The Liver

Question 1

Why do we need to know about the liver

Answer 1

Liver disease affects 2 million people in the UK and the incidence is increasing

Question 2

Describe the statistics associated with liver disease

Answer 2

Accounts for >1million hospital admissions each year
11,575 people died from liver disease in 2009 (9,231 in 2001)
~ 1 in 50 all deaths
1 in 10 deaths of people in their 40’s are due to liver disease
70% die in hospital

Question 3

Where is the Liver found

Answer 3

Most of the liver is found in the URQ, some in the ULQ
Protected by the abdominal tissue and thoracic wall
Sits nicely in the diaphragm

Question 4

Anteriorly, how many lobes does the liver have

Answer 4

The liver can be split into two lobes (right and left), which are separated by the falciform ligament.
Right lobe is larger
Gall bladder sits in right lobe

Question 5

What is the falciform ligament also known as

Answer 5

Ligamentum teres
Joins form coronary ligament (right lobe)
and left triangular ligament (left lobe)

Question 6

What is the role of the ligaments

Answer 6

Attach the liver to parts of the body

Falciform ligament attaches the liver to the diaphragm

Question 7

Posteriorly, what other lobes are seen

Answer 7

Quadrate lobe- below hilus

Caudate lobe- between hilus and left hepatic vein

Question 8

What is found in the hilus of the liver

Answer 8

Hepatic portal vein
Hepatic artery proper
Common bile duct
Gall bladder

Question 9

Describe a Lap cholecyetectomy

Answer 9

Lap cholecyetectomy: gallbladder in junction of segments 4 and 5

Calot’s triangle bound by the cystic duct, bile duct and cytic artery. It is this triangular space which is dissected in a cholectystcomy to identify a window to safely expose the gallbladder

Question 10

Describe Couinaud classification of the Liver

Answer 10

8 functionally independent segments
Centrally: portal vein, hepatic artery and bile duct
Peripherally: hepatic vein

Each segment can be resected without damaging those remaining as they all have their own blood supply and venous drainage

Question 11

Describe the location of the lobes

Answer 11

Caudate lobe
Lateral to falciform ligament and superior to portal venous supply
Lateral to falciform ligament and inferior to portal venous supply
Medial to falciform ligament
Medial and inferior right hemisphere
Posterior portion of right hemisphere
Above 6
Above 5 (medial and superior right hemisphere)

Question 12

Describe the venous drainage of the lobes

Answer 12

Each subsection drains into its own vein, with those subsequently draining into the left, middle and right hepatic veins before joining the vena cava

Question 13

Describe the blood supply to the liver

Answer 13

Rich blood supply- 25% of resting cardiac output

Dual blood supply:
20% arterial blood from the hepatic artery (left and right branches)
80% venous blood draining from the gut through the hepatic portal vein (HPV)

Blood from the liver drains into the inferior vena cava via the hepatic vein

Question 14

What does the dual blood supply to the liver reflect

Answer 14

The liver receives a dual blood supply, which reflects its important metabolic, secretary and immunological functions. The main perfusing vessels are the hepatic artery (blood from heart) and hepatic portal vein (blood from the gut).

Question 15

Describe hepatic lobules

Answer 15

Structural unit of liver that is roughly hexagonal in shape
Each corner consists of a portal triad that links with 3 adjacent lobules
At the centre of each lobule is a central vein which collects blood from the hepatic sinusoids to return it to the systemic venous system via the hepatic veins]
Within the lobule, there are rows of hepatocytes, with each hepatocyte having a sinusoid-facing side and a bile-canaliculi- facing side

Question 16

What does the portal triad consist of

Answer 16

Portal tracts are composed of:
an arteriole
a branch of the portal vein
a bile duct
with blood flowing inwards and bile flowing outwards

Question 17

Describe the role of the hepatic portal vein

Answer 17

This blood vessel is carrying mixed venous blood directly from the G.I organs and spleen
Therefore, it is rich in raw nutrients, bacteria, toxins and waste products (from the spleen)
The hepatocytes can process nutrients, detoxify the blood and excrete waste before the blood returns to the systemic circulation

Question 18

Describe the role of the hepatic artery

Answer 18

brings some oxygen-rich blood to liver tissue to support high energy demand of hepatocytes (fuses with portal vein to form sinusoids)

Question 19

Describe the role of the bile duct

Answer 19

bile produced by hepatocytes drains into tiny canals (bile canaliculi) which coalesce with cholangiocyte-lined bile ducts located around lobules

Question 20

What is key to remember about blood supply to the liver

Answer 20

It is mixed- and so is poorly oxygenated

Question 21

What does the liver have roles in

Answer 21

Digestion, biosynthesis, energy metabolism, storage, degradation and detoxification

