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Transport and Metabolic Functions of the Liver (Functions of the Liver…
Transport and Metabolic Functions of the Liver
Liver is largest gland in the body
The liver
Functional Anatomy
Serve as a filter between blood coming from GIT and blood in the rest of the body
Blood from the intestines and other viscera reach the liver via the portal vein
Blood percolates (filter through a porous substance) in sinusoids between plates of hepatic cells and eventually drains to the hepatic veins, which enter the IVC
During passage through hepatic plates, extensively modified chemically
Bile formed on the other side at each plate, passes to intestine via the hepatic duct
In each hepatic lobule, plates of hepatic cells are usually one cell thick
large gaps occur between the endothelial cells, and plasma is in intimate contact with the cells (space of Disse)
hepatic artery blood also enters sinusoids
Central veins coalesce to form the hepatic veins, which drains into the IVC
Average transit time for blood across the lobule is 8.4s.
Kupffer cells (macrophages) are anchored to the endothelium of sinusoids and project into the lumen
Each liver cell is also opposed to several bile canaliculi, which drain into intralobular bile ducts, which coalesce via interlobular bile ducts to form right and left hepatic duct
Cystic duct drains the gall bladder
Hepatic duct joins the cystic duct to form the common bile duct, which enters the duodenum at the duodenal papilla (surrounded by sphincter of Oddi) along with the pancreatic duct
Sphincter is usually closed, but when gastric contents enter the duodenum, CCK released and gastrointestinal hormone relaxes the sphincter rand makes the gall bladder contract
Walls of extrahepatic biliary ducts and gall bladder contain fibrous tissue and smooth muscle, lined by a layer of columnar cells with scattered mucous glands
In the gallbladder, surface is extensively folded, increasing surface area and gives the interior a honey combed appearance
Cystic duct also folded to form spiral valves, which is believed to increase turbulence of bile as it flows out of the gallbladder, reducing risk of it precipitating and forming gall stones
Hepatic circulation
Intrahepatic branches of hepatic artery and portal vein converge on the sinusoids and drain into the central lobular veins in the liver
Functional unit of liver: acinus
Each acinus is at the end of a vascular stalk containing terminal branches of hepatic veins at the periphery
Zone 1: well oxygenated (closes to hepatic artery and portal vein)
Zone 2: moderately well oxygenated
Zone 3: least well oxygenated, susceptible to anoxic injury
Portal venous pressure: ~10mm Hg, hepatic venous pressure approx 5mm Hg, mean pressure in hepatic artery that converge into sinusoids is 90 mm Hg
pressure in sinusoids is lower than portal venous pressure, so a marked drop occurs along the hepatic arterioles, pressure drop is adjusted so that there is an inverse relationship between hepatic arterial and portal venous blood flow
Maintained in part by rate at which adenosine is removed from the region around arterioles
Adenosine produced by metabolism at a constant rate
When portal flow is reduced, washed away more slowly, local accumulation of adenosine dilates terminal arterioles
between meals, many sinusoids collapse
following a meal, when portal flow to liver increases, reserve sinusoids are recruited
may be impt to prevent fluid loss from highly permeable liver under normal conditions
In diseased state, with increased hepatic pressures, many liters of fluid can accumulate in the peritoneal cavity as ascites
Intrahepatic portal vein radicles have smooth muscles in their walls, innervated by noradrenergic vasoconstrictor nerve fibers reaching the liver via the 3rd and 11th thoracic ventral roots and splanchnic nerves
vasoconstrictor innervation comes from hepatic sympathetic plexus
When systemic venous pressure rises, portal vein radicles dilated passively and amt of blood in the liver increases
In heart failure, hepatic venous congestion may be extreme
When diffuse noradrenergic discharge occurs in response to drop in systemic BP, intrahepatic portal radicles constrict, portal pressure rises, blood flow through liver is brisk, bypassing most of the organ
Most blood in liver enters systemic circulation
Constriction of hepatic arterioles diverts blod from the liver, and constriction of mesenteric arterioles reduces portal inflow
In severe shock, hepatic blood flow may be reduced to such a degree that patchy necrosis of the liver takes place
Functions of the Liver
Metabolism and Detoxification
Plays key roles in carbohydrate metabolism, including glycogen storage, conversion of galactose and fructose to glucose, and gluconeogenesis.
