hepatic physiology

actions of bile acids

(1) Emulsfying and detergent function. They reduce surface tension of fat particles and in conjunction with phospholipids and monoglycerides emulsify the fat particles from food into many minute particles that can be attacked by the lipase enzyme secreted in pancreatic juice → increase hydrophilicity and surface area. (2) Transport or "ferrying" function. Because they are amphipathic (have both hydrophobic and hydrophilic domains), when over a critical concentration, they form micelles. The micelles aid in the transport and absorption of the digested fat end products to and through the intestinal mucosal membrane.

central vein pressure

0mmHg

how long does it take the gallbladder to empty with adequate amounts of fat?

1 hour. The gall bladder then remains contracted, so that hepatic bile is not stored in the gallbladder during digestion

how much cholesterol is secreted into bile

1-2g/day assumed to be a by-product of bile salt formation and secretion Although cholesterol is almost completely insoluble in pure water, in the bile, the bile salts and lecithin combine with it to form soluble micelles

portal venous pressure

10mmHg

how much blood flow does the liver receive

1400-1500 ml/min (70-80% from the portal vein and 20-30% from the hepatic artery.)

what is the max volume of the gallbladder?

30-60ml.

How much hepatic bile is secreted per day?

500-1200 mL

mean hepatic arterial pressure

90mmHg There must be a large pressure drop along the hepatic arterioles as sinusoidal pressure is lower than in the portal vein (hepatic arterioles have high resistance).

enterohepatic circulation

A continual recycling of compounds such as bile acids between the small intestine and the liver.

secretin

A hormone secreted by the small intestine (duodenum) in response to low pH (e.g., from stomach acid). It promotes the release of bicarbonate from the pancreas to act as a buffer.

stage 2 of bile secretion

As the bile flows along the duct system a watery solution of sodium and bicarbonate is added by the epithelial cells (making it alkaline). This second secretion may double the total quantity of bile → this is stimulated by secretin (causes insertion of AQP1 into the apical membrane) Glucose and amino acids are reclaimed in this stage (specific transporters) Glutathione (a tripeptide antioxidant) is broken down to its constituent amino acids which are then reabsorbed.

formation and secretion of bile

Bile is important for fat digestion and excretion of several important waste products like bilirubin and cholesterol.

flow of bile

Bile leaves the liver through right & left hepatic ducts --> fuse to form common hepatic duct which unites with cystic duct --> to form the common bile duct --> united w/ main pancreatic duct --> enters the duodenum at the duodenal papilla --> at orifice is sphincter of Oddi

what helps the sphincter of oddi relax?

CCK peristaltic waves down the common bile duct- bile usually enters the duodenum in squirts which are synchronized with the relaxation phase of the duodenal peristaltic waves

How is bile concentrated?

Concentrated by removal of water (hepatic duct bile is ~ 97% water; gallbladder bile is ~ 89% water) Acidified (hepatic duct bile pH ~ 7.8-8.6; gallbladder bile pH ~ 7.0-7.4)

Bilirubin metabolism and elimination

Haeme is broken down (catalysed by haeme oxygenase) to biliverdin which is then reduced (catalysed by biliverdin reductase) to bilirubin.

enterohepatic circulation of bile

Passive absorption of unconjugated bile acids occurs along the entire small intestine and colon. 90-95% of bile salts are actively absorbed from the terminal ileum in their conjugated form -Apical Na+/bile salt transporter (ASBT) -Sodium independent anion exchanger

Space of Disse

Space between sinusoids and hepatocytes. spaces connect w/ lymphatic vessels in the interlobular septa. b/c of large pores in the endothelium, large plasma proteins can diffuse into the space. Microvilli of hepatocytes extend into this space, allowing proteins and other plasma components from the sinusoids to be absorbed by the hepatocytes.

