Sunday, November 11, 2012

Liver physiological function


Liver weight about 1.5 kg. Parenchyma consists of 80% of the mass of liver. Sinusoids contain non parenchymal cells like Kupffer cells, stellate cells (vitamin A and fat storing cells, also called Ito cells) and NK cells.

Bile produced by hepatocytes is excreted via specific transporters located in the membrane of biliary canaliculi. The canaliculi are formed by invaginations of smooth basolateral membranes between adjacent hepatocytes. The canaliculi formed between adjacent hepatocytes are continuous with canaliculi of other hepatocytes within the plane of the liver cell plate, and drain into ductules and to major bile duct, thence to common bile duct and gut.

Liver has great capacity to regenerate mainly due to epidermal growth factors (EGF), TGFα, hepatocyte growth factor (HGF).


Carbohydrate metabolism:
 Store sugar as glycogen after feeding and supply glucose during fasting by glycogenolysis.
 During prolonged fasting it supply glucose by gluconeogenesis by non carbohydrate sources like lactate, pyruvate, alanine, glycerol, etc.
 During starvation, the body glucose requirement fails (glucose is spared) and demand is met by production of ketone bodies.
 Liver also uses glucose for energy by glycolysis, CAC or for synthesis as fatty acids and TG.
 Acute renal failure hypoglycemia is seen as liver is unable to maintain adequate glucose level. In chronic renal failure hyperglycemia is seen, likely due to failure to take up glucose adequately.
·         Liver also metabolize other sugars like fructose, galactose and convert them to glucose.

Lipid metabolism:

The liver meets its energy requirement by mitochondrial β-oxidation of short chain fatty acids. The resulting acetyl-CoA enters CAC or forms ketone bodies. Liver also synthesize fatty acids, Triacylglycerols, cholesterol, phospholipids and lipoproteins. During alcohol consumption there is inhibition of fatty acid oxidation this is accompanied by hepatic lipogenesis and contribute to fatty liver (steatosis).

Protein metabolism:

Other than Immunoglobulins all proteins are synthesized in liver. Apart from albumin, transcobalamin II and C-RP all are glycoproteins. Glycation with terminal sialic acid residue prevents proteolysis (fibronectin), affects function (FSH), affects half-life (ceruloplasmin). Desialylated glycoproteins are removed from circulation as liver as receptors for exposed carbohydrate moieties.

Liver excretes nitrogen mainly derived from excess amino acid (either from diet or muscle breakdown), as urea which is excreted by kidney. Aromatic amino acids like phenylalanine, tyrosine and tryptophan are metabolized by liver but branched chain amino acids like Leucine, isoleucine and valine are taken up largely by muscle. The ratio of BCA/AAA is decreased in acute liver failure which can lead to hepatic encephalopathy due to toxic effect of increased concentration of ammonia in brain.

Amino acids first undergo transamination to form glutamate, followed by oxidative deamination with the formation of ammonia (ammonia can be formed from Amines, nucleic acids, bacterial action on urea, or directly from glutamine). The ammonia is fed into the Krebs-Henseleit (urea) cycle and excreted as urea or stored transiently as glutamine (glutamine synthase).

Biotransformation and excretion:

Liver biotransforms exogenous substances like drugs or endogenous substances like lipid soluble compounds and make them water soluble so that they can be easily excreted in urine or bile.

In phase I biotransformation attaches polar group (-OH, -COOH) is attached. This mainly occurs in SER and mediated by mixed function oxidase (cytochrome P450 isoenzymes) that utilize atmospheric oxygen.

Phase II reactions involves conjugation by glucuronyl transferase enzymes, with glucuronic acid, acetyl or methyl radicals or in case of bile acids, with glycine, taurine or sulphate.
An alternative, non oxidative pathway of biotransformation is via glutathione.

Bile secretion:

The constituents of bile are conjugated (glycine and taurine) bile salts, cholesterol, phospholipids mainly lecithin, bilirubin mono and diglucuronides, electrolytes, proteins. Liver is the major site of cholesterol synthesis and its conversion to bile acids. The primary bile acids, cholic and chenodeoxycholic acids are conjugated to either glycine or taurine to form bile salts which enhances their solubility. 

This facilitates their main function of solubilizing both biliary cholesterol and dietary fat. Secondary bile acids, deoxycholic and lithocholic acids are derived from primary bile acids by the action of intestinal bacterial 7α-dehydroxylase. Most of the bile acids are reabsorbed by enterohepatic circulation, conjugated and excreted. Ursodeoxycholate (stereoisomer of chenodeoxycholic acid) is found in trace amount and is called tertiary bile acid. 
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