Liver

A large visceral abdominal organ that lies in the right upper quadrant and plays a major role in multiple functions of the body.

Embryology

Common progenitor cell with biliary tree and pancreas
Liver primordium begins to form in week 3, as an outgrowth of endodermal epithelium at the distal end of the foregut - 'hepatic diverticulum' or 'liver bud'
- The connection between the hepatic diverticulum and foregut persists, albeit narrowed, as the bile duct
Hepatic cells develop cords and intermingle with the vitelline and umbilical veins to form hepatic sinusoids
Mesoderm of the septum transversum connects the liver to the ventral abdominal wall and foregut, and eventually form the falciform ligament and lesser omentum
Some mesoderm differentiates into visceral peritoneum on the surface of the liver
In the fetal circulation, the vitelline veins carry blood from the yolk sac to the sinus venosus and ultimately form a network of veins around the foregut that drain into the developing hepatic sinusoids. These vitelline veins eventually fuse to form the PV, SMV and splenic veins. The sinus venosus eventually becomes the hepatic veins and retrohepatic IVC. The paired umbilical veins carry oxygenated blood to the fetus, initially draining into the sinus venosus, but from week 5 onwards, they begin to drain into the hepatic sinusoids. The right umbilical vein ultimately disappears, and the left umbilical vein later drains via the ductus venosus into the hepatocardiac channel, which will later become the retrohepatic IVC.
Bile is first formed in week 12, and can enter the GIT

Gross anatomy

General description

- Solid organ weighing 1.2-1.6kg

Coverings

- Fibrous capsule of Glisson
- Capsule invaginated by each portal triad at the hilum, forming a portal pedicle surrounded by a fibrous sheath (sometimes called valoean sheath)
  - Within each sheath the PV is surrounded by loose areolar tissue - dissection is relatively easy
  - Condensation of tissue around artery and duct is denser and tougher
  - Within the sheath, the bile duct tends to be elliptical rather than round, and inferior aspect usually faces the corresponding artery, and is always close to it
  - PV tends to lie posterior to the bile duct and hepatic artery
  - The sheath can be mobilised and ligated as a whole from within the liver substance - often easier and safer
- Visceral peritoneum (apart from GB fossa, porta hepatis and two wedge-shaped areas on either side of the IVC)
- Bare area - area between the coronary ligaments/triangular ligaments which is not covered by peritoneum. See below under 'coronary ligament'.

Divisions

- Historically, was divided into (small) left lobe and (large) right lobe using the umbilical fissure/falciform ligament, however this has been abandoned in favour of functional anatomy
- Divisions now based on functional anatomy - three hepatic veins that travel in three portal scissurae (fissures/clefts), along with bile ducts and hepatic artery branches
  - Right liver/left liver is more correct than right lobe/left lobe, because there are no external markings.
  - Middle hepatic vein (in the main fissure) divides liver into right and left hemilivers along Cantlie's line
    - This plane is known as the main fissure of the liver (see 'main fissure' below)
  - Right and left hepatic vein scissura further divide the liver into four separate portal sectors (right anterior - V and VIII; right posterior - VI and VII; left anterior - III and IV; left posterior - II)

