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SURGICAL WEBSITES             KIDNEY SURGERY         POSTGRADUATE SURGERY LINKS 

BREAST DISEASE     Breast cancer Breast lump Breast awareness Breast calcifications  Breast cysts Breast pain Duct ectasia Fat necrosis Fibroadenoma Hyperplasia Intraductal papilloma Phyllodes tumour Sclerosing adenosis                                                                                                                                                 

LIVER ABSCESS      Anatomy of liver Physiology of liver Method of examination of liver Haematology of liver disease. Amoebic liver abscess .Pyogenic liver abscess. Percutaneous needle aspiration of liver abscess. Case study.  Result Result continued  Discussion                                                                 

CHOLECYSTECTOMY    Introduction   Historical Review  Anatomy of Gallbladder Physiology of Gallbladder Physiologic effects of pneumoperitoneum Pathology  of Gallbladder Investigations Pre- operative preparation of laparoscopic cholecystectomy Contraindications  Treatment modalities for gallstones.  Anaesthesia                                                                                                                       

INGUINAL HERNIA    HOW SURGICAL OPERATION IS DONE     THYROID EXAMINATION MANAGEMENT OF SEVERELY INJURED PATIENT      SEPSIS AND MULTIPLE ORGAN FAILURE CHEST TRAUMA     BRONCHOGENIC CARCINOMA     TETANUS AND ANAEROBIC INFECTIONS 

ANATOMY OF LIVER.

Liver is the largest organ of the body weighs about 1200- 1500g and comprises one-fifteenth of the total adult body weight. It occupies a substantial portion of the abdominal cavity.

I. Location: Sheltered by ribs in the right hypochondrium, the upper border lies at the level of the nipples. Extends into left hypochondrium. Enclosed in a layer of connective tissue-Glisson’s capsule. Covered by peritoneum except bare area on the superio-posterior surface.

II. Divisions: There are two anatomical lobes, the right being about six times the size of left and is divided into anterior and the posterior segments. Lesser segments of the right lobe are caudate lobe on the posterior surface and the quadrate lobe on the inferior surface.

III. Ligaments and Fissures: The main lobar fissure divides the liver into the right and the left lobe. In foetal development the falciform ligament carries the umbilical vein. After birth the vein collapses and forms a cord, the ligamentum teres (round ligament). The falciform ligament (and thus the ligamentum teres since it is contained within the falciform ligament) divides the left lobe into medial and lateral segments. The ligamentum venosum is the remnant of the foetal ductus venosus. Ligamentum venosum divides the caudate from the left lobe.

V. Biliary tract: The right and the left hepatic ducts emerge from the liver and unite in the porta hepatis to form the common hepatic duct. This is soon joined by the cystic duct from the gallbladder to form the common bile duct. The common bile duct runs between the layers of the lesser omentum, lying anterior to the portal vein and to the right of the hepatic artery.

VI. Sectors and segments: Based on the external appearance described above the liver has a right and a left lobe. This separation how ever does not correlate with blood supply or biliary drainage. A functional anatomy is now recognised based upon the studies of vascular and biliary casts made by injecting vinyl into the vessels and bile ducts. The classification is helpful in surgical resection of liver ⁸.

            The main portal vein divides into right and left branches and each of these supplies to further sub-units (variously called sectors). The sectors on the right side are anterior and posterior and in the left lobe, medial and lateral - giving a total of four sectors. Using this definition, right and left side of the liver are divided not along the line of the falciform ligament, but along a slightly oblique line to the right of this, drawn from the inferior vena cava below to the gall bladder bed above. The right and the left sides are independent with regards to the portal and arterial blood supply, and bile drainage. Three plains separate the four sectors and contain the three major hepatic vein branches.

LIVER SEGMENTS: Closer analysis of these four hepatic sectors produces a further subdivision into segments. The Couinaud classification divides the liver into 8 independent segments, each of which has its own vascular flow, outflow and biliary drainage. Because of this division into self-contained units each can be resected without damaging those remaining. In most cases, the vascular outflow for each segment is provided by three hepatic veins at its periphery, however accessory hepatic veins are common.

The intersegmental plane defined by right hepatic vein subdivides the right lobe of the liver into anterior (V and VIII) and posterior (VI and VII) divisions. The lateral border of the liver contour is formed by segments VIII (superiorly) and V (inferiorly) as the liver viewed in situ. Segments VI and VII lie posterior to VIII and V respectively. The plane defined by the middle hepatic vein subdivides the liver into the true right and left lobes. Segments IVa and IVb lie to the left of the plane while segment V and VIII being superior to VI. Because the plane of the middle hepatic vein usually intersects the gall bladder fossa, Cantlie’s line (the projection of the liver surface of a plane between the gall bladder and inferior vena cava) is generally a valid line of division between the right and the left lobes. However it is the vasculature that determines the true boundary.

