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2. Review of literature
2.1. Liver overview
2.1.1. Liver anatomy and physiology
The liver is considered to be the largest organ in the human body whose weight ranges from 1200 – 1500g and is located in the upper right portion of the abdominal cavity and is closely associated with the small intestine. It consists of two anatomical lobes where the right lobe is about six times larger than the left one. Lesser segments of the right lobe are the caudate lobe on the posterior surface and the quadrate lobe on the inferior surface. The right and left lobes are separated anteriorly by a fold of peritoneum called the falciform ligament, posteriorly by the fissure for the ligamentum venosum and inferiorly by the fissure for the ligamentum teres CITATION sag l 1033 (Plaats, 2005) CITATION JAM11 l 1033 (Dooley, Lok, Burroughs, & Heathcote, 2011).

Fig. (1): Anterior and posterior views of the human liver
The functional tissue of the liver (parenchyma) is composed of at least seven distinct types of cells : hepatocytes, cholangiocytes, sinusoidal endothelial cells, macrophages, lymphocytes of several different phenotypes, dendritic cells, and stellate cells(Ito cells), all arranged in a matrix that mediates their interaction CITATION Irw09 l 1033 (Arias, et al., 2009). Hepatocytes are polygonal in shape and approximately 30µm in diameter. They comprise about 60-70% of the normal liver parenchyma. During fetal period, hepatocytes are characterized by their highly proliferative capacity. In the adult liver, they are generally quiescent although they are capable of regeneration in response to hepatocyte loss CITATION Dhi09 l 1033 (Haridass, et al., 2009). They contain a high percentage of endoplasmic reticulum as well as enormous number of mitochondria per cell which makes this cell fitted for their regenerative potential CITATION Mal05 l 1033 (Malarkey, Johnson, Ryan, Boorman, & Maronpot, 2005).
Almost all blood that enters the liver passes via the portal tract, (a vessel originates from the gastrointestinal tract as well as from the spleen), pancreas and gallbladder. A second blood supply to the liver comes from the hepatic artery, branching directly from the celiac trunk and descending aorta. The portal vein supplies venous blood with low O2 content to the liver, on the other hand, blood from the hepatic artery which originates directly from the aorta is saturated with O2. Blood from both vessels then joins in the capillary bed of the liver and leaves via central veins to the inferior caval vein CITATION sag l 1033 (Plaats, 2005).

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Sinusoids are low pressure vascular channels that receive blood from terminal branches of the hepatic artery and portal vein at the periphery of lobules and deliver it into central veins. They are aligned in a radial form in the lobule and hepatocytes are separated from them by the space of Disse (perisinusoidal space). The sinusoid is the home of non-parenchymal cells which include: 1. Fenestrated sinusoidal endothelial cells, which form the sinusoid lining that is in contact with the blood, 2. Phagocytic Kupffer cells, which adhere on the luminal aspect, 3. Hepatic stellate cells, specialized pericytes that extend processes throughout the space of Disse and serve as myofibroblasts during times of hepatic injury and repair and finally 4. Pit cells, which are immune-reactive natural killer (NK) cells that are attached to the abluminal surface of the sinusoid and are part of a population of liver-associated lymphocytes CITATION San17 l 1033 (Sanyal, Boyer, Terrault, & Lindor, 2017). Circulating proteins and plasma components migrate through these lining cells into the perisinusoidal space where direct contact with the hepatocytes occurs and uptake of nutrients and oxygen occurs. Bile canaliculi are minute channels between adjacent hepatocytes that deliver bile into bile ductules in the portal area. The bile is kept apart from the blood and the space of Disse. CITATION sag l 1033 (Plaats, 2005).

Hepatic stellate cells (HSC), also known as perisinusoidal cells are pericytes found in the  HYPERLINK “https://en.wikipedia.org/wiki/Space_of_Disse” o “Space of Disse” perisinusoidal space of the liver . The stellate cell is the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage.The body of HSC contains lipid droplets which stores vitamin A. CITATION Win07 l 1033 (Winau, et al., 2007).

Fig. (2): Illustration of part of a mammalian liver lobule by U. Frevert, S. Engelmann, S. Zougbédé, J.Stange, B. Ng, et al., 2005; based on the research article “Intravital Observation of Plasmodium berghei Sporozoite Infection of the Liver”, PLoS Biology, doi:10.1371/journal.pbio.0030192.g011.