Substrates for these reactions derived from absorption that are transported from the intestine to the liver in portal blood
Liver also play major role in maintaining stability of blood glucose levels in post prandial period, removing excess glucose from blood and returning when needed
glucose buffer reaction
in liver failure, hypoglycemia commonly seen
Liver also contribute to fat metabolism
high rate of fatty acid oxidation to supply energy
Amino acids and two C fragments derived from carbohydrates also converted to fats here
Synthesizes most lipoproteins required by body and preserve cholesterol homeostasis by synthesizing this molecule and also converting excess cholesterol to bile acids
Also detoxify blood
Physical in nature
Bacteria and other particulates trapped in and broken down by strategically located kupffer cells
Remaining reactions are biochemical, mediated in their first stages by large no. of cytochrome P450 enzymes expressed in hepatocytes
Converts xenobiotics and other toxins to inactive, less lipophilic metabolites
Phase I
oxidation, hydroxylation, and other reactions mediated by cytochrome P450s
Phase II
Esterification
Ultimately, metabolites secreted into bile for elimination via GIT
Dispose drugs, metabolism of essentially all steroid h ormones
liver disease can result in apparent overactivity of relevant hormone systems
Synthesis of plasma proteins
Many proteins
Albumin quantitatively most significant, accounts for majority of plasma oncotic pressure
Many are acute-phase proteins, which are synthesized and secreted into plasma on exposure to stressful stimuli
Others transport steroids and other hormones in the plasma
Clotting factors (except factor VIII)
Following blood loss, liver replace plasma proteins in days to weeks
Only major class of plasma proteins not synthesized by liver is immunoglobulins
Bile
Made up of bile acids, bile pigments and other substances dissolved in an alkaline electrolyte solution that resembles pancreatic juice
500mL per day
some are reabsorbed in intestine and excreted again by liver (enterohepatic cycle)
Digestion, absorption of fats, is also major excretory route for lipid-soluble waste products
Glucoronides are bile pigments, bilirubin and biliverdin
responsible for golden yellow colour of bile
Bilirubin metabolism and excretion
Most bilirubin formed in tissues is by break down of hemoglobin
Bilirubin bound to albumin in circulation
Though most are tightly bound, some can dissociate in the liver and free bilirubin enter liver cells via a member of organic anion transporting polypeptide (OATP), and then bound to cytoplasmic proteins
it is next conjugated to glucoronic acid, catalyzed by glucoronyl transferase (primarily in SER)
ea bilirubin react with 2 uridine diphosphoglucuronic acid (UDPGA) to form bilirubin diglucuronide
This salt is more water soluble than free bilirubin, is transported against concentration gradient into bile canaliculi (most) and goes to small intestines via bile ducts
small amount of conjugated bilirubin escapes into blood, bounds less tightly to albumin, excreted in urine (can go through glomerulus)
Total blood plasma bilirubin normally includes free bilirubin and a small amount of conjugated bilirubin
Intestinal mucosa relatively impermeable to conjugated bilirubin, but permeable to unconjugated bilirubin and urobilinogens (derivative of bilirubin formed by action of bacteria in intestine)
thus, some bile pigments and urobilinogens reabsorbed into portal circulation, with some excreted by liver again, while small amts of urobilinogen enter general circulation and are excreted in the urine
Jaundice
free or conjugated bilirubin accumulate in the blood, skin, scleras and mucous membranes turn yellow
usually detectable when total plasma bilirubin >2mg/dL (34umol/L)
Hyperbilirubinemia could be due to
excess production (hemolytic anemia)
Decreased uptake of bilirubin into hepatic cells
Decreased intracellular protein binding or conjugation
Disturbed secretion of conjugated bilirubin into bile canaliculi
Intrahepatic or extrahepatic bile duct obstruction
First 3 will show increase in free bilirubin
will cause bilirubin glucuronide regurgitate back into blood, and predominantly the conjugated bilirubin in plasma is elevated
Other substances conjugated by glucuronyl transferase
Steroids and various drugs
Compete with bilirubin for the enzyme system where present in appreciable amounts
several barbiturates, antihistamines, anticonvulsants etc cause marked proliferation of SER -> increase in hepatic glucuronyl transferase activity
Other substances excreted in bile
Cholesterol and alkaline phosphatase
In jaundice due to intra or extrahepatic obstruction of bile duct, blood level of these two usually rise
Small rise when jaundice is non-obstructive
Adenocortical and other steroid hormones and no. of drugs excreted in bile and subsequently reabosrbed
Ammonia metabolism and excretion
liver critical for ammonia handling in body
Levels must be carefully controlled because it can be toxic to CNS, and freely permeable across BBB.
