013). ALD begins with the accumulation of lipid droplets in the liver. The consequence of lipid accumulation is the autocatalytic process of lipid peroxidation which has been reported in ALD and in non-alcoholic fatty liver disease (NAFLD). During peroxidation, biogenic derivatives (e.g. hydroxyoctadecadienoic acids – HODEs and hydroxyeicosatetraenoic acids – HETEs), are produced and may act as the mediators of these diseases (Raszeja-Wyszomirska et al., 2012).
1.2.3.Non-Alcoholic fatty liver disease
The term (NAFLD) is used to describe a wide range of liver disorders which, histologically, are very similar to those caused by alcohol. NAFLD develops in patients who do not drink alcohol, or who drink less than 20 g/day, level above which alcohol can cause liver damage. NAFLD has become the most common liver disorder in Western countries and is increasingly being recognized in developing nations. It encompasses a spectrum of pathological processes that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and to cirrhosis (Chalasani et al., 2012).
The pathophysiology of NAFLD is thought to be a two-step process: an accumulation of triglycerides in hepatocytes due to insulin resistance and hepatocyte injury secondary to oxidative stress. Insulin resistance (IR) and obesity are two important factors in the pathogenesis of NAFLD. Both increase the inflow of FFAs to the liver from subcutaneous and visceral fat and “de novo” intrahepatic synthesis of FFAs by overexpressing of lipogenic transcription factors such as - sterol regulatory element bound protein (SREBP-1c) or the bound protein response element to carbohydrates (ChREBP). Activation of SREBP-1c increases malonyl-CoA, which inhibits oxidation of the FFAs, although SREBP-1c inhibits the formation of microsomal triglyceride transfer protein(MTTP) and there may be also a reduction in apolipoprotein B (apoB) synthesis. When the rate of TG synthesis exceeds the capacity for production of VLDL or for exporting them, TG accumulate within the hepatocytes, leading to steatosis, a definitive marker for NAFLD (Brea and Puzo, 2013).
Figure (1.4) Pathophysiology of NAFLD.Influence of insulin resistance in NAFLD (Brea&Puzo 2013). (↑= increased, ↓=decreased)
1.2.4.Viral hepatitis
Viral hepatitis A, B and C remains among the major public health problems in the world with considerable morbidity and mortality, The viral proteins expressed in hepatocytes may influence the severity and progression of liver disease. However, extensive studies suggest that the mechanisms of liver injury in viral hepatitis are due to the host immune responses, but not to the direct cytopathic effects of viruses. The direct killing of infected cells by virus specific CD8+ cytotoxic T lymphocytes (CTLs) is considered as the central mechanism resulting in both liver damage and virus control ((b)Wang et al., 2012).
Viruses can contribute to the development of human cancers by a variety of mechanisms including stimulation of cell proliferation through viral oncogenes or causing cellular injury, insertional mutation, and immunosuppression. Hepato cellular carcinoma (HCC) usually develops after several decades of persistent infection with HBV or HCV (Yu and Chen, 1994).
1.2.5.Hepato cellular carcinoma (HCC)
Tumors of the liver are either primary (arising from.