Question 22

List the cell types found in the liver

Answer 22

Hepatocytes
c.80%
Endothelial cells
Lining blood vessels and sinusoids
Cholangiocytes (aka bile duct epithelial cells)
Lining biliary structures
Kupffer cells
Fixed phagocytes (liver macrophages)
Hepatic stellate cells
Vitamin A storage cells (Ito cells), may be activated to a fibrogenic myofibroblastic phenotype

Question 23

Describe the endothelial cells in the Liver

Answer 23

have no basement membrane, with many fenestrations and a discontinuous endothelium to become very leaky to allow transfer of lipids/proteins/carbs
Found between hepatocytes and space of disse and lining the hepatic sinusoids

Question 24

Describe the kuppfer cells

Answer 24

sinusoidal macrophages that are stellate shaped and attached to endothelial cells to eliminate and detoxify substances arriving into liver from portal circulation
15% of liver population
Attach to endothelial cells lining the hepatic sinusoids

Question 25

Describe the stellate cells

Answer 25

exist in quiescent state to store VItA in liver cytosolic droplets, becoming activated in response to liver damage; proliferate and deposit collagen in the extracellular matrix they are chemotactic too perisinusoidal (attach to endothelial cells in space of disse)

Question 26

Describe hepatocytes

Answer 26

approx. 80% liver mass, cuboid cells that synthesise albumin, clotting products and bile salts while receiving nutrients and metabolising drugs

Question 27

Describe cholangiocytes

Answer 27

secrete bicarbonates and water to form bile

Question 28

What is meant by the space of disse

Answer 28

region of free space between capillaries and hepatocytes

Question 29

How are hepatocytes arranged in the liver

Answer 29

Cords (sheets) of hepatocytes Radiating from a central vein. 80% of the liver mass.

Question 30

What is meant by the hepatic acinus

Answer 30

functional unit of liver tissue that is harder to define; consists of two adjacent sixths of a lobule that share two portal triads and extend as far into the lobule as the central veins

Question 31

Describe the inter lobule structure

Answer 31

One portal triad sits at the junction between 3 lobules

Question 32

Summarise the different zones of the acinus

Answer 32

The terminal acinus is centred on the the portal tract and each hepatic acinus is centred on the line connecting two portal triads It is the elliptical shaped appearance of the histological appearance and is demarcated by zone: 1. Periportal 2. Transition zone 3. Pericentral Unit of hepatocytes divided into zones dependent on proximity to arterial blood supply

Question 33

Describe the relations of the bile canaliculus

Answer 33

Canaliculus interface between sinusoids (sinusoidal faces) and hepatocytes (lateral faces)

Question 34

Describe the 3 zone model of the acinus

Answer 34

blood received from vessels at A and drains to B, so those in zone one receive early exposure to toxins, but also most oxygen; Zone 1 = high toxin risk but also high oxygen supply; Zone 2 = medium toxin risk and medium oxygen supply; Zone 3 = low toxin risk but also low oxygen supply Portal triad is at A

Question 35

Describe the histology of the endothelial cells

Answer 35

nuclei red and flat

Question 36

Describe the histology of the kupffer cells

Answer 36

cytoplasm blue | nuclei red

Question 37

Describe the histology of hepatocytes

Answer 37

nuclei red and round

Question 38

What does the activation of hepatic stellate cells lead to

Answer 38

Vitamin A storage Activation = ECM production (fibrogenesis) has a role in liver cirrhosis activated by pro-inflammatory environments

Question 39

What are the other roles of Kupffer cells

Answer 39

Phagocytosis (inc. RBC breakdown) Secretion of cytokines that promote HSC Activation - proliferation, contraction and fibrogenesis remove bilirubin from RBCs important physiologically but can be pathological

Question 40

Summarise the metabolism of carbohydrates

Answer 40

Important to control blood glucose (endocrine course) After a meal, blood glucose  and is taken up by tissues Stored as glycogen mainly in muscle and liver Breakdown liver glycogen maintains blood glucose concentration between meals (muscle cannot release glucose back into blood) 24h fast will exhaust liver glycogen (80g

Question 41

Describe gluconeogenesis

Answer 41

Muscles: glucose enters muscles and is used for glycolysis to produce pyruvate; either used to produce Acetyl CoA for TCA or undergoes fermentation to lactate Hepatocytes: lactate travels to liver and is converted to pyruvate using lactate dehydrogenase; 6 ATP are invested in gluconeogenesis to produce glucose

Question 42

When can gluconeogenesis take place

Answer 42

During muscle contractions, ATP is constantly being used to supply energy and more ATP is produced to replenish supplies. If muscular activity continues, the availability of oxygen for use at the end of the electron transport chain becomes the limiting factor and the cells soon exhaust their supplies of oxygen. When this happens, the citric acid cycle is inhibited and causes pyruvic acid to accumulate. However, glycolysis continues even under anaerobic conditions even though the citric acid cycle works only under aerobic conditions.