            The umbilical plane divides the left lobe of the liver into medial (segment IV) and lateral (segment II and III) divisions. This division is the only vertically oriented plane of division that is not defined by the hepatic veins. It can be defined on the surface of the liver by its associated land marks. It extends from the umbilical fissure anteriorly through the ligamentum venosum along the lateral aspect of the caudate lobe. Structures within the plane of the umbilical fissure include the falciform ligament, ligamentum venosum, and ligamentum teres are remnant of ductus venous and umbilical veins respectively.

The significance of the left hepatic vein plane is shown to coincide with the umbilical fissure. In reality the left hepatic vein courses to the left umbilical fissure. The plane of the left hepatic vein is a true intersegmental boundary between segment II and segment III. In II and III are usually removed based on the plane formed by the umbilical fissure. Because the plane of the umbilical fissure is oblique, it forms a division between segment III anteriorly and segment II posteriorly.

            The plane defined by right branch of the portal vein divides the anterior and posterior divisions of the right liver superiorly and inferiorly, thus dividing the right lobe into four segments (V-VIII). The medial segment of the left lobe can also be divided into two segments by the plane of the portal vein (IVa and IVb). While the portal vein plane has often been portrayed as transverse, it may be oblique since the left branch runs superiorly and the right branch runs inferiorly. In addition to forming an oblique transverse plane between segments, the left and right portal veins branch superiorly and inferiorly to project into centre of each segment.

Segment 1: The Caudate Lobe: The most unique of the segments is segment I which corresponds to the caudate lobe (also known as the Spigel lobe). It is located on the posterior surface of the liver adjacent to the segment IV. Its medial and lateral boundaries are defined by inferior vena cava and ligamentum venosum respectively.

            Segment I is different than the other segments in that its portal inflow is derived from the left and the right branches of the portal vein and it often has its own short hepatic veins connecting directly to inferior vena cava. Because of the extensive crossing of the vessels and its position relative to the porta hepatis and inferior vena cava, segment I is not often resected.

            Segments I, II, VI, and VII are most posteriorly and hidden from the surgeon’s view in the operating room. Before surgical resection, the focal liver lesion must be defined in relation to the deep vessels and the segmental anatomy. This is easily and quickly accomplished using intraoperative ultrasound ⁹. The right anterior sector contains the segment VI and VII; left medial, III and IV; left lateral sector, segment II. There are no vascular anastomoses between macroscopic vessels of the segments but communication exists at the sinusoidal level. Segment I, the equivalent of the caudate lobe is separate from the other segments and does not derive blood directly from the major portal branches or drain by any of the three major hepatic veins. The hepatic veins are inter-segmental. They divide the liver into segments. Left hepatic vein divides the left lobe of the liver into medial and lateral segments. Right hepatic vein divides the right lobes into anterior and posterior segments. This functional anatomical classification allows interpretation of radiological data and is of importance to the surgeon planning a liver resection.

VII. Vascular Supply: The liver has double blood supply. It receives 2/3^rd of its blood from portal vein, which brings (partially oxygenated) venous blood from the intestine and spleen. It receives1/3^rd of its blood supply from hepatic artery, coming from the coeliac axis, supplies the liver with (oxygenated) arterial blood. These vessels enter the liver through a fissure, the porta hepatis, which lies far back on the inferior surface of the right lobe. Inside porta, the portal vein and hepatic artery divide into branches to the right and left lobes, and the right and the left hepatic ducts join to form the common hepatic ducts. The hepatic nerve plexus contains fibres from the sympathetic ganglia T7 to T10, which synapses in the coeliac plexus, the right and the left vagi and the right phrenic nerve.

The ligamentum venosum, a slender remnant of the ductus venosus of the foetus, arises from the left branch of the portal vein and fuses with the inferior vena cava at the entrance of left hepatic vein. The ligamentum teres, a remnant of umbilical vein of the foetus, runs in the free edge of falciform ligament from the umbilicus to the inferior border of the liver and joins the left branch of the portal vein. Small vein accompanying it connects the portal vein with vein around umbilicus. These become prominent when the portal venous system is obstructed inside the liver. The arterial blood supply to the supraduodenal bile duct is by two main axial vessels which run besides the bile ducts. These are supplied predominantly by the retroduodenal artery from below and the right hepatic artery from above, although many other vessels contribute ¹³.

            The venous drainage from the liver into the right and left hepatic veins which emerge from the back of the liver and at once enter the inferior vena cava very near its point of entry in the right atrium. Lymphatic vessels terminate in small groups of glands around the porta hepatis. Efferent vessels drain into glands around coeliac axis. Some superficial hepatic lymphatics pass through the diaphragm in the falciform ligament and finally reach the mediastinal glands. Another group accompanies the inferior vena cava into the thorax and ends in a few small glands around the intrathoracic portion of the inferior vena cava.