Segments

- The liver is further divided into eight portal segments based on their supply by independent portal pedicles (each containing a 'portal triad' of portal vein, hepatic artery and bile duct)
- Start at the inferior part of the liver and go around the PV in an anticlockwise direction to name the segments
- Caudate lobe (segment I) is the dorsal part segment of the liver, lying directly on the IVC and aorta. The main bulk is to the left of the IVC, but a small 'caudate process' intervenes between the IVC and left portal triad. Vascular inflow and biliary drainage to the caudate lobe comes from both right and left pedicles. A number of small posterior veins drain directly into the IVC - usually 1-3, but 70% have only one, usually emerging from lower or middle third of the caudate lobe. The caudate lobe may have a fibrous component posteriorly that attaches to the diaphragm and completely encircles the IVC - the caval ligament - important in mobilising the right liver or caudate lobe off the IVC. Can continue to function well in hepatic venous outflow obstruction due to preserved links to IVC. Many high cholangiocarcinomas also involve the ducts of segment I.
- Segment II: left posterior sector. Often small, and unusual to remove that sector alone. Only a single Glissonian sheath to segment II.
- Segment III: Lies between the base of the falciform ligament and umbilical fissure on the right, and the left fissure and segment II on the left. Commonly joined to segment IV by a bridge of liver tissue over the ligamentum teres in the umbilical fissure, which is easily broken down. Predominantly drains to left hepatic vein, but can occasionally drain via the vein of the umbilical fissure.
- Segment IV: between the main fissure on the right, and the umbilical fissure on the left. Separated from segment I by the dorsal fissure. Some authors refer to the anterior part of segment IV as the quadrate lobe, calling it segment IVb. Don't necessarily need to remove IVa if IVb is being resected. Lots of variation in portal pedicles - most variable area in the liver. Resection requires careful dissection, and usually means dissecting outside the Glissonian sheaths. Often start off 5mm within segment IV itself, then dissecting outwards to find the external boundary, to be sure not to miss any variations.
- Segment V: between the main fissure and the right fissure, anterior and inferior to segment VIII. Variable size, in accordance with the variable location of right fissure.
- Segment VI: forms the right inferior extremity, to the right and behind the right fissure. Venous drainage mainly to right hepatic vein, but can be to middle hepatic.
- Segment VII: forms the major portion of the posterior part of the right liver.
- Segment VIII: mainly on the superior aspect of the liver, with little to define its borders.
- Riedel lobe - rare malformation in which a tongue of liver extends inferiorly off the right liver.

Fissures

- The limit between the territories supplied by two adjacent pedicles. The blood flow from one pedicle cannot trespass the fissure, although continuity is secured by the sinusoids. Therefore, very helpful in defining anatomical resections.
- The important fissures do not exist as such, but have to be made by the surgeon
- Some sources say 'scissura' can be used interchangeably, but 'fissure' is more common
- Main fissure
  - Separates the right side from the left, with a constant vertical plane through Cantlie's line
    - Posteriorly: from supra-hepatic IVC, through the middle of the cystic fossa, then passes slightly to the left at the porta hepatis to pass in the middle of the region where the portal structures bifurcate, and then across the caudate process
    - Anteriorly: Cantlie's line can be estimated from the middle of the gallbladder notch back to the point where the falciform ligament disappears posteriorly
    - Runs between segments V and VIII, and segment IV
  - Main trunk of middle hepatic vein lies within this fissure
- Left fissure
  - Separates left lateral from left medial
  - Runs between two points:
    - On superior liver edge, halfway between falciform ligament and left edge of liver
    - Left side of base of falciform ligament in front of IVC
  - Contains main trunk of left hepatic vein
- Umbilical fissure
  - Lies deep to the falciform ligament attachment
  - Contains the left portal pedicle
  - Often also contains an important vein - the vein of the umbilical fissure
  - Note that the umbilical fissure is not a scissura because it does not contain a hepatic vein - it just contains the left portal pedicle
- Fissure venosum
  - The continuation of the umbilical fissure on the posterior surface of the liver
  - Lesser omentum passes in here
  - Contains the obliterated ductus venosum
  - Lies more or less in the coronal plane, and is continued in the plane of the dorsal fissure - with fingers placed in the fissure venosum, they point to the dorsal fissure in front
- Dorsal fissure
  - The least definable fissure
  - Separates posterior segment IV from segment I
- Right fissure
  - Between right anterior and right posterior sectors
  - Contains right hepatic vein
  - Indicated by the point midway between GB bed and right extremity of liver, but in about 40% of cases lies much closer to the right margin of the GB bed, and can also be found in the opposite direction sometimes
  - Can sometimes be seen on the under surface of the liver as the fissure of Gans
- Porta hepatis
  - The transverse fissure in the liver between the quadrate lobe in front and the caudate process and caudate lobe behind
  - Receives structures of the hepatic pedicle at its left end, and GB neck at its right end
  - Note that the CBD tends to be in the free edge of lesser omentum, while the artery lies in front of the PV