Liver - Immunity

The Kupffer cells phagocytose bacteria and other foreign material in the sinusoids - reduce the bacterial load reaching the systemic circulation from the portal blood to about 1%. The liver also secretes immunoglobulin A into the intestine

1st stage of bile secretion by liver

The initial portion secreted by the hepatocytes contains lots of bile acids, cholesterol and other organic constituents a. Active secretion of bile acids and various other substances (establishing an osmotic gradient) b. Passive diffusion of water (and other substances) into the canaliculus across the tight junction

liver role in protein metabolism

The liver is critically important for protein metabolism. Death ensues if this function is not carried out for more than a few days. deamination of amino acids formation of urea - removal of ammonia interconversions among the different amino acids and between amino acids and other compounds formation of nonessential amino acids formation of plasma proteins (see below)

Vagal activity

The vagus nerve is responsible for the regulation of internal organ functions, such as digestion, heart rate, and respiratory rate, as well as vasomotor activity, and certain reflex actions, such as coughing, sneezing, swallowing, and vomiting

medical treatment of gallstones?

Ursodeoxycholic acid mechanism: Increases volume of bile Increased [bile acid] in bile makes cholesterol more soluble Reduces secretion of cholesterol into bile

effects of increased systemic venous pressure and shock

When systemic venous pressure rises, the portal venous system dilates and the amount of blood in the liver increases. When arterial blood pressure drops (e.g. in response to haemorrhage), most of the blood in the liver enters the systemic circulation. Meanwhile, constriction of the hepatic arterioles diverts blood away from the liver. In severe shock, hepatic blood flow may be reduced sufficiently to cause patchy necrosis.

biliverdin

a bile pigment produced from hemoglobin breakdown formed in the reticuloendothelial tissues when old red blood cells are destroyed (eg spleen). The globin molecule is split off and the heme is converted to biliverdin. In humans, most biliverdin is rapidly reduced to bilirubin. Note: Heme is a closed tetrapyrrole. In its conversion to bilirubin the iron atom is lost, and the cyclic tetrapyrrole is opened.

adenosine

a nucleoside; a combination of ribose and adenine; serves as a neuromodulator in the brain produced by metabolism at a constant rate. When portal blood flow is reduced, less is washed away and the local accumulation dilates the terminal arterioles and hepatic blood flow is increased.

vasoconstrictor

agent or nerve that narrows the blood vessels happens for both portal vein branches and hepatic artery branches

cholecystagogue

agent that causes gall bladder contraction Main one: cholecystokinin. released when fatty acids and amino acids enter the duodenum. weak contractions are stimulated by the vagus nerve and enteric nervous sys

what is bilirubin bound to in circulation?

albumin can dissociate in liver free bilirubin enters liver cells via organic anion transporting polypeptide, where it is bound to cytoplasmic proteins.

Glycine

amino acid with many impressive health benefits. Your body needs glycine to make important compounds, such as glutathione, creatine and collagen. This amino acid may also protect your liver from alcohol-induced damage and improve sleep quality and heart health. conjugation occurs in liver

factors involved in the formation of gallstones?

bile stasis supersaturation of bile w/ cholesterol nucleation factors (precipitated particles)

Vascular functions of the liver

blood storage and filtration. the liver is very expandable. Normal blood volume 450 ml, can be expanded by 0.5-1 liter in right heart failure liver acts as a reservoir in times of excess blood volume and is capable of supply extra blood in diminished blood volume. destroys old erythrocytes

oxygenation zone 3

cells closest to the central vein - most vulnerable to anoxic injury. drug metabolism, biotransformation

what are gallstones composed of?

cholesterol (85%) or calcium bilirubinate (15%)

intestinal mucosa is relatively impermeable to...

conjugated bilirubin but is permeable to unconjugated bilirubin and urobilinogen (formed by the action of bacteria in the intestine). Thus, some of these are reabsorbed in the portal circulation and are either again excreted by the liver (95%) or excreted in the urine (5%). After exposure to air in urine, urobilinogen is oxidized to urobilin. In feces, it becomes altered to stercobilinogen and oxidized to form stercobilin