Question 43

What is meant by hitting the wall

Answer 43

loss of glycogen stores

Question 44

Describe protein metabolism

Answer 44

Metabolism of proteins: important to produce plasma proteins Muscles: in fasted state, break down amino acids Hepatocytes: use amino acids to produce proteins such as plasma proteins, clotting factors and lipoproteins; also perform transamination reactions to produce amino acids not found in diet e.g. Alanine and alpha-ketoglutarate converted to pyruvate and glutamate and deaminations

Question 45

Describe the synthesis of non-essential amino acids

Answer 45

Synthesis of dietary “non-essential” amino acids. Start with appropriate -keto acid precursor (carboxylic acid and ketone group). Exchange of an amine group from an amino acid to a keto-acid. In this example, alanine enters the liver and can react with the keto acid (alpha keto glutarate) to produce the amino acid glutamate and the ketoacid pyruvate (requires the relevant transaminase enzyme plus cofactor). This reaction is reversible in the presence of a different transaminase that could then convert glutamate and pyruvate back to alanine and alpha keto glutarate.

Question 46

Describe transamination

Answer 46

Different keto-acids can be converted to multiple amino acids depending on the transaminase enzyme (vital for production of non-essential amino acids. different keto acids as amine acceptors and different transaminases to produce different amino acids

Question 47

List some transaminase reactions

Answer 47

AlphaKG: glutamate, proline and arginine Pyruvate: alanine, valine and leucine Oxaloacetate: aspartate, methionine and lysine

Question 48

List some non-essential amino acids

Answer 48

Glutamate proline Alanine aspartate

Question 49

What is the issue for muscles in terms of respiring amino acids

Answer 49

Muscle can potentially utilise amino acids to produce glucose for energy; BUT To convert pyruvate to glucose requires energy To remove nitrogen as urea requires energy Solution – transfer problem to the liver (glucose-alanine cycle)

Question 50

Describe the process of deamination

Answer 50

occurs using the glucose-alanine cycle; alanine transferred to liver and reacts with alphaKG to form glutamate and pyruvate; glutamate then converted to urea using 4ATP and pyruvate converted to glucose using 6ATP Alanine is made from pyruvate (glycolysis) and glutamate (a,a breakdown) in muscle cells Urea is excreted into the blood- to go to the kidney for removal

Question 51

What is the importance of urea

Answer 51

Glutamate metabolism actually produces NH3 which is very toxic to the body (especially brain), so liver converts it to water soluble urea.

Question 52

Describe some important amino acids

Answer 52

Four of the amino acids: glutamate, aspartate, alanine and glutamine are present in cells at much higher concentrations than the other 16. All four have major metabolic functions in addition to their roles in proteins, but glutamate occupies the prime position. Glutamate is special because it is chemically related to 2-oxoglutarate (= alpha keto glutatarate) which is a key intermediate in the citric acid (Krebs) cycle. Glutamate can be reversibly converted into oxoglutarate by transaminases or by glutamate dehydrogenase. In addition, glutamate can be reversibly converted into glutamine, an important nitrogen carrier, and the most common free amino acid in human blood plasma. Alanine is the principal amino acid released from muscle tissue during starvation. It is an important substrate for hepatic gluconeogenesis, and alanine transamination is required for the proper maintenance of fasting blood glucose concentrations.

Question 53

What is the main energy store in the body

Answer 53

Fat main energy store in body - 100x glycogen. Stored in adipose and liver. When glycogen stores full, liver can convert excess glucose and amino acids to fat for storage

Question 54

Describe triglyceride metabolism

Answer 54

Adipose tissues: convert triglycerides to NEFAs Hepatocytes: NEFAs converted into acetyl coA (beta oxidation) Used in TCA cycle or to make ketone bodies for tissue energy source ketones are mobile acetyl-coA

Question 55

What can glucose be converted into once it enters the hepatocyte

Answer 55

Glucose entering the liver can be converted to several components of lipoproteins – glycerol, fatty acids and cholesterol. Glucose can be directly converted to glycerol or via the TCA cycle and be converted to acetyl CoA via pyruvate (within the mitochondria). Acetyl CoA can be converted to cholesterol (via HMG CoA reductase) or can also be converted to fatty acids (via the intermediate malonyl CoA).