Or Diagram showing main cell types of Liver-hepatocytes, endothelial cells, Kupffer cells and Stellate cells. Source: Tissupath specialist pathway services, Retrieved 2017. www. Tissupath.com.au
2.1.2. Liver functions
Cells in the mature liver must perform their role in a coordinated manner for the liver to function properly. Proper liver function is essential for maintaining metabolic homeostasis in mammals. Surprisingly, about 500 separate biochemical processes takes place within one single liver cell. CITATION sag l 1033 (Plaats, 2005). Many organs have a ‘functional unit’ that is defined as the smallest section of the organ that can carry out the basic function of that organ. The liver is divided into ‘classical’ lobules with a central venule in the middle, and in some of the corners of the polygon (typically drawn as a hexagon) surrounding this is a ‘portal triad’ containing branches of the portal vein and the hepatic artery, and a bile duct CITATION Sar09 l 1033 (Sargent, 2009)(Figure.3).

Fig.(3):The structure of the liver’s functional units or lobules. Blood enters the lobules through branches of the portal vein and hepatic artery proper, then flows through sinusoids and leaves via branches of the hepatic vein. Source: Anatomy ; Physiology, Connexions Web site,2013.

Liver performs numerous functions includes:
2.1.2.1. Metabolic functions
The liver has an essential role in the metabolism of carbohydrate, fat, proteins and in detoxification of toxic substancesCITATION Par97 l 1033 (Chandrasoma ; Taylor, 2001)2.1.2.1.1. Carbohydrate metabolism
The liver contributes to maintenance of the physiological blood glucose concentrations as it releases glucose when blood levels are low (hypoglycemia) and takes it up when supply is plentiful (hyperglycemia); a situation regulated by the interplay between insulin and its antagonists. Added to that, glucose is also stored within hepatocytes in the form of glycogen (glycogenesis). Glycogen is readily broken down into glucose (glycogenolysis)CITATION Kun l 1033 (Kuntz ; Kuntz, 2009). During fasting about 11% of glycogen stores are used each hour. After a few hours, the liver increasingly turns to gluconeogenesis to supply glucose. This is the production of new glucose from non-carbohydrates, mainly lactate, amino acids and glycerol (not fatty acids). CITATION Sar09 l 1033 (Sargent, 2009). When there is a glucose deficiency, the liver metabolizes fatty acids to form keton bodies, which represent an alternative energy source for many tissues CITATION Kru99 l 1033 (Kruszynska, 1999).

2.1.2.1.2. Fat metabolism
The liver plays an essential role in the digestion of dietary fats. It produces bile salts which are essential to emulsify fat substances within the gut. Almost all fats in the diet are absorbed from the intestines into the lymphatic system. The fats are broken down into monoglycerides and fatty acids that are absorbed into the intestinal epithelial cells and then enter the lymphatic system as tiny, dispersed particles called chylomicrons. Therefore, functions of the liver in the metabolism of fat can be summarized as, uptake and oxidation of fatty acids to supply energy, synthesis of cholesterol, phospholipids and lipoproteins as well as conversion of proteins and carbohydrates into fats. CITATION Sar09 l 1033 (Sargent, 2009)CITATION Can07 l 1033 (Canbay, Bechmann, ; Gerken, 2007).

2.1.2.1.3. Protein metabolism
The liver participates in protein metabolism in many different aspects such as deamination and transamination of amino acids, followed by conversion of the non-nitrogenous part of those molecules to glucose or lipids. Moreover, it is responsible for synthesis of non-essential amino acids. Several of the enzymes involved in these previous pathways (for example, alanine and aspartate aminotransferases) are commonly produced by the liver and are assayed in serum to assess liver damage. Additionally, ammonia, the highly toxic substance which has harmful effects on the body if accumulates, is removed by the liver in the form of urea. Albumin and other plasma proteins are essentially synthesized within hepatocytes CITATION Ber02 l 1033 (Berg, Tymoczko, ; Stryer, 2002).
2.1.2.2. Synthesis of clotting factors
Also, the liver produces many of the clotting factors necessary for blood coagulation and their inhibitors CITATION Ami02 l 1033 (Amitrano, Guardascione, Brancaccio, ; Balzano, 2002). Clotting factors are protein in nature. They include coagulation factors I (fibrinogen), II (prothrombin), V, VII, VIII, IX, X, XI, XIII, as well as protein C, protein S and antithrombin. The liver is a major site of production for thrombopoietin, a glycoprotein hormone that regulates the production of platelets by the bone marrow CITATION Jel01 l 1033 (Jelkmann, 2001).

2.1.2.3. Detoxification function and drug processing
According to CITATION Kun l 1033 (Kuntz ; Kuntz, 2009), removal of endogenous and exogenous substances from the body is necessary as long as they are not serviceable in energy production, not needed for the maintenance of structure, or cannot be stored without causing detrimental effects on the body. As a result, xenobiotics (foreign bodies) and harmful substances must be broken down and/or detoxified then converted to a water-soluble state in order to be excreted in the stool or urine. The liver is considered to be the principle organ for the detoxification processes of the injurious nitrogenous compounds derived from the intestine and many drugs and chemicalsCITATION Par97 l 1033 (Chandrasoma ; Taylor, 2001).