Lymph formation

depends on tissue fluid formation Large amounts of lymph form in the liver because the sinusoid endothelium is very permeable The liver forms about half of all the lymph formed in the body under resting conditions. This lymph has a high protein content (6g/100ml), because the pores in the endothelium are so large.

periodic discharge of bile from gallbladder assists w/

digestion but it is not essential. Ppl without gallbladders are still healthy

what happens to the remaining 5-10% of bile salts

enter the colon and are converted to the salts of deoxycholic acid (absorbed) and lithocholic acid (relatively insoluble and only 1% absorbed). absorbed salts are transported back to the liver in the portal vein. Almost totally absorbed on the first passage into hepatocytes (NTCP and OATP) and are re-excreted in bile

liver role in carbohydrate metabolism

especially important for maintaining a normal blood glucose (glucose buffer function) -storage of glycogen -gluconeogenesis -glycogenolysis conversion of galactose and fructose to glucose

Liver synthesis of plasma proteins

essentially all plasma proteins except gamma globulins (i.e. about 90% of plasma proteins) - includes albumin, acute phase proteins, binding proteins (e.g. transferrin) and clotting factors (factors 2, 7, 9, 10 and fibrinogen) - note the liver's role in clotting includes producing the bile salts essential for vitamin K absorption.

how can portal blood flow be reduced?

fasting

functional anatomy of liver

functional units called lobules - hexagon-like structures surrounding central vein - at corners b/n the lobules are portal spaces which contain branch of hepatic artery, portal vein, and bile duct along sinusoids there are Kupffer cells

Where is bile stored and concentrated?

gallbladder until it is needed in the duodenum

How much bile enters the gallbladder during overnight fasting?

half of the hepatic bile. Remained passes into the small intestine. Bile acids are reabsorbed in the ileum and re-secreted.

taurine

helps support nerve growth. It might also benefit people with heart failure by lowering blood pressure and calming the nervous system. conjugation occurs in liver

formation and secretion of bile

hepatic bile. Once it has been concentrated and modified during storage in the gall bladder = gallbladder bile bile is made of bile acids, bile pigments, cholesterol, fatty acids, lecithin, fat, alkaline phosphatase, xenobiotics in alkaline electrolyte solution

oxygenation zone 1

hepatocytes closest to the vascular stalk/portal space - receive the best blood supply. lots of oxidative metabolism and other functions

oxygenation zone 2

intermediate between the zone 1 and 3 - moderately well oxygenated

what happens it bile and cystic duct are closed?

intrabiliary pressure rises to about 320mm of bile in 30 min, and bile secretion stops. However, if the cystic duct is left open, water is reabsorbed in the gallbladder and the intrabiliary pressure rises to only about 100 mm of bile in several hours.

the is a _____ relationship b/n hepatic arterial and portal venous blood flow

inverse. The mechanism for this may be related to the rate of removal of adenosine from around the arterioles

hepatocytes

liver cells; produce bile, absorb and secrete nutrients like glucose, and secrete plasma proteins organized into cellular plates that radiate from the central vein like lil spokes on a wheel. each hepatic plate is 2 cells thick -surrounded by sinusoids and has the bile collecting system at the center

Kupffer cells

liver macrophages

resistance in sinusoids is low or high?

low

NTCP

main uptake transporter for bile acids in hepatocytes

reabsorption in the gallbladder

mainly via active sodium transport followed by secondary absorption of chloride, water etc. Bile is normally concentrated about 5-fold, but it can be concentrated up to 20-fold.

