Liver - intoduction to its function

Question 1

what are the cells of the liver?

Answer 1

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

Question 2

What is the functional unit of the liver?

Answer 2

hepatic lobule

hexagonal plates of hepatocytes around central hepatic vein –
at each of 6 corners is triad of branches of portal vein, hepatic artery and bile duct

Question 3

Importance of hepatic lobule

Answer 3

Blood enters the lobules through branches of the portal vein and hepatic artery, it then flows through small channels called sinusoids that are lined with primary liver cells (i.e. hepatocytes).

The hepatocytes remove toxic substances, including alcohol, from the blood which then exits the lobule through the central vein (hepatic venule).

Flow of this blood (from hepatic artery and portal vein) is in the opposite direction to bile flow.

Question 4

How does the liver’s microstructure support its roles?

Answer 4

Massive surface area for exchange of molecules

Sophisticated separation of blood from bile.

Specific positioning of pumps to achieve specific localisation of materials (at a cellular level)

Question 5

Blood Supply to 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

Protective Barrier in the liver

Answer 6

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 7

Bile

What is it?

Answer 7

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

Question 8

Bile

Where does it come from?

Answer 8

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-)
» release is stimulated by hormone Secretin in response to acid in duodenum.

Question 9

Gall Bladder & Bile

Answer 9

Bile from hepatic ducts 
↓
common bile duct 
↓
duodenum (Entry into the doudenum is controlled by opening of the Sphincter of Odii)

OR

diverted via cystic duct 
↓
GALL BLADDER
↓  
concentrated
 & stored (30-50ml)
↓
Released by cholecystokinin in response to presence of fat in duodenum

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 righthepatic ducts. These ducts amalgamate to form thecommon hepatic duct, which runs alongside the hepatic vein.

Question 10

importance of bile

Answer 10

Essential for fat digestion and absorption

Bile and pancreatic juices neutralise acid entering the duodenum

Elimination of waste products esp. Bilirubin, cholesterol

Question 11

Formation of Bile Acids

Answer 11

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.

Exist as sodium salts = bile salts

The intestinal bacteria convert it to secondary bile acids.

Question 12

Enterohepatic circulation of bile acids

Answer 12

Bile acids from liver/gall bladder are secreted into the small intestine where they play a role in fat absorption.

95% of bile acids are re-absorbed back into the blood at the terminal ileum and carried back to the liver in the hepatic portal vein where they are taken up into hepatocytes.

They are then re-secreted in new bile. The total pool of bile acids are re-circulated 6-8x a day.

5% of bile acids are lost in faeces.

Question 13

Gallstones

Answer 13

Cholesterol is virtually insoluble in aqueous solution but is made soluble in bile. In abnormal conditions the cholesterol precipitates out of solution forming gallstones.

There are two types of stones: Cholesterol (80%) and pigment (20%).

Question 14

Risk factors for gall stones

Answer 14

High fat diet -> increased synthesis of cholesterol

Inflammation of GB epithelium changes absorptive characteristic of mucosa e.g excessive absorption of H20 & bile salts -> cholesterol concentrates

More common in women than men
Risk factors = obesity, excess oestrogen (eg during pregnancy), HRT

Gallstones can form anywhere along the biliary tract

Question 15

Physiological significance of bile

Answer 15

Essential for fat digestion & absorption via emulsification

Bile + pancreatic juice neutralises gastric juice as it enters the small intestine -> aids digestive enzymes

Elimination of waste products from blood in particular bilirubin & cholesterol - 500g of cholesterol converted to bile acids per day

Question 16

Excretion of waste products

What is Bilirubin?

Answer 16

Yellow pigment formed from breakdown of haemoglobin

Useless & toxic but made in large quantities (~6g/day) therefore must be eliminated

Question 17

Formation & Elimination of Bilirubin

Answer 17

Haeme converted to free Bilirubin by phagocytes, released into the blood and transported by albumin - pre hepatic stage

Absorbed by hepatocytes and conjugated with glucoronic acid - hepatic stage

Conjugated Bilirubin secreted into bile and metabolised by bacteria in intestinal lumen - posthepatic stage

Excreted as stercobilin in faeces or urobilin/ urobilinogen in urine

Question 18

colour of eliminated bilirubin

Answer 18

Major metabolite in faeces is Stercobilin – brown colour

In urine – Yellow urobilin & urobilinogen

Question 19

How does the liver control carbohydrate metabolism?