2.1.2.4. Exocrine function
Approximately about 500 mL of bile is secreted daily by the liver. It consists mainly of water, inorganic electrolytes as well as organic solutes such as bile salts which have a detergent-like effect in the gut lumen, emulsifying dietary fat in order to facilitate its digestion. Bile is continuously secreted by hepatocytes into biliary canaliculi. Between meals contraction of the sphincter of Oddi causes bile to accumulate in the gallbladder where the bile salts are concentrated CITATION Sar09 l 1033 (Sargent, 2009).

2.1.3. Liver diseases
Liver diseases affect the normal functions of the liver. Liver capacity for regeneration following a single damage is excellent. A hepactectomy may involve the removal of two thirds of the liver, but the remaining hepatocytes can reproliferate to restore the mass of the organ within days to weeks CITATION Gua06 l 1033 (Guangsheng ; Steer, 2006).

2.1.3.1. Acute vs. chronic liver diseases (?????)
An acute illness is one that lasts less than six months while a chronic illness lasts more than six months. A patient with a chronic liver disease may have few or no symptoms for some time, until the disease worsens and symptoms suddenly become apparent. In some viral infections, an individual suddenly becomes ill and displays a variety of symptoms, such as chills, fever and vomiting. Although some viral infections can be serious, even deadly, the infection usually runs a swift course, and the patient recovers within a few days. The possibility of the acute liver disease to turn chronic is still present, however it often depends on the causative agent. Hepatitis A and hepatitis E, for example, never turn chronic; the vast majority of hepatitis C cases, however, do become chronic. When a patient is suffering from acute liver disease, the goal is to cure the patient and keep the disease from becoming chronic. In contrast, the onset of the chronic disease is often less clear and more insidious than that of an acute illness. Hepatitis C, for example, usually displays no obvious early symptoms. Most individuals infected with hepatitis C are not even aware that they have become infected. It can last alifetime unless the individual receives medical treatment, and even then only half the patients manage to eliminate the virus from their bodies. With chronic disease, the goal is to cure the disease if possible, to keep it from becoming worse, or to control the complications that may occur. In the case of liver disease, that means keeping the disease from progressing to cirrhosis, in which the scarring is so extensive that the liver becomes distorted and often develops cancer. If cirrhosis is already present, the goal of treatment is to prevent further deterioration of liver function and to control the complications CITATION Jam06 l 1033 (Chow ; Chow, 2006).

2.1.3.2. Liver inflammation (Hepatitis)
Hepatitis refers to an inflammatory condition of the liver which has multiple causes. It’s commonly triggered by a viral infection however, autoimmune hepatitis and hepatitis that occurs as a secondary result of medications, drugs, toxins, and alcohol are also taken into consideration. It is characterized by the presence of inflammatory infiltrates in the tissue of the organ CITATION Tin l 1033 (Lee & Dienstag, 2015).

2.1.3.2.1. Viral hepatitis
Viral hepatitis is the most common type of hepatitis worldwide where the liver undergoes inflammatory conditions due to a viral infection. Viral hepatitis is caused by five different viruses (hepatitis A, B, C, D, and E). Both hepatitis A and hepatitis E behave similarly and share the same etiology which is ingesting food or water contaminated by feces from a person infected with the virus. The latter viral infections are more common in developing countries, and do not turn to chronic hepatitis CITATION Kum15 l 1033 (Kumar, Abbas, & Aster, 2015).

Hepatitis B, hepatitis C, and hepatitis D are transmitted when blood or mucus membranes are exposed to infected blood and body fluids, such as semen and vaginal secretions. Hepatitis B and C can present either acutely or chronically. Hepatitis D is a defective virus that requires hepatitis B to replicate and is only found with hepatitis B co-infection CITATION Mys18 l 1033 (Mysore & Leung, 2018). In adults, hepatitis B infection is most commonly self-limiting, with less than 5% progressing to chronic state, and 20 to 30% of those chronically infected developing cirrhosis and/or liver cancer. However, infection in infants and children frequently leads to chronic infection CITATION Eug11 l 1033 (Schiff, Maddrey, & Sorrell, 2011).

2.1.3.2.2. Alcoholic hepatitis
Alcoholic liver disease (ALD) is one of the most widespread liver diseases which occurs as a result of excessive alcohol consumption and it is usually associated with fatty liver, an early stage of ALD that may lead to the progression of fibrosis and end upwith cirrhosis making ALD a major cause of mortality CITATION Tor15 l 1033 (Torok, 2015). Alcohol abuse negatively affects all organs within the body especially the liver being the body’s first line of defense against toxins. Liver metabolizes any ingested alcohol into less toxic by-products, and converts fat-soluble substances into water-soluble substances for elimination CITATION Jam06 l 1033 (Chow ; Chow, 2006).