How do ketones affect body?

metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. When ketones build up in the blood, they make it more acidic. They are a warning sign that your diabetes is out of control or that you are getting sick. High levels of ketones can poison the body. When levels get too high, you can develop Diabetic ketadosis

excretion via the bile

of many endogenous (e.g. bilirubin and cholesterol) and foreign organic molecules and trace metals (e.g. copper and calcium)

slight elevations in venous pressure cause

only 3-7mmHg above normal causes excessive lymph formation and "sweating" from the free surface resulting in ascites (fluid filled abominal cavity) When venal caval pressure is 10-15 mmHg above normal, lymph flow can be increased 20-fold

OATP

organic anion transporting polypeptide

liver role in fat metabolism

oxidation of fatty acids production of ketone bodies formation of most of the lipoproteins synthesis of cholesterol and phospholipids conversion of large quantities of carbohydrates and proteins to fat.

liver - inactivation

phase 1 (oxidation or reduction) phase 2 reactions (conjugation)

where does blood in the sinusoids come from?

portal venules and the hepatic arterioles /9which also supply the arterial blood to septal tissue like the biliary duct sys) The hepatic arterioles tend to empty directly into the sinusoids mostly about 1/3 of the distance away from the fibrous septa. Blood in the sinusoids flows in a centripetal direction to reach → the central vein of the lobule. Average transit time in the sinusoids is about 8.4 seconds. From the central vein, the blood empties into the hepatic vein and then into the vena cava

What happens to bilirubin after it enters liver cells?

reacts with one or two uridine diphosphoglucuronic acid molecules (conjugation) to form → bilirubin monoglucuronide or bilirubin diglucuronide in a reaction catalysed by glucuronyl transferase in the smooth endoplasmic reticulum. These glucuronides are more water soluble than free bilirubin. They are then transported (probably actively via MRP-2) into the bile canaliculi. Some escapes into the blood where it is bound loosely to albumin and is excreted in the urine. 80% of bilirubin is conjugated to form bilirubin glucuronide. 10% is bilirubin sulfate, 10% is with many other substances.

bile lost in the stool is

replaced by synthesis in the liver (0.2-0.6g). The total bile salt pool of approx. 3.5 g recycles repeatedly via the enterohepatic circulation twice per meal - 6-8 times per day.

endocrine functions of the liver

secretion of insulin-like growth factor I (IGF-1) contributing to the activation of vitamin D formation of triiodothyronine (T3) from thyoxine (T4) secretion of angiotensinogen metabolism of a number of hormones - e.g. metabolizes oestrogen

bile canaliculi

small ducts between hepatocytes that collect bile lining is formed by specialized regions of hepatocyte cell membrane. canaliculi run b/n adjacent cells and drain into intralobular bile ducts. Bile flow is centrifugal

stellate cells

small star-shaped interneurons located in space of Disse. produce growth factors, store retinoids, produce collaged

what needs to be relaxed in order for the gallbladder to empty?

sphincter of oddi

cholerectics

substances that increase bile secretion. The most important cholerectics are bile salts Their absorption from the intestine inhibits the synthesis of new bile acids, but they themselves are promptly secreted and markedly increase bile flow. choleretic activity of the bile acid molecule is about 7-10 µl/µmol

bile acids

synthesized from cholesterol. 2 primary bile acids: cholic acid and chenodeoxycholic acid. then converted into the secondary bile acids - deoycholic acid and lithocholic acid by the action of bacteria in colon - dehydroxylation at position 7

t or f? There are no vasodilator fibers that reach the liver

t

what happens when enterohepatic circulation is interrupted?

the amount of fat in the stools is increased because the liver cannot increase the rate of bile salt production sufficiently to compensate

why is there a lot of contact b/n blood and hepatocytes?

there are large gaps in the endothelial cells of the sinusoids (some pores are almost 1 µm diameter) most cells are directly adjacent to a sinusoid (capillary that serves as a location for mixing of the oxygen-rich blood from the hepatic artery and the nutrient-rich blood from the portal venules

what happens when bile is excluded from the intestine?

up to 50% of ingested fat appears in the feces. Severe malabsorption of fat soluble vitamins

storage of vitamins in liver

vitamins A, D, and B12 iron glycogen