Attachments

- These 'ligaments' are really peritoneal duplications on the liver surface
- Coronary (and triangular) ligaments
  - Peritoneal reflections
  - Attaches the posterior surface of the liver to the diaphragm
  - Need to be taken down early to avoid bleeding when mobilising the liver
    - Be wary of right hepatic vein and IVC for mobilising the superior leaf
    - Be wary of IVC for the inferior leaf
  - Right
    - Superior and inferior leaflets of the right coronary ligament run laterally
    - The lateral aspect, including both superior and inferior ligaments, is called the right triangular ligament
  - Left
    - A mirror of the right, but smaller
    - Really just the triangular ligament on this side
  - The 'bare area' lies within the coronary/triangular ligaments - liver surface up against diaphragm without a peritoneal covering. Liver attached to diaphragm by fibro-alveolar tissue, which is not avascular, and varies in the density of the fibrous component.
    - IVC and hepatic veins lie within the bare area
- Falciform ligament
  - Formed by fusion of left and right anterior coronary ligaments
  - Vestige of the ventral mesogastrium
  - Suspends liver to anterior diaphragm, and then extends down the abdominal wall as far as the umbilicus
  - Ligamentum teres runs in the free edge
  - The superior-posterior part of the falciform ligament attachment to the liver also serves as a guide to the IVC - there is a slight depression in the middle, with left hepatic vein on one side and right hepatic vein on the other
- Ligamentum teres hepatis
  - Runs from umbilicus to inferior margin of the liver as the inferior edge of falciform ligament, where it enters the umbilical fissure and joins the left branch of the portal vein
  - Remnant of obliterated left umbilical vein - supposedly a fibrous cord
  - In reality it is generally closed rather than obliterated and it can be dissected at the umbilicus, dilated and used to access the left portal vein in 50% of patients
  - This channel occasionally opens up in portal hypertension, forming a collateral channel to bypass hepatic circulation, and in such situations can become quite large
  - Surgical significance
    - Can get in the way during upper abdominal operations - may need to be divided. If so, ensure to ligate the small para-umbilical veins carefully before dividing, which can link with the portal system.
    - Can be divided near the liver or near the umbilicus, with the free end being used as an anchor - e.g. as a sling to anchor the oesophagus intra-abdominally
    - As a guide to the ductal system of segment III for biliary enteric drainage procedures, by following ligamentum teres down in the fissure between segment III and IV
- Ligamentum venosum
  - Remnant of obliterated ductus venosum/sinus venosus
  - Runs from left PV in the porta hepatis to left hepatic vein and IVC, allowing fetal blood to bypass the liver
  - Also runs in a fissure
  - Needs to be divided for safe dissection of left hepatic vein