            The inferior vena cava makes a deep groove to the right of the right of the caudate lobe about 2cm from the mid-line. The gallbladder lies in a fossa extending from the inferior border of the liver to the right end of porta hepatis.

            The liver is completely covered with except in three places. It comes into direct contact with the diaphragm through the bare area, which lies, to the right of the fossa for inferior vena cava and gallbladder. The liver is kept in position by peritoneal ligaments and by the intra abdominal pressure transmitted by the tone of the muscles.

EMBRYOLOGY OF LIVER

       The liver begins as a hollow endodermal bud from the foregut (duodenum) during the third week of gestation. The bud separates into two parts – hepatic and biliary. The hepatic part contains bipotential progenitor cells that differentiates into hepatocytes or ductal cells, which form the early primitive bile duct structures (ductal plate). Differentiation is accompanied by changes in cytokeratin type within the cell. This collection of rapidly proliferating cells penetrates adjacent mesodermal tissue (the septum transversum) and is met by ingrowing capillary plexus from the vitelline and the umbilical veins, which will form the sinusoids. The connection between this proliferating mass of cells and the foregut, the biliary part of the endodermal bud, will form the gallbladder and extrahepatic bile ducts. Bile begins to flow at about the twelfth week. Haemopoietic cells, Kupffer cells and connective tissue cells are derived from the mesoderm of the septum transversum. The foetal liver has a major haemopoietic function, which subsides during the last two months of the intrauterine life so that only a few haemopoietic cells remain at birth.

ANATOMICAL ABNORMALITIES OF LIVER

       These are being increasingly diagnosed with more widespread use of computed tomography (C.T.) and ultrasound scanning. The knowledge of the anomalies in the development of the liver and in relation the gallbladder is important in the surgical management of the liver diseases ¹¹.

1.    Accessory lobes: The liver of the pig, dog and camel is divided into distinct and separate lobes by strands of connective tissue. Occasionally the human liver may show this reversion and up to 16 lobes have been reported. This abnormality is rare and without clinical significance. The lobes are small and usually on the under surface of the liver so that they are not detected clinically but noted incidentally at scanning, operation or autopsy. Rarely they are intra-thoracic. An accessory lobe may have its own mesentery containing hepatic artery, portal vein, bile duct and hepatic vein. This may twist and demand surgical intervention.

2.    Riedel’s lobe: It is fairly common and is a downward tongue like projection of the right lobe of liver. It is a simple anatomical variation; it is not a true accessory lobe. The condition is more frequent in women. It is detected as a mobile tumour on the right side of the abdomen, which descends with the diaphragm. On respiration it may come as close down as low as right iliac fossa. It is easily mistake n for other tumours in this area, especially a visceroptotic right kidney. It does not cause symptoms and treatment is not required. Scanning may be used to identify Riedel’s lobe and other anatomical abnormalities.

3.    Cough furrows on the liver: These are parallel groves on the convexity of the right lobe. They are one to six in number and run antero-posteriorly, being deeper posteriorly. They are said to be associated with chronic cough.

4.    Corset liver: This is a fibrotic furrow or pedicle on the anterior surface of both the lobes of the liver just below costal margin. The mechanism is unknown, but it affects elderly women who have worn corset for many years. It presents as an abdominal mass in front of and below the liver and is isodense with the liver. It may be confused with a hepatic tumour.

5.    Lobar atrophy: Interference with the portal supply or biliary drainage of a lobe may cause atrophy. There is usually hypertrophy of the opposite side. Left lobe atrophy found at post-mortem or during scanning is not uncommon and probably related to reduced blood supply via the left branch of the portal vein. The lobe is decreased in size with thickening of the capsule, fibrosis and prominent biliary and vascular markings. The vascular problem may date from the time of birth. Obstruction of right or left hepatic bile duct by benign stricture or cholangiocarcinoma is now the most common cause of lobar atrophy. The alkaline phosphatase is usually elevated. The bile duct may not be dilated within the atrophied lobe. Relief of obstruction may reverse the changes if cirrhosis has not developed.

6.    Agenisis of the right lobe: This rare lesion may be an incidental finding associated, probably coincidentally, with biliary tract disease and also with other congenital abnormalities. It can cause pre-sinusoidal portal hypertension. SURFACE ANATOMY OF LIVER

       The upper border of the right lobe is at the level of the 5^th rib at a point 2 cm medial to the right mid clavicular line. The upper border of the left lobe corresponds to the upper border of the 6^th rib at a point in the left mid clavicular line. Here only diaphragm separates the liver from the apex of the heart.

