The Liver Flashcards
Why do we need to know about the liver
Liver disease affects 2 million people in the UK and the incidence is increasing
Describe the statistics associated with liver disease
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
Where is the Liver found
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
Anteriorly, how many lobes does the liver have
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
What is the falciform ligament also known as
Ligamentum teres
Joins form coronary ligament (right lobe)
and left triangular ligament (left lobe)
What is the role of the ligaments
Attach the liver to parts of the body
Falciform ligament attaches the liver to the diaphragm
Posteriorly, what other lobes are seen
Quadrate lobe- below hilus
Caudate lobe- between hilus and left hepatic vein
What is found in the hilus of the liver
Hepatic portal vein
Hepatic artery proper
Common bile duct
Gall bladder
Describe a Lap cholecyetectomy
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
Describe Couinaud classification of the Liver
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
Describe the location of the lobes
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)
Describe the venous drainage of the lobes
Each subsection drains into its own vein, with those subsequently draining into the left, middle and right hepatic veins before joining the vena cava
Describe the blood supply to the liver
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
What does the dual blood supply to the liver reflect
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).
Describe hepatic lobules
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
What does the portal triad consist of
Portal tracts are composed of: an arteriole a branch of the portal vein a bile duct with blood flowing inwards and bile flowing outwards
Describe the role of the hepatic portal vein
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
Describe the role of the hepatic artery
brings some oxygen-rich blood to liver tissue to support high energy demand of hepatocytes (fuses with portal vein to form sinusoids)
Describe the role of the bile duct
bile produced by hepatocytes drains into tiny canals (bile canaliculi) which coalesce with cholangiocyte-lined bile ducts located around lobules
What is key to remember about blood supply to the liver
It is mixed- and so is poorly oxygenated
What does the liver have roles in
Digestion, biosynthesis, energy metabolism, storage, degradation and detoxification
List the cell types found in the liver
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
Describe the endothelial cells in the Liver
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
Describe the kuppfer cells
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
Describe the stellate cells
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)
Describe hepatocytes
approx. 80% liver mass, cuboid cells that synthesise albumin, clotting products and bile salts while receiving nutrients and metabolising drugs
Describe cholangiocytes
secrete bicarbonates and water to form bile
What is meant by the space of disse
region of free space between capillaries and hepatocytes
How are hepatocytes arranged in the liver
Cords (sheets) of hepatocytes
Radiating from a central vein.
80% of the liver mass.
What is meant by the hepatic acinus
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
Describe the inter lobule structure
One portal triad sits at the junction between 3 lobules
Summarise the different zones of the acinus
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:
- Periportal
- Transition zone
- Pericentral
Unit of hepatocytes divided into zones dependent on proximity to arterial blood supply
Describe the relations of the bile canaliculus
Canaliculus interface between sinusoids (sinusoidal faces) and hepatocytes (lateral faces)
Describe the 3 zone model of the acinus
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
Describe the histology of the endothelial cells
nuclei red and flat
Describe the histology of the kupffer cells
cytoplasm blue
nuclei red
Describe the histology of hepatocytes
nuclei red and round
What does the activation of hepatic stellate cells lead to
Vitamin A storage
Activation = ECM production (fibrogenesis)
has a role in liver cirrhosis
activated by pro-inflammatory environments
What are the other roles of Kupffer cells
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
Summarise the metabolism of carbohydrates
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
Describe gluconeogenesis
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
When can gluconeogenesis take place
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.
What is meant by hitting the wall
loss of glycogen stores
Describe protein metabolism
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
Describe the synthesis of non-essential amino acids
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.
Describe transamination
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
List some transaminase reactions
AlphaKG: glutamate, proline and arginine
Pyruvate: alanine, valine and leucine
Oxaloacetate: aspartate, methionine and lysine
List some non-essential amino acids
Glutamate
proline
Alanine
aspartate
What is the issue for muscles in terms of respiring amino acids
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)
Describe the process of deamination
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
What is the importance of urea
Glutamate metabolism actually produces NH3 which is very toxic to the body (especially brain), so liver converts it to water soluble urea.
Describe some important amino acids
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.
What is the main energy store in the body
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
Describe triglyceride metabolism
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
What can glucose be converted into once it enters the hepatocyte
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).
Describe lipoprotein synthesis
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)
Describe the different types of lipoproteins
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.
Describe the storage roles of hepatocytes
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
Describe the roles of hepatocytes in detoxification
P450 enzymes make compounds more hydrophilic and then phase 2 enzymes attach water soluble side chains to make them less reactiv
Describe the ultrastructure of hepatocytes
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
Describe the biliary tree
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.
What are the functions of bile
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
What is in bile
cholesterol
bile salts
bilirubin and drug metabolites (for excretion in faeces)
bile is an aqueous solution- so lots of water and other solutes
What are bile acids/salts
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
Describe the production of bile
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
What does bile do
reduces surface tension of fats
helps form micelles
When is bile released
constantly being synthesised and stored in gall bladder
CCK stimulates gall bladder for a big dose
What does the gall bladder do
stores 50ml bile, acidifies by absorbing HCO3-, and concentrates by reabsorbing ions to create an osmotic gradient- removing around 80-90%of its volume
Describe the enteropathic circulation
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
Describe how the liver may process some drugs
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.
