Hepatic Physiology

I. Introduction

A. General description & circulatory supply: The liver is the largest organ in the body and the most important metabolically

1. It weighs 4 to 5 pounds in an average adult

2. It is divided into a smaller left lobe and a larger right lobe

3. On the inferior surface of the right lobe is the gall bladder

4. It is well vascularized and supplied by two sources:

a. Hepatic artery: A branch off of the aorta – 25% blood

b. Hepatic Portal Veins: 75% of blood – Is unusual – Blood drains from the digestive system and comes into the hepatic portal vein and goes to the liver and then to the hepatic vein

B. Functional Overview

1. Metabolic Processes: Major nutrients such as carbohydrates, fats and proteins are processed in the liver after absorption

a. Due to the arrangement of the hepatic portal vein food stuffs are picked up (absorbed) from the body but they don’t go directly through the circulation but go to the liver instead

2. Detoxification: From the waste in the body or ingested waste – All has to be detoxified

3. Synthesis of Plasma Proteins: All the plasma proteins except for gama globulin are synthesized in the liver

4. Storage: Glycogen, fats, vitamins, minerals (iron)

5. Activation of Vitamin D

6. Removal of bacteria, worn out red blood cells, Kupffer cells (part of the reticular epithelial system)

7. Excretion of cholesterol and Bilirubin

8. Produce Bile Salts: Important in fat digestion

9. Alters hormone function: Somatomedins (impede growth hormone)

II. Anatomy

A. Lobule: Donut shaped – 50000-100000 lobules in the body – Constructed around the central vein (hole in the donut)

1. Part of the central vein which leads to the vena cava

2. Cells are arranged like spokes on a wheel surrounds the central vein (in the middle)

B. Microanatomy - See Figure

1. Picture is like a piece of the donut – Hepatic cells are like the spokes on a wheel

2. Circulatory supply from 2 sources: Branch of the hepatic portal vein and above branch of the hepatic artery

a. Both drain into the elongated sinusoids which run between the cords of the cells – Sinusoids is a special name for capillaries

3. Rows of hepatic cells of the liver which are bathed on either side by the sinusoids

4. Bile canalicula: Drain bile out of the liver and into the small intestines – Kupffer cells also

C. Blood Flow

1. Anatomy: Blood into the liver via the hepatic artery à Hepatic portal vein à Sinusoids à Central vein à Drain hepatic vein à Vena cava à Heart
2. Dynamics & Pressures: There is very little resistance to flow through the sinusoids but if you increase the sinusoid resistance it is generally from Cirrhosis because the sinusoids become destroyed and are replaced by scar tissue (connective tissue) – This increases the resistance and increases portal pressure of the hepatic portal vein

a. Edema of the liver usually results because there is an accumulation of fluid as it flows out within the body cavity (there is increased fluid being filtered) – This edema in the body cavity causes a swollen abdomen

b. Due to increased portal resistance the pressure builds up and backs up the hepatic portal vein and the esophageal vein and the result if varicose veins called esophageal veins – These can burst and cause severe hemorrhaging and death

III. Liver - Gall Bladder - Duodenum - Relationships

A. Release of Bile: Hepatocytes continuously to make bile – It goes to the bile canalicula and is drained by the hepatic duct which leads to the cystic duct and then the gall bladder – The bile is stored within the gall bladder – A liter or so a day of bile is secreted but the gall bladder doesn’t hold this much, it reabsorbs water and concentrates the bile into bile salts – The gall bladder contracts and forces the bile into the common bile duct and then into the duodenum and the digestive system – Secretion of bile occurs only at appropriated times like when food is in the small intestines – Bile is not released from the gall bladder all the time – Regulated by two hormones:

1. Cholecystokinin: Mucosal cells of the small intestines produce cholesterol – Released in response to some foods especially fats

a. Fats in the duodenum causes the release of cholesterol – Cholesterol affects the gall bladder and the gall bladder releases bile salts in the duodenum

