The liver: an introduction to its function

Question 1

What are the major aspects of the structure of the liver which influence function?

Answer 1

1. Vascular system
2. Biliary tree
3. 3D arrangement of liver cells with the vascular & biliary systems

Question 2

How many lobes has the liver got, and what divides the lobes?

Answer 2

Traditionally divided into 2 primary lobes by the falciform ligament

Question 3

Does each lobe have a blood supply?

Answer 3

Yes

Question 4

What is the green sac in the liver?

Answer 4

Gall bladder delivering bile into the duodenum

Question 5

Describe the blood supply of the liver

Answer 5

• 75% of blood supply from portal vein i.e. blood returning from GI tract
• ~25% from hepatic artery
• Central veins of liver lobules drain into hepatic vein and back to the vena cava

Question 6

What are the 3 cell types in the liver?

Answer 6

The cells of the liver are:

1. Hepatocytes (60%) – perform most metabolic functions
2. Kupffer cells (30%) – type of tissue macrophage
3. Others are liver endothelial cells & stellate cells

Question 7

Describe the function of the 3 cell types

Answer 7

Hepatocytes – perform most metabolic functions of the liver

Endothelial Kupffer cells (aka reticuloendothelial cells – type of macrophage) - phagocytic activity by removing aged/damaged red blood cells, bacteria, viruses and immune complexes

Question 8

How does the livers microstructure support its role?

Answer 8

• Massive surface area for exchange of molecules

* Sophisticated separation of blood from bile.

Question 9

Describe the role of kupffer cells in the protective barrier

Answer 9

• Kupffer cells-found in sinusoids;
Represent approx 80% of all fixed tissue macrophages
and function as mononuclear phagocyte system (MPS)
exposed to blood from gut that contain pathogenic substances.
clear gut-derived endotoxin from portal blood

Question 10

What is bile?

Answer 10

1. Complex fluid = water, electrolytes + mix of organic molecules
2. Organic molecules = bile acids, cholesterol, bilirubin and phospholipids

Question 11

Where does bile come from?

Answer 11

Bile secreted in 2 stages:
 By hepatocytes
• (bile salts, cholesterol & other organic constituents)
 By epithelial cells lining bile ducts
• (large quantity of watery solution of Na+ & HCO3-)
 stimulated by hormone Secretin in response to acid in duodenum.

Question 12

Describe the movement of bile from the hepatocytes to the duodenum

Answer 12

Bile is initially secreted from hepatocytes and drains from both lobes of the liver via canaliculi, intralobular ducts and collecting ducts into the left and right hepatic ducts. These ducts amalgamate to form the common hepatic duct, which runs alongside the hepatic vein.

As the common hepatic duct descends, it is joined by the cystic duct – which allows bile to flow in and out of the gallbladder for storage and release.

the common hepatic duct and cystic duct combine to form the common bile duct.

The common bile duct descends and passes posteriorly to the first part of the duodenum and head of the pancreas. It is joined by the main pancreatic duct, forming the hepatopancreatic ampulla (commonly known as the ampulla of Vater) – which then empties into the duodenum via the major duodenal papilla. This papilla is regulated by a muscular valve, the sphincter of Oddi.

Entry into the duodenum is controlled by opening of the Sphincter of Odii. Bile can also be diverted into the gall bladder via the cystic duct where it is stored and concentrated 5-fold.

1. Bile from hepatic ducts
2. Common bile duct
3. Duodenum or diverted to the cystic duct
4. Gall bladder
5. concentrated and stored (30-50ml)
6. Released by cholcystokinin in response to the presence of fat in the duodenum

Question 13

Describe the Enterohepatic circulation of bile acids

Answer 13

1. Liver synthesises bile acids from cholesterol to primary bile acids, a) Cholic acid; 3-OH groups, b) Chenodeoxycholic acid; 2-OH groups
2. Synthesis regulated by the enzyme 7 α- hydroxylase which requires O2, NADH and cytochrome P-450
3. Presence of -COOH and -OH groups makes bile acids water soluble than cholesterol
4. Primary acids conjugate with glycine or taurine, prior to secretion into bile canalicular. (ratio of glycine to taurine 3:1)
5. Conjugated bile salts in sinusoidal blood actively taken up and transported against conc gradient into bile canaliculi by ATP-dependent carrier hBSEP also referred to as cBAT (canalicular bile acid transporter).

hBSEP – human bile sale export pump.

Bile acids are derivatives of cholesterol and made in hepatocytes. Cholesterol is converted into bile acids cholic & chenodeoxycholic acids. These are conjugated with amino acids (either glycine/taurine) to make it more soluble. This conjugated form is secreted into cannaliculi. The intestinal bacteria convert it to secondary bile acids.