Liver is the only organ with the complete urea cycle, converting circulating ammonia into urea which can then be excreted in urine
ammonia in circulation comes primarily from colon and kidneys with lesser amounts deriving from breakdown of RBC from metabolism in muscles
As pass through liver, almost all ammonia in circulation is cleared into hepatocytes
Converted in mitochondria to carbamoyl phosphate, which reacts with ornithine to generate citrulline
A series of cytoplasmic reactions produce arginine, and dehydrated into urea and ornithine, starting the cycle again while urea diffuses back to sinusoidal blood, filtered in kidneys and lost as urine
Biliary system
Bile formation
Contains substances that are actively secreted into it across the canalicular membrane, such as bile acids, phophatidylcholine, conjugated bilirubin, cholesterol and xenobiotics
Each enters bile by means of specific canalicular transporter
active secretion of bile acids believed to be the primary driving force for the initial formation of canalicular bile
As they are osmotically active, canalicular bile is transiently hypertonic, but tight junctions that join adjacent hepatocytes are relatively permeable to a number of substances that allow its entrance through passive diffusion
Water, glucose, calcium, glutathione, amino acids and urea
Phosphatidylcholine that enter bile forms mixed micelles with bile acids and cholesterol
bile acid: Phosphatidylcholine:cholesterol is 10:3:1
deviations may cause cholesterol to precipitate -> gallstones
Bile transferred to progressively larger bile ductules and ducts, where it undergoes modification of its compositions
bile ductule lined by cholangiocytes, specialized columnar epithelial cells with less permeable tight junctions (than hepatocytes) although remain freely permeable to water -> bile remains isotonic
ductules scavenge plasma constituents, like glucose and amino acids, and return them to circulation by active transport
glutathione also hydrolyzed to constituent amino acids by gamma glutamyltranspeptidase (expressed on apical membrane of cholangiocyte)
removal of glucose and a.a. impt to prevent bacterial overgrowth of bile particularly during gallbladder storage
ductule also secrete bicarb in response to secretin in postprandial period, as well as IgA and mucus for protection
Functions of Gall Bladder
Bile flows into gallbladder when sphincter of Oddi is closed (between meals)
In gallbladder, bile concentrated by absorption of water
hepatic bile 97%water, gallbladder bile 89% water
However, as bile acids are micellar solution, micelles simply become larger since osmolarity is a colligative property, bile remains isotonic
Bile becomes less alkaline as sodium ions are exchanged for protons
when bile duct and cystic duct are clamped, intrabiliary pressure rises to about 320 mm of bile in 30 min and bile secretion stops
when bile duct is clamped and cystic duct is opened, water is reabosrbed in the gallbladder and intrabiliary pressure only rises to about 100mm in several hours
Regulation of biliary secretion
when food enters mouth, resistance of sphincter of Oddi decreases under both neural and hormonal influces
Fatty acids and amino acids in duodenum release CCK, cause gallbladder contraction
production of bile increased by stimulation of vagus nerves and by hormone secretin, which increases the water and HCO3- content of bile
Substances that increase secretion of bile are choleretics, with bile acid themselves being the most important physiological choleretics
Effects of cholecystectomy
Period discharge of bile from gallbladder aids digestion but is not essential for it
Cholecystectomized patients maintain good health and nutrition with constant slow discharge of bile into duodenum, although bile duct eventually becomes somewhat dilated, more bile tends to enter duodenum after meals than other times
Can even tolerate fried foods, although they generally must avoid foods that are particularly high in fat content
Visualizing the gallbladder
Ultrasonography of right upper quadrant
Computed tomography (CT)
nuclear cholescintigraphy
Response of gallbladder to CCK can then be observed following intravenous administration of the hormone
Injecting contrast mediafrom endoscope channel maneuvered into sphincter of Oddi (endoscopic retrograde cholangiopancreatography (ERCP)
Also possible to insert small instrument with which to remove gallstone fragments that may be obstructing flow of bile, pancreatic juice or both