Vascular anatomy

Portal vein

- Provides about 75% of hepatic inflow, and 50-70% of oxygen requirement. No valves, so accommodates high flow at low pressure
- Embryology
  - Forms from right and left vitelline veins
  - Left vitelline vein becomes lower part of PV
  - Upper part of right vitelline vein becomes upper part of PV
- Course
  - Forms behind the neck of the pancreas from SMV and splenic vein. Also gets blood from left gastric vein, with variable point of inflow.
  - Length 5.5-8cm, diameter 1cm
  - Runs behind D1 (with GDA just anterior to it) and into the hepatoduodenal ligament, where it runs along the right border of the lesser omentum (posterior to CBD and PHA)
  - Tributaries below duodenum enter from the right, posteriorly and the left, but not anteriorly; gentle blunt dissection anterior to PV can open up a plane behind the neck of the pancreas
  - Does not tend to have tribs above the duodenum, but some tributaries may be found lower down
    - Pancreaticoduodenal vein - enters on the right side, behind or immediately above the duodenum
    - Right and sometimes left gastric vein - if entering PV, do so on the left, usually behind the duodenum
  - Divides into main right and left branches at the hilum of the liver
- Branches
  - Right portal triad - short extrahepatic course (1.5cm), which appears to be the continuation of the main PV, before entering the liver and branching into anterior and posterior sectoral branches. Division to right lateral sector describes a gentle curve towards right posterior liver; right medial sector can arise at an angle. These branches can sometimes be seen extra-hepatically and can come off the main PV. Usually a small caudate process branch off the main right PV.
  - Left portal triad - longer extrahepatic course (4cm) and runs transversely along the base of segment IV in a peritoneal sheath, which is the upper end of the lesser omentum. Then runs anterior and caudally in the umbilical fissure, giving branches to segments II and III on the left, branches to the left side of the caudate lobe, and recurrent branches to segment IV on the right. Ligamentum teres is attached to the vein in the umbilical fissure.
- Tributaries
  - SMV and splenic vein
  - Right and left gastric veins
  - Superior pancreaticoduodenal veins
  - Cystic vein/s into the right branch of the portal vein
  - Periumbilical veins running with ligamentum teres
- Portosystemic shunts
  - Submucosal veins in upper stomach and oesophagus - drain cephalad into azygos system - varices
  - Varices of the inferior rectal (haemorrhoidal) veins in the wall of the rectum. Note that these are different to haemorrhoids - these are true veins, occurring cephalad to the haemorrhoidal venous plexuses.
  - Ligamentum teres - occasionally the umbilical vein itself opens up, but more often small para-umbilical veins which run with the ligamentum teres, enlarge and allow dilatation of contiguous veins in the umbilicus and abdominal wall
  - Retroperitoneum - multiple, usually small, veins from the splenic venous system can enlarge and communicate with diaphragmatic, adrenal, or renal veins
- Variations
  - Standard anatomy seen in 70%
  - Most common variation is the 'portal vein trifurcation': main PV divides into left, right posterior and right anterior branches.
  - Other common variation is the right posterior PV originating as the first branch of the PV, or the right anterior PV arising from the left PV
  - Other very rare variations:
    - PV found anteriorly to neck of pancreas and duodenum
    - Direct entry of PV to IVC
    - Pulmonary vein entering PV
    - Congenital absence of left branch of PV (with right branch coursing peripherally through the liver to supply the left liver)