Question 14

Why do gallstones form?

Answer 14

Imbalance in the chemical make-up of bile inside the gallbladder leads to gallstones.

Question 15

What are the two types of gall stones?

Answer 15

2 types of stones:

Cholesterol (80%) & Pigment (20%)

Question 16

What 3 factors increase the risk of cholesterol gallstones?

Answer 16

o High fat diet
 increased synthesis of cholesterol
o Inflammation of GB epithelium changes absorptive characteristic of mucosa
 excessive absorption of H20 & bile salts  cholesterol concentrates
o More common in women than men
 Risk factors = obesity, excess oestrogen (eg during pregnancy), HRT

Question 17

Where can gallstones form?

Answer 17

Gallstones can form anywhere along the biliary tract

Question 18

The liver metabolises and excretes many compounds, one of these is bilirubin.

How is bilirubin excreted?

Answer 18

Albumin-bound bilirubin is stripped of albumin and absorbed into hepatocytes.
Part of the bilirubin is broken down to colourless substances, hepatocytes produce urobilinogen, and colonic bacteria convert this to stercobilinogen. Both substances can be oxidised to yellow urinary urobilin and brown faecal stercobilin. The renal excretion of urobilin and stercobilinogen is increased in cases of hepatitis and other damage to hepatocytes.

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• Haem converted into free bilirubin
• Released into plasma – carried around bound to albumin
• Free bilirubin absorbed by hepatocytes → conjugated with glucoronic acid
• Conjugated bilirubin secreted into bile → metabolised by bacteria intestinal lumen & eliminated into faeces/urine
• Major metabolite in faeces is Stercobilin – brown colour
• In urine – Yellow urobilin & urobilinogen

Question 19

What is jaundice and what can cause it?

Answer 19

• Excessive quantities of either free or conjugated bilirubin accumulate in ECF
A yellow discoloration of the skin, sclera and mucous membranes is observed
• Normal plasma [bilirubin] = 1mg/dl, discolouration >1.5mg/dl
• Rare case of “green” jaundice reported – caused by mutation of biliverdin reductase gene
• Hence biliverdin was NOT converted to bilirubin and built up in plasma giving the green colour

Question 20

Describe the Pathophysiology of Jaundice

Answer 20

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Question 21

How do sunlight canopies help for treatment of neonatal jaundice?

Answer 21

• Development of sunlight canopies for use in low-resource countries
• Sunlight includes blue light
• Filters out most of the ray (UVA, UVB, UVC, IR etc) but allows therapeutic blue light to pass through » decreases risk of over-heating or sunburn.

Question 22

How is the liver involved with the storage of fat-soluble vitamins?

Answer 22

• Hepatocytes (stellate cells in particular) are important depots for storage of fat-soluble vit D, K, E and Vit A
Liver dysfunction ⇒fat malabsorption ⇒vitamin deficiency
• Stores Vit B12 and enough stored to last 2-3 years
Vit B12 deficiency⇒pernicious anaemia
• Stores folate, which is required in early pregnancy.
• Iron is stored as ferritin (blood-Fe buffer)

Question 23

What substances does the liver metabolise and excrete, these are all toxic to the body?

Answer 23

• Bilirubin
• Ammonia
• Hormones e.g. all steroid hormones (androgens, oestrogens, cortisol, aldosterone, thyroxine) inactivated by conjugation & excretion
• Drugs & exogenous toxins e.g. aspirin, paracetamol, ethanol

Question 24

How is ethanol metabolised?

Answer 24

Alcohol is readily absorbed from the gastrointestinal tract; however, alcohol cannot be stored and therefore, the body must oxidize it to get rid of it. Alcohol can only be oxidized in the liver, where enzymes are found to initiate the process and then it enters into normal metabolic pathways and metabolised as if it were fat.
The first step in the metabolism of alcohol is the oxidation of ethanol to acetaldehyde catalyzed by the enzyme alcohol dehydrogenase containing the coenzyme NAD+.
Excess NADH produced by oxidation of ethanol must be got rid of:
The conversion of pyruvic acid to lactic acid requires NADH. Pyruvic Acid + NADH + H+ —> Lactic Acid + NAD+
This pyruvic acid is intended for conversion into glucose by gluconeogenesis, but since most of it gets converted to lactic acid then this pathway is inhibited, which could result in hypoglycemia from lack of glucose synthesis. Also the excess NADH produced by alcohol metabolism can result in acidosis from lactic acid build-up.
Excess NADH may be used as a reducing agent in two pathways involved in lipogenesis–one to synthesize glycerol and the other to synthesis fatty acids. As a result, heavy drinkers may initially be overweight.
The NADH may be used directly in the electron transport chain to synthesize ATP as a source of energy. This reaction has the direct effect of inhibiting the normal oxidation of fats in the fatty acid spiral and citric acid cycle. Fats may accumulate or acetyl CoA may accumulate with the resulting production of ketone bodies. Accumulation of fat in the liver can be alleviated by secreting lipids into the blood stream. The higher lipid levels in the blood may be responsible for heart attacks.
The excess acetaldehyde itself it toxic to the liver leading to hepatitis and cirrhosis.