2. Secretin: Has a role in bile secretion – Not as important

IV. Constituents of Bile: Water is the most important, but phospholipids, bile salts and cholesterol also make up bile

A. Bilirubin - See R. B. C. notes – Waste product from the heme portion
B. Bile Salts

1. Function in Fat Digestion – The chemical structure has a water soluble and a lipid soluble end and because of this is able to provide two important functions

a. Emulsification: When fat globules comes into the intestines it is digested by lipases (which are water soluble) – The ball of fat is attacked by lipases and since the lipases are water soluble they can only attack the fat’s surface so it would take a long time to digest the fat if that was the only way – If fat is pulled apart into little droplets it wouldn’t take as long to digest (increase the surface area) – Lipase can function better because the chemical structure of bile salts emulsify fat into smaller droplets
b. Micelle formation: When fats are digested by pancreatic lipases they are converted from free fatty acids into monoglycerides – The environment of the lumen of the small intestines is an aqueous one – Free fatty acids are not water soluble and they stay where they are digested – If they accumulate the reaction slows down or stops so you need to get rid of the monoglycerides and the fatty acids – Need to be absorbed but it is difficult to transport these in an aqueous environment – Bile salts form Micelles or fat “taxi cabs” – Bile salts have a lipid soluble portion and a water soluble portion – Micelles get together (or huddle) and the center is the lipid soluble portion so monoglycerides and free fatty acids can be dissolved on the inside even though the outside is still water soluble – Can now transport to the intestinal mucosa where the monoglycerides and free fatty acids are absorbed – Micelles go back and pick up more and continue cycle

2. Fate of Bile Salts: A number of bile salts are recycled – Within the ileum of the small intestines bile salts are absorbed and put into the portal circulation and into the liver where they’re used again – 95% of bile salts that are secreted are recycled – 5% are lost in the feces

C. Cholesterol

1. Function: A component of bile but has known function

a. The precursor in the synthesis of bile salts

b. It is important that cholesterol be maintained at an appropriate ratio/concentration

2. Gall Stones: Cholesterol could precipitate out and form gall stones which are found in the gall bladder – They are a combination of cholesterol, Bilirubin, etc., and are insoluble – They get into the cystic duct or the common bile duct and block them - 10-20% of people in the U.S. are affected by gall stones - Treatment:

a. Spincterotomy: Depends where the stone is located – If in the bile duct then put an endoscope in and try to get it and remove it

b. Lithotripsey: Sound waves used to blast the stones (in a tank with water) – Focus the ultrasound and fragment the stone so that it moves along

c. Pharmacological: Actigall dissolves the stones and is used predominantly for cholesterol stones but some stones are bile pigments and this is not helpful for these

d. Could remove the gall bladder in order to remove the stones – Bile will still be produced and will trickle in all the time into the small intestines instead of being regulated

V. Metabolic Functions of the Liver

A. CHO 's

1. Metabolism of monosaccharides: EX: If test blood sugar then would see that it is fairly constant – Plasma glucose levels don’t change a lot and the liver plays a role and acts by metabolism of the monoglycerides – If increased sugars the body absorbs them and they go through the hepatic portal vein and then to the liver – Simple sugars are absorbed by carrier facilitated diffusion and taken into the liver and converted to glucose-6-phosphate almost immediately and then is further processed – Increase the simple sugars and the liver takes it and makes G-6-P and glycogen from it
2. Gluconeogenesis: If you decrease your food intake the plasma glucose levels will remain constant because the liver is involved in gluconeogenesis which is the production of glucose from a non-carbohydrate source – Liver is important an gluconeogenic organ – The liver pursues this pathway to make glucose from a non-carb source
3. Glycogen metabolism: Plasma glucose levels are maintained because of the liver’s role in glycogen metabolism – The liver takes glycogen and makes it into glucose through glycogenolysis

B. Protein Metabolism

1. Plasma Protein Synthesis: All but the gama globulin
2. Transamination: Biochemical reactions where one amino acid is converted into another amino acid – The essential amino acids (don’t have to have in the diet) the liver can make through transamination
3. Urea Synthesis: Important – During the metabolizing of proteins you produce nitrogen and the nitrogen produces ammonia which is very toxic but the liver takes the ammonia and makes urea – Convert it to a less toxic substance which is then taken to the kidneys and excreted