Hepatic artery

Provides 25% of the hepatic blood flow and 30-50% of its oxygenation
Embryology
- The embryo receives blood from a right, middle and left hepatic artery
- Usually the right and left arteries disappear
Intra-hepatic
- Variations are relatively common but most do not have significance
Extra-hepatic
- Classic course (seen 60% of the time - persistent of the middle primordial artery)
  - Classic anatomy is the CHA arises from coeliac trunk, passes forward and to the right along the superior border of the pancreas (behind the posterior wall of lesser sac), then becomes hepatic artery proper after giving off GDA. There is consistently a large flat ovoid lymph node just anterior to hepatic artery at the point where it gives off GDA, and removal of this node is the easiest way of accessing hepatic artery proper.
  - Hepatic artery proper runs along the right side of the lesser omentum, ascending toward the hepatic hilum, anterior to PV and to the left of the CBD
  - Hepatic artery proper bifurcates into a left and right hepatic artery at the hepatic hilum
    - Variable point of bifurcation - 20% have a low bifurcation, 5% have early division where RHA arises first and crosses behind PV
  - RHA travels transversely, posterior to CHD in 90-95% of patients, and eventually travels through the triangle of Calot, at which point gives off the cystic artery. As RHA enters the hilar plate, it often bifurcates into anterior and posterior branches, with the latter entering the sulcus of Rouviere as it joins the right posterior portal pedicle
  - LHA enters through the umbilical fissure to supply segments II, III, and IV. LHA also usually gives off a middle hepatic artery branch that supplies segment IV. LHA is usually the most anterior and left-lying structure in porta hepatis.
- Variations - highly variable - below are some of the variations, not exhaustive - there is a classification system by Michel et al in 1955 types I-X
  - Classic anatomy is seen in about 60%
  - CHA
    - Origin:
      - Coeliac trunk >90%
      - Aorta 2%
      - SMA 2-4%
        Hepatic artery will then run behind portal vein
    - Division
      - Early division CHA - can originate as far back as separate branches from SMA 5%
      - Low division CHA 15%
      - Trifurcation into RHA, LHA and GDA
  - RHA
    - Origin (replaced RHA)
      - CHA 85%
      - SMA 12.5%
      - Coeliac trunk 2.5%
    - Path
      - Crossing anterior to CHD instead of posterior - dangerous for lap cholecystectomy
      - Moynihan's ('caterpillar') hump - makes a deviation into hepatocystic triangle before giving off a short cystic artery then curling back towards porta hepatis, often after passing anterior to CHD
  - LHA
    - Origin (replaced LHA)
      - CHA 85%
      - Left gastric artery 7.5%
  - Middle hepatic artery
    - Origin
      - LHA
      - RHA (uncommon)
      - CHA (trifurcation) uncommon
  - Accessory vessels
    - RHA
      - Accessory RHA from SMA 4%
        Usually arises from SMA and ascends behind HOP and duodenum, passing behind PV in the free edge of lesser omentum
        
        Degree of supply to liver varies from supplemental to sole segmental
      - Accessory RHA from aorta, coeliac trunk, GDA - all rare
    - LHA
      - Accessory LHA from left gastric artery 7.5%
        Very rare for this to be the sole blood supply to the left liver
        
        Runs in lesser omentum, and enters liver through the fissure venosum
      - Accessory LHA from RHA
      - Accessory LHA from coeliac, aorta, splenic, GDA - all rare
    - Accessory LHA and RHA: 1%
- Branches
  - Right gastric
    - See 'stomach'
  - GDA
    - Arises from CHA behind or above duodenum
      - Can occasionally arise from SMA
    - Just anterior to PV as it initially descends, behind duodenum but in front of neck of pancreas, in a groove on pancreatic capsule
    - Main trunk or supraduodenal branch is commonly involved in bleeding ulcers
    - Terminates by dividing into the right gastro-epiploic artery and two superior pancreaticoduodenal arteries (those anterior and posterior branches descend between duodenum and HOP, anastomosing with corresponding branches of inferior pancreaticoduodenal arteries)

Hepatic veins

- Do not correspond with portal segmentation
- Major hepatic veins lie between the four main sectors
- There are only two major hepatic veins entering the IVC
- Course
  - Right hepatic vein - runs in the right scissura between the anterior and posterior sectors of the right liver, and drains most of the right liver. Usually the largest, but also the most variable. Enters IVC at about the upper pole of the caudate lobe, a few mm lower than the left hepatic vein.
  - Left and middle hepatic veins usually join intra-hepatically and enter the left side of the IVC as a single vessel, but with the common trunk usually only 5mm in length before reaching IVC.
    - Left hepatic vein runs in the left scissura between segments II and III and drains those segments only. Takes the ligamentum venosum. Situated in the posterior 2cm of the left fissure, making up part of the posterior edge of liver, only being covered by connective tissue of the left triangular ligament.
      - Also receives tributaries from the vein of the umbilical fissure and a posterior branch from the posterior part of the left liver, which can sometimes still allow segment IV to drain after resection of middle hepatic vein
    - Middle hepatic vein runs in the portal scissura between segment IV and the right anterior sector, and drains segment IV and some of the right anterior sector
  - Umbilical vein, if patent, usually empties into left hepatic vein, in umbilical fissure
  - Small inferior veins from segment VIII and caudate lobe drain directly into IVC
    - In 15% of patients, there is a moderately large right vein here, termed the accessory right hepatic vein
    - Approach and ligate these by mobilising the liver then exposing to the opposite side of the vein
  - Also common tributary from caudate love into left hepatic vein