Question 25

What does a liver function test do?

Answer 25

Liver function tests check the levels of certain enzymes and proteins in the blood, and can be used to indicate various conditions:
• Screen for liver infections, such as hepatitis
• Monitor the progression of a disease, such as viral or alcoholic hepatitis, and determine how well a treatment is working
• Measure the severity of a disease, particularly scarring of the liver (cirrhosis)
• Monitor possible side effects of medications

Question 26

What are common sections of the liver function tests?

Answer 26

• Alanine aminotransferase (ALT)
• Aspartarte aminotransferase (AST)
• Alkaline phosphatase (ALP) - enzyme found in bile duct, indicates obstruction in bile flow
• Gamma glutamyl transferase (GGT or ‘Gamma GT’) – also indicates obstruction
• Bilirubin - jaundice
• Albumin - decreased in chronic liver disease/malnutrition
• Clotting studies, i.e. prothrombin time (PT) or international normalised ratio (INR) - if low levels of clotting factors are present, the prothrombin time is longer.

Question 27

When does alcoholic liver disease occur?

Answer 27

Alcoholic liver disease occurs after prolonged heavy drinking, typically for at least 10 years and particularly among those who are physically dependent on alcohol.

Question 28

What liver problems are caused by alcoholic liver disease?

Answer 28

Liver problems caused by alcohol include:

· Fatty liver
Alcohol abuse can lead to the accumulation of fat within the liver cells.

· Alcoholic hepatitis
Excessive use of alcohol can cause acute and chronic hepatitis (inflammation of the liver).

· Alcoholic cirrhosis
Anything which results in severe liver injury can cause cirrhosis. Common causes include excessive alcohol intake, chronic hepatitis B and C infection, intake of certain chemicals and poisons, too much iron or copper, severe reaction to drugs and obstruction of the bile duct.
Cirrhosis of the liver is a degenerative disease where liver cells are damaged and replaced by scar formation

Question 29

Do adult hepatocytes undergo cell division?

Answer 29

Adult hepatocytes are long lived and normally do not undergo cell division i.e. they are in G0 phase of cell cycle

Question 30

What happens to hepatocytes during partial hepatectomy or response to toxic injury?

Answer 30

Hepatocytes rapidly re-enter the cell cycle and proliferate

Question 31

How fast is liver regeneration and when does it stop?

Answer 31

• This regeneration is rapid and proliferation stops once the original mass of the liver is established
o Allows for use of partial livers from living donors for transplantation

Question 32

What two pathways are involved with liver regeneration?

Answer 32

• Still not understood fully but 2 pathways involved:
o Growth-factor mediated pathway → most important HGF (hepatocyte growth factor) and TGFα (transforming growth factor alpha)
o Cytokine signalling pathway using IL-6 via TNFα binding to its receptor on Kuppfer cells

Question 33

Describe the mechanism of liver regeneration

Answer 33

After partial hepatectomy or liver injury, several signals are initiated simultaneously in the liver. Gut-derived factors, such as lipopolysaccharide (LPS), are upregulated after liver injury or hepatectomy and reach the liver through the portal blood supply. They activate hepatic non-parenchymal cells (including Kupffer cells and stellate cells) and increase the production of tumour necrosis factor (TNF) and interleukin (IL)-6. Other factors are released from the pancreas (insulin), duodenum or salivary gland (epidermal growth factor; EGF), adrenal gland (norepinepherine), thyroid gland (triodothronine; T3) and stellate cells (hepatocyte growth factor; HGF). Cooperative signals from these factors allow the hepatocytes to overcome cell-cycle checkpoint controls and move from G0, through G1, to the S phase of the cell cycle. This leads to DNA synthesis and hepatocyte proliferation. Transforming growth factor (TGF) signalling, which inhibits hepatocyte DNA synthesis, is blocked during the proliferative phase but is restored at the end of the process of regeneration by helping to return hepatocytes to the quiescent state.