C. Lipid Metabolism

1. Synthesis of lipoproteins: An important function

a. Types

i. Chylomicrons
ii. VLDL's
iii. LDL's and HDL's: Low density lipoprotein and high density density lipoprotein – Involved in the transport of lipids in the blood (aqueous medium) – Attach the lipids to these proteins – LDLs are involved in cholesterol transport from the liver to other organs – HDLs transport cholesterol from organs back to the liver

b. Application in cholesterol biology: Artherosclerosis

i. There is a difference in the function of LDLs and HDLs – LDLs are the bad guys and transport cholesterol to blood vessel walls – HDLs are the good guys

2. Synthesis of cholesterol: Cholesterol important biological molecule – Precursor to bile salts – Involved in the synthesis of Vitamin D and in the synthesis of sex steroids – Some people have too much of it
3. Synthesis of lipoproteins: Phospholipids make up the cell membrane structure
4. Hypolipemic drugs: Drugs decrease the plasma cholesterol levels – These are important drugs used a lot with artherosclerosis

a. Lopid
b. Lipitor: Inhibit cholesterol synthesis and lower plasma cholesterol levels – The 6^th most frequently prescribed drug
c. Zocor: Inhibit cholesterol synthesis and lower plasma cholesterol levels – The 6^th most frequently prescribed drug

VI. Storage by Liver: Vitamin A, D, K, minerals such as iron

VII. Detoxification by Liver

A. Detox of hormones, alcohol, and a number of drugs

B. Drugs are foreign to the body so it tries to destroy them and dosing of medications is important concerning this

C. Enzymes influencing the detoxification of drugs – Are influenced by a number of factors such as: Age (important because of drug dosing and the rate that meds are metabolized in the body because the same dosage that a 30 year old needs may be too much for an 80 year old), cigarette smoking, and the presence of other drugs is also an important factor (drug interactions)

D. EX: The drug (Coumadin) is used to keep blood from clotting and is metabolized in the liver and by the enzyme P450 oxidase – It breaks down Coumadin into metabolites – Phenobarbitol increase P450 oxidase activity - Patient with both Coumadin and Phenobarbitol so in order to keep Coumadin active since Phenobarbitol enhances the rate at which Coumadin is broken down you have to increase the dosage of Coumadin – If the patient is sent home and taken off Phenobarbitol then Coumadin levels would be too high and the patient would bleed

E. Various factors alter the detoxification of the liver

VIII. Modulate Hormone Action: Growth hormone

A. Thyroxin: The thyroid produces a lot of T4 thyroxin but T4 changes to T3 (more potent) – T4 is a prohormone but is broken down or modulated into T3 in the liver

IX. Pathologies

A. Hepatitis: An inflammation of the liver caused by a virus – Has a predominant affect on the liver

1. HAV: Hepatitis A Virus or Infectious Hepatitis – The most common in the U.S. – Transmitted by a fecal-oral route usually in children without good hygiene or in shell fish (feces in the water and contaminate the fish) – Runs its course in a few months

2. HBV: Hepatitis B Virus or Serum Hepatitis: Caused by intimate contact with the body fluids, contaminated body fluids – Also contaminated blood products, transfusion, dirty needles, or sexually transmitted – Involves a longer incubation period and is more serious – Healthcare providers concerned about this kind

3. HCV: Hepatitis C Virus or Non A-Non B: Most commonly transferred by dirty needles, blood transfusion, or may be sexually transmitted

4. HDV: Hepatitis D Virus: Only affect people who’ve had Hepatitis B previously – Hepatitis B and D significantly damage the liver

5. HEV: Hepatitis E Virus: Contaminated food and water and is the most common worldwide but is rare in the U.S. – Is acute in pregnant females and causes fatalities

B. Hemophilia
C. Thrombus & Embolus
D. Disseminated Intravascular Clotting