2.1.3.2.3. Drug-induced hepatitis
Drug-induced hepatitis (DIH), also known as toxic hepatitis, is caused by ingesting medications by mouth or by injection CITATION Jam06 l 1033 (Chow ; Chow, 2006). Chemical agents such as medications, industrial toxins and dietary complements that enters the body’s circulation must undergo biotransformation within the liver due to its chief role in the process of detoxification and drug metabolism. Liver injury due to drugs can vary from acute hepatitis to chronic hepatitis to acute liver failure CITATION Tin l 1033 (Lee & Dienstag, 2015). DIH can results in liver inflammation via various mechanisms such as direct cellular damage , disruption of cell metabolism, and causing structural deformationsCITATION Wil03 l 1033 (Lee W. M., 2003) and CITATION Law15 l 1033 (Lawrence & Friedman, 2015).

2.1.3.2.4. Autoimmune hepatitis (AIH)
Autoimmune hepatitis (AIH) is a chronic disease in which the body’s immune system attacks the normal components, or cells, of the liver and causes inflammation and liver damage . It is characterized by hypergammaglobulinemia, autoantibodies detection and interface hepatitis and is considered a serious medical situation that may worsen over time if not treated CITATION Gat15 l 1033 (Gatselis, Zachou, Koukoulis, ; Dalekos, 2015). Autoimmune hepatitis can lead to cirrhosis and liver failure. CITATION Ans11 l 1033 (Lohse ; Mieli-Vergani, 2011).

2.1.3.3. Liver Fibrosis
Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix (ECM) in almost all patients with chronic liver injury CITATION Eug11 l 1033 (Schiff, Maddrey, ; Sorrell, 2011). Undoubtedly, activation of hepatic stellate cells (HSCs) is the crucial event in hepatic fibrosis. These perisinusoidal cells secrete large amounts of matrix proteins in a form of scar tissue in response to an injury. Their mode of action is mediated not only by cytokines and chemokines but also by non-peptide signals such as reactive oxygen species, lipid mediators and prostaglandins CITATION Pin04 l 1033 (Pinzani ; Rombouts, 2004). Hepatic damage that initiates the fibrotic process can be a result of different numerous causes including excessive alcohol abuse, viral hepatitis, drugs, toxins and autoimmune liver disease. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation CITATION Ram05 l 1033 (Bataller ; Brenner, 2005).
2.1.3.4. Liver Cirrhosis
CITATION Sch08 l 1033 (Schuppan ; Afdhal, 2008) defined cirrhosis as the histological development of nodules of regenerating hepatocytes surrounded by dense fibrotic septa formed in response to chronic liver injury. The latter case produces hepatocellular dysfunction, increased intrahepatic resistance to blood flow, which results in hepatic insufficiency, portal hypertension and end stage liver disease CITATION Gin04 l 1033 (Gines, Cardenas, Arroyo, ; Rodes, 2004) CITATION McC l 1033 (McCormick, 2011). The primary causes of hepatic cirrhosis determine its rate of progression, years or decades, and its treatment strategy. For this reason, it can thus be prohibited by proper screening for chronic liver diseases so that a personalized treatment plan can be applied in time CITATION Wie13 l 1033 (Wiegand ; Berg, 2013). Currently, liver transplantation remains the only curative option for a selected group of patients, however, drug therapies that can stop progression to decompensated cirrhosis or even reverse cirrhosis are now being developed CITATION Sch08 l 1033 (Schuppan ; Afdhal, 2008).

2.1.3.5. Hepatocellular carcinoma
Hepatocellular carcinoma (HCC), also called malignant hepatoma, is the most common type of liver cancer and is a growing cause of cancer related mortality. Most cases of HCC are as a result of either a viral hepatitis infection (hepatitis B or C), metabolic toxins such as alcohol or  HYPERLINK “https://en.wikipedia.org/wiki/Aflatoxin” o “Aflatoxin” aflatoxin), conditions like hemochromatosis and alpha 1-antitrypsin deficiency or non-alcoholic steatohepatitis  (NASH) CITATION Kum15 l 1033 (Kumar, Abbas, ; Aster, 2015). Cirrhosis is the most important risk factor for developing HCC and is present in 80% to 90% of individuals. Treatment options for HCC and prognosis are dependent on many factors but especially on tumor size, staging, and extent of liver injury CITATION Wag15 l 1033 (Waghray, Murali, ; Narayanan Menon, 2015).

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