Question 56

Describe lipoprotein synthesis

Answer 56

lycerol is converted to triglycerides and when combined with fatty acids, cholesterol, apoproteins and phospholipids, lipoproteins are formed (usually HDLs and VLDLs are produced where HDLs are empty and pick up excess cholesterol and VLDLs transport fatty acids to tissues)

Question 57

Describe the different types of lipoproteins

Answer 57

The liver produces two lipoproteins. VLDL and HDL. VLDL has a high triacylglycerol component and it’s major role is to deliver fatty acids to body tissues (lipoprotein lipase cleaves the fatty acids from triglycerides). Those fatty acids can be used as an energy source of can be stored in the adipose tissue as tri-glycerides. HDL are often referred to as ‘empty’ lipoproteins – they have high protein content but low fat content. Their role is to mop up excess cholesterol in the circulation and return to the liver – hence why they are often referred to as ‘good’ fat. Once VLDL have delivered fatty acids to tissues, they are converted to LDL which are very high in cholesterol. The LDL deliver cholesterol to tissues which then use the cholesterol to make hormones and to maintain cell membrane integrity. Any excess cholesterol is returned to the liver and excreted in bile.

Question 58

Describe the storage roles of hepatocytes

Answer 58

Storage of fat soluble vitamins (A,D,E,K). Stores sufficient 6-12 month except Vit K where store is small. Vit K essential blood clotting Storage of iron as ferritin. Available for erythropoiesis Also store copper

Question 59

Describe the roles of hepatocytes in detoxification

Answer 59

P450 enzymes make compounds more hydrophilic and then phase 2 enzymes attach water soluble side chains to make them less reactiv

Question 60

Describe the ultrastructure of hepatocytes

Answer 60

Peroxisomes: key role in detoxification, waste management and cholesterol/bile synthesis Cytoplasmic enzymes: support deamination/glycogenolysis Smooth ER: essential for carb/phospholipid synthesis Mitochondria: produces ATP to meet high demand Rough ER: abundant for protein synthesis e.g. Clotting factors/albumin Golgi Apparatus: package many manufactured molecules for exocytosis Lysosomes: acidic organelle needed for breakdown of lipids/proteins/carbs and nucleic acids Glycogen: stored glucose polymer

Question 61

Describe the biliary tree

Answer 61

The biliary tree describes the anatomical structures responsible for the transit and storage of bile. Technically, the biliary tree starts in millions of bile canaliculi adjacent to the hepatocytes (bile producing cells). These canaliculi then drain into small ductules, which in turn drain into small bile ducts. Small bile ducts coalesce into larger bile ducts for each liver segment (e.g. 2, 4a). These merge together to form the right and left hepatic ducts, which converge to form the common hepatic duct. Connected to this duct is the cystic duct, which connects the gall bladder (a small muscular storage organ) to the biliary tree. The merging of the common hepatic duct and the cystic duct forms the common bile duct, which extends towards the duodenum. At its distal end the pancreatic duct joins and the vessel is then called the ampulla of Vater, which opens up into the medial wall of the duodenum at the duodenal papilla.

Question 62

What are the functions of bile

Answer 62

Functions of bile: Cholesterol homeostasis: secretion/excretion to fine tune serum concentration Absorption/digestion: bile salts solubilise fats and VitA/D/E/K (lipid-soluble vitamins) Toxin excretion: endogenous/exogenous

Question 63

What is in bile

Answer 63

cholesterol bile salts bilirubin and drug metabolites (for excretion in faeces) bile is an aqueous solution- so lots of water and other solutes

Question 64

What are bile acids/salts

Answer 64

Primary bile acids secreted in liver: Cholic acid chenodeoxycholic acid converted to deoxycholic and lithocholic acids respectively by gut bacteria; aq solution so also contains water and solutes, and is yellow/green due to biliverdin/bilirubin

Question 65

Describe the production of bile

Answer 65

500ml day-1 with 60% from hepatocytes (reflect serum concentrations; secrete bile acids, lipids and organic ions) and 40% from cholangiocytes (alter pH, allow water to enter bile, reabsorb sugars/acids and secrete HCO3- and Cl-, IgA exocytosed

Question 66

What does bile do

Answer 66

reduces surface tension of fats | helps form micelles

Question 67

When is bile released

Answer 67

constantly being synthesised and stored in gall bladder | CCK stimulates gall bladder for a big dose

Question 68

What does the gall bladder do

Answer 68

stores 50ml bile, acidifies by absorbing HCO3-, and concentrates by reabsorbing ions to create an osmotic gradient- removing around 80-90%of its volume

Question 69

Describe the enteropathic circulation

Answer 69

cycling of substances between gut and liver by continuous reabsorption in the gut and hepatocyte secretion; allows for recycling of bile salts to be more efficient; some drugs are secreted to bile and faeces but enterohepatic circulation may lead to reabsorption and re-entering the portal circulation cyclically to increase their half-life

Question 70

Describe how the liver may process some drugs

Answer 70

One way the liver processes some drugs is to excrete them via bile (to avoid them going into circulation), and eventually the faeces. However they may get reabsorbed in the small intestine and re-enter the portal circulation cyclically, significantly increasing their half-life.