Biliary system

Biliary radicals
- First-order: right and left CHD
- Second-order: the next-largest ducts upstream
- Third-order: unusual to see these on MRCP
- The main duct draining each Couinaud segment is named after it: B1, B2, B3, etc.
Each portal pedicle contains an intra-hepatic bile duct - the terminal branches of the right and left hepatic ducts. The bile duct branches are usually superior to the portal vein, with the hepatic artery further inferior.
Left hepatic bile duct
- Drains segments II, III, and IV
- Forms from intra-hepatic ductal branches at the base of the umbilical fissure
- Exposed by dividing the peritoneum at the base of the quadrate lobe and opening the hilar plate. The duct is usually the most superficial of the portal triad structures here.
Right hepatic bile duct is formed from:
- Right anterior sectoral duct (segments V and VIII) - runs vertically
- Right posterior sectoral duct (VI and VII) - runs in a horizontal and posterior direction, typically curving around the right anterior duct (Hjortso's crook)
  - This crook places RPSD at risk when RASD is divided
Caudate lobe
- Drains through both sides 80%
- Drains through left only 15%
- Drains through right only 5%
The RHD bifurcates close upstream from the CHD, into anterior and posterior segmental ducts. Variable confluence - see diagram below
- Note that 30% of patients have some right ducts draining into the main left hepatic duct, usually RPSD - always tie the left duct as far to the left as possible

Innervation

SNS from T7-T10
- Pass through coeliac ganglia before giving off post-ganglionic fibres to liver and bile ducts
- Supply hepatic arteries
PNS from both vagal nerves
Right-sided coeliac ganglia and right vagal nerve form an anterior hepatic nerve plexus, accompanying the hepatic artery
Left-sided coeliac ganglia and left vagal nerve form a posterior hepatic nerve plexus running posterior to the bile duct and portal vein
Acute distension of the liver, and capsular stretch, can refer to the right shoulder through the phrenic nerve

Lymphatics

Most lymph from the liver drains to the hepatoduodenal ligament
From here, it usually continues along the hepatic artery to the coeliac lymph nodes and then to the cisterna chyli
Lymph can also follow the hepatic veins to lymph nodes in the supra-hepatic IVC and through the diaphragmatic hiatus

Microscopic anatomy

Structure of a lobule
- Each lobule is made up of a central terminal hepatic venule, surrounded by 4-6 terminal portal triads that form a polygonal unit
- In between the vein and triad, hepatocytes are arranged in once-cell-thick plates, surrounded on each side by endothelium-lined and blood-filled sinusoids - the functional unit of the liver
- Blood flows from the portal triad through the sinusoids into the terminal hepatic venule through three zones, which have different enzymatic makeups and respond differently to toxin exposure and hypoxia
  - Zone 1 (periportal): rich in nutrients and oxygen
  - Zone 2 (intermediate): poorer
  - Zone 3 (peri-venular zone): poor, and most susceptible to decreases in oxygen delivery (explains the phenomenon of centrilobular necrosis)
- Bile is formed within the hepatocytes and empties into terminal canaliculi, which form on the lateral walls of the intercellular hepatocyte, and ultimately coalesce into bile ducts and flow toward the portal triads

