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  FUNCTIONS OF THE LIVER

Liver perform multiple functions important for survival of human being. These include:

Regulations, Synthesis, and Secretion

Hepatocytes are metabolically active cells They are involved in regulation of various biochemical and metabolic functions and are involved in synthesis of various substances in the body. They take up glucose, minerals, and vitamins from portal and systemic blood and store them. Many important substances such as blood clotting factors, transporter proteins, cholesterol, and bile components are synthesized by the hepatocytes. The hepatocytes also regulate blood levels of substances such as cholesterol and glucose, the liver helps maintain body homeostasis.

Glucose

The liver store glucose when it is in excess after the person has food and release glucose in the blood when he is starving. This is an important function which when impaired during liver disease, result in hypoglycemia (low blood glucose).

Proteins

Most blood proteins (except for antibodies) are synthesized and secreted by the liver. One of the most abundant serum proteins is albumin. Impaired liver function results in decreased serum albumin level. The liver also produces most of the proteins responsible for blood clotting, called coagulation or clotting factors. Hence in severe liver disease, excessive bleeding may result due to lack of these factors.

Bile

Hepatocyte synthesize bile. Bile is a greenish fluid containing cholesterol, phospholipids, bilirubin (a metabolite of red blood cell hemoglobin), and bile salts. It is secreted into biliary ducts. It then leaves the liver to be temporarily stored in the gallbladder before emptying into the small intestine. Bile salts act as "detergents" that aid in the digestion and absorption of dietary fats. Liver damage or obstruction of a bile duct (e.g., gallstone) can lead to cholestasis, (the blockage of bile flow, which causes the malabsorption of dietary fats), steatorrhea (foul-smelling diarrhea caused by non-absorbed fats), and jaundice.

Lipids

Liver synthesizes cholesterol. It is then packaged and distributed to the body or excreted into bile for removal from the body.
Increased cholesterol concentrations in bile may predispose to gallstone formation. The liver also synthesizes lipoproteins. These are made up of cholesterol, triglycerides phospholipids, and proteins.
Lipoproteins transfers cholesterol between the liver and body tissues. Most liver diseases do not significantly affect serum lipid levels. However, cholestatic diseases, may be associated with increased levels.

Storage

As mentioned above, the liver store important substances eg glucose (in the form of glycogen). The fat-soluble vitamins (vitamins A, D, E and K), folate, vitamin B 12 , and minerals such as copper and iron.

Purification, Transformation, and Clearance

The liver removes harmful substances (such as ammonia, toxins, various drugs) from the blood and then breaks them down or transforms them into less harmful compounds.

Ammonia

The liver converts ammonia to urea. Urea is then excreted into the urine by the kidneys. In the presence of severe liver disease, ammonia accumulates in the blood because of both decreased blood clearance and decreased ability to form urea. Elevated ammonia levels can be toxic, especially to the brain, and may lead to the the development of hepatic encephalopathy.

Bilirubin

Bilirubin is a yellow pigment. It is formed as a breakdown product of red blood cell hemoglobin. The spleen, which destroys old red cells, releases ünconjugated" bilirubin into the blood, where it circulates in the blood bound to albumin. The liver takes up bilirubin and "conjugates" it with glucuronic acid to form "water-soluble" bilirubin that can be excreted into bile. Increased production or decreased clearance of bilirubin results in jaundice.

Hormones

Liver plays important roles in hormonal modification and inactivation. chronic liver disease may cause hormonal imbalances. For example, the masculinizing hormone testosterone and the feminizing hormone estrogen are metabolized and inactivated by the liver. Men with cirrhosis, have increased circulating estrogens relative to testosterone derivatives. This may result in testicular atrophy and gynaecomastia.

Drugs

Most drugs are metabolized by the liver. Especially, oral drugs are absorbed in the intestine and then In the liver, drugs may undergo first-pass metabolism, a process in which they are modified, activated, or inactivated before they enter the systemic circulation, or they may be left unchanged.In patients with liver disease, drug detoxification and excretion may be dangerously altered, resulting in drug concentrations that are too low or too high or the production of toxic drug metabolites.