Answer 19

Carb metabolism is critical for all animals to maintain (glucose) in blood within narrow range, known as Glucose Buffer Function. The liver does this through the following:

Glycogenesis: Excess glucose entering blood after meal rapidly removed and stored as glycogen (stimulated by insulin). Liver stores large amounts of glycogen.

Glycogenolysis: When blood glucose falls, the liver activates other pathways to break glycogen and return glucose to blood (stimulated by glucagon and adrenaline)

Gluconeogenesis: When hepatic glycogen reserves become exhausted, blood glucose concentrations are still maintained, glucose is synthesised from lactate, amino acids and glycerol (from triglycerides)

Glycolysis: Process by which glucose is converted into pyruvate releasing energy

Question 20

Fat Metabolism in Liver

Answer 20

There are three sources of fatty acids for metabolism, dietary source of triglycerides, triglycerides stored in adipocytes and triglycerides synthesised in the liver.

Triglycerides are oxidized in hepatocytes to produce energy. (lypolysis)

Lipoproteins are synthesised in the liver

Excess carbohydrates and proteins are converted into fatty acids and triglycerides and hence stored in adipose tissue

There is synthesis of large quantities of cholesterol and phospholipids, some packaged as lipoproteins.

Question 21

why is ammonia bad?

Answer 21

Ammonia is very dangerous and can depress cerebral blood flow & cerebral oxygen consumption.

Large amounts of ammonia formed by deamination & in gut by bacteria. If there is no urea formation then plasma [ammonia] increases & is extremely toxic especially to brain → hepatic encephalopathy

Question 22

Protein metabolism

Answer 22

There is deamination and transamination of amino acids, there is then conversion of the non-nitrogenous part of the AAs to glucose and lipids. Through the remaining nitrogen pool, this can be built into tissue protein or put into urea cycle.

There can be synthesis of non-essential amino acids in the liver.

There is also synthesis of nearly all plasma proteins (90%) e.g. albumin, transferrin

As mentioned above there is synthesis of urea which removes ammonia from the body. Ammonia is very dangerous and can depress cerebral blood flow and cerebral oxygen consumption and it also interferes with GABA and dopamine, this leads to hepatic encephalopathy. Large amounts of ammonia are formed by deamination and in gut by bacteria, if there is no urea formation then plasma ammonia increases and this is extremely toxic, causing what was previously mentioned.

Question 23

Coagulation Factor Synthesis

Answer 23

Blood clotting factors are synthesised in the liver, these include:

• Fibrinogen
• Prothrombin
• Nearly all the other factors e.g. V, VI, IX, X, XII

Vitamin K is essential for formation of pro-thrombin and factors II,VII, IX and X.

Question 24

Liver Storage

Answer 24

Hepatocytes (stellate cells in particular) are important depots for storage of fat-soluble vitamins A,D,E,K. Liver dysfunction can lead to fat malabsorption and hence vitamin deficiency.

The liver also stored vitamin B12 and enough is stored to last 2-3 years. Vitamin B12 deficiency eventually leads to pernicious anaemia.

Liver also stores folate, which is required in early pregnancy.

Iron is stored as ferritin (also acts as an Fe buffer for blood).

Question 25

How does the liver act as an iron buffer?

Answer 25

Hepatic cells contain large amnts of apoferritin protein, which combines reversibly with Fe (when in excess) to form ferritin, until needed. When Fe in circulating body fluids reaches low level, the ferritin releases Fe. . Hence acts as a blood iron buffer as well as storage system.

Question 26

What is jaundice and what can cause it ?

Answer 26

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

Question 27

Pathophysiology of Jaundice

Answer 27

There are three types of jaundice. Pre-hepatic (haemolytic), hepatic and post-hepatic (obstructive).

Pre-hepatic = Increased haemolysis can cause excess free bilirubin and the liver doesn’t have the capacity to process/conjugate it. Unconjugated bilirubin cannot be excreted in urine and remains in circulation. Example = neonatal jaundice (fetal Hb replaced by adult Hb and liver still immature, treated by light therapy).

Hepatic = Problems with hepatocytes (e.g. damage to hepatocytes and biliary tree from cirrhosis, drugs, viral infections – hepatitis A,B,C,E; Gilberts syndrome) cause an increase in unconjugated and conjugated serum bilirubin.