Hepatic microcirculation
- Arterial and PV flow varies inversely in the sinusoids and can be compensatory. Local control likely depends on arteriolar sphincters, and contraction of the sinusoidal lining by endothelial cells and hepatic stellate cells or portal myofibroblasts.
- Unidirectional flow from zone 1 to zone 3 and then into the terminal hepatic venule
- Sinusoidal endothelial cells
  - The sinusoids are 7-15microm wide but can increase up to 10-fold
  - Should be a low-resistance and low-pressure (2-3mmHg) system
  - Sinusoidal endothelial cells account for 15-20% of the total hepatic cell mass
  - Sinusoidal endothelial cells are separated from hepatocytes by the space of Disse (peri-sinusoidal space), where hepatocytes project microvilli
  - Endothelial cells fenestrated and have no intercellular junctions/basement membrane
- Kupffer cells
  - Derived from macrophage-monocyte system, phagocytic
  - Line the sinusoids, insinuating between endothelial cells
  - Trap foreign substances and initiate inflammatory responses
  - Natural killer, CD4 T and CD8 T cells also exist
- Hepatic stellate cells
  - Vitamin A storage and synthesis of extracellular collagen and other ECM proteins
  - Activated to a myofibroblast state in acute and chronic liver injuries
  - Key role in progression of fibrosis to cirrhosis
- Hepatocytes
  - Make up 60% of the hepatic cellular mass
  - Every hepatocyte has contact with adjacent hepatocytes, the biliary space and the peri-sinusoidal space
  - Functions
    - Uptake, storage and release of nutrients
    - Synthesis of glucose, fatty acids, lipids, and numerous plasma proteins (including CRP and albumin)
    - Production and secretion of bile for digestion of dietary fats
    - Degradation and detoxification of toxins
  - Bile canaliculi form a ring around the hepatocyte that drains into small bile ducts known as canals of Hering, which empty into a bile duct at a portal triad
  - The monoclonal antibody HepPar1 (hepatocyte paraffin 1) identifies a unique antigen on hepatocyte mitochondria and can be used to identify hepatocytes on immunohistochemical examination