Toxins

The liver is responsible for detoxifying many chemical agents and poisons including alcohol. Liver disease may inhibit or alter detoxification processes and thus increase the toxic effects of these agents. Additionally, exposure to chemicals or toxins such as alcohol may directly affect the liver, ranging from mild dysfunction to severe and life-threatening damage.

Regeneration of the Liver
The liver has a remarkable capacity to regenerate after injury and to adjust its size to match its host. Within a week after partial hepatectomy, which, in typical experimental settings entails surgical removal of two-thirds of the liver, hepatic mass is back essentially to what it was prior to surgery. Some additional interesting observations include: are too low or too high or the production of toxic drug metabolites.

  • In the few cases where baboon livers have been transplanted into people, they quickly grow to the size of a human liver.
  • When the liver from a large dog is transplanted into a small dog, it loses mass until it reaches the size appropriate for a small dog.
  • Hepatocytes or fragments of liver transplanted in extrahepatic locations remain quiescent but begin to proliferate after partial hepatectomy of the host.

These types of observations have prompted considerable research into the mechanisms responsible for hepatic regeneration, because understanding the processes involved will likely assist in treatment of a variety of serious liver diseases and may have important implications for certain types of gene therapy. A majority of this research has been conducted using rats and utilized the model of partial hepatectomy, but a substantial body of confirmatory evidence has accumulated from human subjects.


The Dynamics of Liver Regeneration

Partial hepatectomy leads to proliferation of all populations of cells within the liver, including hepatocytes, biliary epithelial cells and endothelial cells. DNA synthesis is initiated in these cells within 10 to 12 hours after surgery and essentially ceases in about 3 days. Cellular proliferation begins in the periportal region (i.e. around the portal triads) and proceeds toward the centers of lobules. Proliferating hepatocytes initially form clumps, and clumps are soon transformed into classical plates. Similarly, proliferating endothelial cells develop into the type of fenestrated cells typical of those seen in sinusoids.

It appears that hepatocytes have a practically unlimited capacity for proliferation, with full regeneration observed after as many as 12 sequential partial hepatectomies. Clearly the hepatocyte is not a terminally differentiated cell.

Changes in gene expression associated with regeneration are observed within minutes of hepatic resection. An array of transcription factors (NF-kB, STAT3, fos and jun) are rapidly induced and probably participate in orchestrating expression of a group of hepatic mitogens. Proliferating hepatocytes appear to at least partially revert to a fetal phenotype and express markers such as alpha-fetoprotein. Despite what appears to be a massive commitment to proliferation, the regenerating hepatocytes continue to conduct their normal metabolic duties for the host such as support of glucose metabolism.

Stimuli of Hepatic Regeneration

Hepatic regeneration is triggered by the appearance of circulating mitogenic factors. This conclusion was originally supported by experiments demonstrating that quiescent fragments of liver that had been transplanted to extrahepatic sites would begin to proliferate soon after partial hepatectomy, and also that hepatectomy in one of a pair of parabiotic rats led to hepatic proliferation in the other of the pair.

As might be expected, liver regeneration seems to be supported by a group of mitogens and growth factors acting in concert on several cell types. Some of the major and well-studied players that act together in this process include:

  • Hepatocyte growth factor (scatter factor) levels rise to high levels soon after partial hepatectomy. This is the only factor tested that acts by itself as a potent mitogen for isolated hepatocytes cultured in vitro. This factor is also of critical importance in development of the liver, as target deletions of its gene lead to fetal death due to hepatic insufficiency.
  • TNF-alpha, which stimulates proliferation of hepatic endothelial cells.
  • Interleukin-6, which acts as a biliary epithelial mitogen.
  • Epidermal growth factor.
  • Norepinephrine potentiates the mitogenic activity of EGF and HGF.
  • Insulin is required for regeneration but appears to play a permissive rather than mitogenic role.

The processes and signals involved in shutting down the regenerative response are less well studied than those that stimulate it. TGF-beta1, which is known to inhibit proliferative responses in hepatocytes, is one cytokine involved in this process, but undoubtedly several others participate.



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