Post-hepatic = Passage of conjugated bilirubin into the duodenum is blocked (e.g. gallstones, carcinoma of pancreas/bile ducts) and it leaks into circulation and urine making it very dark.

Question 28

Biotransformation/Detoxification

What does it excrete?

Answer 28

The liver is vital in metabolism and excretion of various substances that can be toxic to the body including:

Bilirubin
Ammonia
Hormones e.g. all steroid hormones (androgens, oestrogens, cortisol, aldosterone) and thyroxine are inactivated by conjugation in the liver and then excreted
Drugs and exogenous toxins e.g. aspirin, paracetamol and ethanol.

Question 29

Biotransformation/Detoxification

the two stages?

Answer 29

The liver metabolises drugs and hormones in two phases.

Phase 1 (is primarily oxidation/reduction reactions) occurs in the smooth ER and catalyzed by a family of cytochrome P450 enzymes (though other reactions do also occur). Usually the common feature of these reactions is to make the substrate more polar (which is sometimes more toxic).

Phase 2 is conjugation in order to make the drug water soluble to be eliminated, conjugation with glucuronyl is most important/prevalent.

Note that not all drugs use both phases,

There is then elimination of the conjugated substance into blood or bile using ATPase pumps, this is sometimes referred to as being phase 3.

Question 30

Detoxification of Paracetamol

Answer 30

Paracetamol aka acetaminophen is metabolised by three pathways:

Glucoronidation (45%-55%)
Sulfation (20-30%)
N-hydroxylation and dehydration, forming an intermediate product NAPQI which is toxic, this is then detoxified by glutathione (GSH) conjugation (<15%)

Paracetamol has a narrow therapeutic index and accidental overdose is common, due to the liver having only a limited capacity of these enzymes and stores of glutathione.

In paracetamol o/d the liver enzymes are saturated and glutathione stores rapidly depleted, so left with toxic NAPQI.

Treatment is via infusion of N-acetyl cysteine, which is a precursor to glutathione and so raises its levels.

Maximum dose 4g/day or 1g/dose

Not to be taken after alcohol consumption

Question 31

Ethanol Metabolism

Answer 31

Alcohol is readily absorbed from the GI tract however, alcohol cannot be stored and therefore the body must oxidise it to get rid of it. Alcohol can only be oxidized in the liver where enzymes are found to initate 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:

1) 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 into lactic acid (due to the excess NADH), this gluconeogenesis pathway is inhibited which can 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.

2) Excess NADH may be used as a reducing agent in two pathways involved in lipogenesis, one to synthesise glycerol and the other to synthesis fatty acids. As a result heavy drinkers may initially be overweight.

3) The NADH may be used directly in the electron transport chain to synthesise ATP as a source of energy. This reaction has the direct effect of inhibiting the normal oxidation of fats in the fatty acid 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.
Blue star = alcohol dehydrogenase

The excess acetaldehyde itself is toxic to the liver leading to hepatitis and cirrhosis. It is converted to acetate via the enzyme acetaldehyde dehydrogenase (ALDH2) and then released harmlessly into circulation.

Alcohol Flush Reaction is a condition in which the face and/or body experiences flushes or blotches due to accumulation of acetaldehyde. 50% of Asians have a deficiency in ALDH2 due to mutation of one copy of the ALDH2 gene. Hence they are more likely to experience accumulation of acetaldehyde resulting in Alcohol Flush Reaction

Question 32

Alcohol & the Liver

Answer 32

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

Fatty liver – Alcohol abuse can lead to the accumulation of fat within liver cells (reversible)

Alcoholic hepatitis – Excessive use of alcohol can cause acute and chronic hepatitis (inflammation of liver, recovery possible)

Alcoholic cirrhosis – Liver cells damaged and replaced by scar formation (irreversible)

Question 33

Effects of Impaired Detoxification

A 32 year old male patient with normal secondary sex characteristics, no testicular mass, no history of drug ingestion, no other endocrine abnormalities and a normal neurological examination.

Nevertheless, he had a history of more than 15 years of large amounts of alcohol intake and a liver biopsy confirm alcoholic cirrhosis

Answer 33

Gynecomastiais an enlargement or swelling of breast tissue in males, most commonly caused by male oestrogen levels that are too high or are out of balance with testosterone levels.

Gynecomastia due to alcoholic cirrhosis

Question 34

Liver Regeneration

Answer 34

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.