Functions

Energy
- Glycogenolysis from glycogen and gluconeogenesis from lactate pyruvate, glycerol, propionate, and alanine
Blood flow
- Portal pressure is normally 6-10mmHg and sinusoidal pressure is normally 2-4mmHg
- Arteriolar tone is regulated by autonomic nervous system, circulating hormones, bile salts, and metabolites
- Hepatic arterial flow can be increased to compensate decreased portal vein flow, but the opposite does not occur
- Total portal vein occlusion cannot be fully compensated by the hepatic artery, leading to ipsilateral atrophy
Bile formation
- Bile is used to dispose of secreted substances and to provide enteric bile salts to aid in digestion of fats, and absorption of fat-soluble vitamins (ADEK) and lipophilic drugs
- Secreted by hepatocytes into canaliculi
- 1500mL of bile is secreted daily, and 80% of this is secreted by hepatocytes into canaliculi (largely the result of water flow in response to active solute transport.
- Bile flow has a linear relationship with bile acid secretion, known as bile acid-dependent flow
- Epithelial cells of the biliary tract continue to actively reabsorb and secrete water and electrolytes into and from bile, but usually with a net secretion, accounting for the other 20% of biliary secretion
- Gallbladder acts as the reservoir of the biliary tree - function is to store bile in the fasting state
- The gallbladder reabsorbs water, concentrating stored bile, and secretes mucin
- Bile contents
  - Osmolality is approximately 300mOsm/kg (similar to blood) and is accounted for by the inorganic solutes
  - Major organic solutes are bile acids, bile pigments, cholesterol and phospholipids
Enterohepatic circulation
- Bile salts (primarily cholic acid and chenodeoxycholic acid) are produced in the liver from cholesterol
- These primary bile acids are modified by intestinal bacteria to form the secondary bile acids (deoxycholic acid and lithocholic acid), which are reabsorbed passively in the jejunum and actively in the ileum
- After returning to hepatocytes in the portal venous circulation, up to 90% of the bile acids are extracted, and only a small proportion spill over into the systemic circulation
- A small amount of intestinal bile acids are not reabsorbed and are excreted in the stool
- This circulation is also the major mechanism for excreting excess cholesterol
Bilirubin metabolism
- Bilirubin-albumin complex in blood enters the peri-sinusoidal space, and is disassociated
  - Portosystemic shunts (cirrhosis and portal HTN) decrease first-pass hepatic clearance of bilirubin, leading to mildly increased serum levels
- Free bilirubin is taken up by the hepatocyte, where it is conjugated with glucuronic acid and then secreted against a concentration gradient into canalicular bile
- The majority of conjugated bilirubin-glucuronic acid is deconjugated within the intestine to a group of compounds known as urobilinogens
  - The majority passes through the GIT without reabsorption and is excreted in the stool as stercobilin
  - Some urobilinogens are further oxidised and reabsorbed into the enterohepatic circulation. Some is re-conjugated and cleared by the liver, and some reaches the systemic circulation.
  - A small percentage of the reabsorbed urobilinogens are excreted into urine - contributing to the yellow colour of urine
Carbohydrate metabolism
- Contains up to 65g of glycogen/kg of liver tissue, which can be broken down through glycogenolysis
- Between meals, the liver is the primary source of glucose; especially important for brain and erythrocytes, which rely on glucose for metabolism
- In fasting, liver uses lactate to produce glucose via the Cori cycle
- During a prolonged fast, fatty acids from adipose breakdown are beta-oxidised in the liver, which releases ketone bodies that then become the primary fuel for the brain
- Transition between metabolic states is mostly dependent on hormones and sinusoidal glucose concentration
- Derangements of carbohydrate metabolism are common in cirrhotics and liver disease in general. Only with massive hepatocyte loss in fulminant liver failure does gluconeogenesis fail and hypoglycaemia ensue.
Lipid metabolism
- Fatty acids synthesised in the liver during states of glucose excess, which are then stored in adipose tissue
- Prolonged increased circulating fatty acids will override the liver's ability to handle them, resulting in fatty accumulation in the liver, known as steatosis, and when added to chronic inflammation in more advanced states, steatohepatitis. Diabetes, steroid use, starvation, obesity, and chemotherapeutic agents are associated with this state.
Protein metabolism
- Excess amino acids not used by peripheral tissues are either oxidised for energy or converted to other energy sources in the liver
- Ammonia, glutamine, glutamate and aspartate are produced through catabolisation of amino acids throughout the body, then processed in the liver, where waste nitrogen is converted to urea in the urea cycle, and the urea is generally excreted in the urine
- Liver is responsible for production of albumin, ceruloplasmin, iron storage and binding proteins, and alpha-1 antitrypsin
- Liver is also responsible for many acute phase response proteins
Vitamin metabolism
- Metabolism of fat-soluble vitamins ADEK
- Vitamin is solely stored in the liver, and overdose can result in hepatic toxicity
- Cholestasis syndromes can result in inadequate absorption secondary to poor micellization in the intestine
  - Metabolic bone disease (vit D deficiency)
  - Neurologic disorders (vit E deficiency)
  - Coagulopathy (vit K deficiency)
Coagulation
- Synthesises almost all the identified coagulation factors, and for clearing coagulation products
- Hepatic synthetic dysfunction leads to abnormal PT, mostly through inability to activate factor VII by vitamin K in the liver
Metabolism of drugs and toxins
- Phase 1 reactions increase the polarity and thus water-solubility of compounds, to allow easier excretion, and occur in the cytochrome P450 system
- Phase 2 reactions generally act to create a less toxic or less active by-product, generally through transferase reactions
Regeneration
- Hyperplastic response of all cell types in the liver, in which the microscopic anatomy is maintained
- Maximal hepatocyte DNA synthesis occurs 24-36 hours post-partial hepatectomy, and most of the increase in hepatic mass is seen by 3 days in rodents, and it is usually almost complete after 7 days
- A variety of factors have been implicated, but many questions still remain, and we are not able to induce hepatic growth in a normal host yet