       The lower border passes obliquely upwards from the 9^th right to the 8^th left costal cartilage. In the right nipple line it lies between a point just under to 2 cm below the costal margin. It crosses the midline about midway between the base of the xiphoid and the umbilicus and the left lobe extends only 5 cm to the left of the sternum. Surface anatomy is shown in figure 4.

HISTOLOGY OF LIVER

HEPATIC MORPHOLOGY.

       Kiernan (1833) introduced the concepts of hepatic lobules as the basic architecture. He described circumscribed pyramidal lobules consisting of central tributary of the hepatic vein and at the periphery a hepatic tract containing bile duct, portal vein radical and hepatic artery branch. Columns of liver cells and blood containing sinusoids extended between these two systems.

       Stereoscopic reconstruction and scanning electron microscopy have shown the human liver as columns of liver cells radiating from a central vein and interlaced in orderly fashion by sinusoids.

       The liver tissue is pervaded by two systems of tunnels, the portal tract and the hepatic central canals, which dovetail in such a way that they never touch each other; the terminal tunnels of the two systems are separated by about 0.5mm. As far as possible the two systems of tunnels run in plane perpendicular to each other. The sinusoids are irregularly disposed, normally in a direction perpendicular to each other. The sinusoids are irregularly disposed, normally in a direction perpendicular to the lines connecting the central veins. The terminal branch of the portal vein discharge their blood into the sinusoids and the direction of flow is determined by higher pressure in the portal vein than in the central vein.

       The central hepatic canals contain radicles of the hepatic veins and the adventitia. A limiting plate of liver cells surrounds them. The portal triads contain the portal vein radicle, the hepatic arteriole and bile duct with a few round cells and a little connective tissue. A limiting plate of liver cells surrounds them. The liver has to be divided functionally. Traditionally the unit is based on a central hepatic vein and its surrounding liver cells. However, Rappaport envisages a series of functional acini, each centred on the portal triad with its terminal branch of portal vein, hepatic artery and bile duct. These interdigitate, mainly perpendicularly, with terminal hepatic veins of adjacent acini. The circulatory peripheries of acini suffer most from injury whether viral, toxic or anoxic. Bridging necrosis is located in this area. The region closer to the axis formed by afferent vessels and the bile ducts survive longer and may later form the core from which regeneration will proceed. The contribution of each acinar zone to liver cell regeneration depends on the acinar location of damage.

       The liver cells (hepatocytes) comprise about 60% of the liver. They are polygonal and approximately 30µm in diameter. The nucleus is single or less often, multiple and divide by mitosis. The life span of liver cells is about 150 days in experimental animals. The hepatocytes have three surfaces: one facing the sinusoid and space of Dissė, the second facing the canaliculus and the third facing neighbouring hepatocytes. There is no basement membrane.

       The walls of the sinusoids consist of endothelial and phagocyte cells of the reticuloendothelial system. The fat cell component is known as Kupffer cell. The approximately 202*10³ cells in each milligram of normal human liver, of which 171*10³ are parenchymatous and 31*10³ littoral (sinusoidal, including Kupffer cells). The space of Dissė is a tissue space between hepatocytes and sinusoidal lining cells. The hepatic lymphatics are found in the peri-portal connective tissue and are lined throughout by endothelium. Tissue fluid seeps through endothelium into lymphatic vessels.

       The branch of the hepatic arteriole forms a plexus around the bile duct and supplies the structures in the portal tract. It empties into the sinusoidal network at different levels. There are no direct hepatic arteriolar-portal venous anastomoses. The excretory system of the liver begins with the bile canaliculi. These have no walls but are simply grooves on the contact surface of the liver cells. Their surface is covered by microvilli. The plasma membrane is reinforced by microfilaments forming a supportive cytoskeleton. The canalicular surface is sealed from the rest of the intercellular by junctional complexes including tight junctions. Gap junctions and desmosomes. The intralobular canalicular network drains into thin walled terminal bile duct or ductules (cholangioles, canals of Hering) lined with cuboidal epithelium. These terminate in larger (interlobular) bile ducts in the portal canals. They are classified into small (less than 100µmin diameter) medium ( ⁺_{_}100µm), large (more than 100µm).

ELECTRON MICROSCOPY

       The liver cell margin is straight except for a few anchoring pegs (desmosomes). From it, equally sized and spaced microvilli project into the lumen of the bile canaliculi. Along the sinusoidal border, irregularly sized and spaced microvilli project into perisinusoidal connective tissue space. The microvillous structure indicates active secretion or absorption, mainly of fluid.

       The nucleus contain deoxyribonucleo-protein. In the chromatin network one or more nucleoli are embedded. The nucleus has a double contour with pores along interchange with the surrounding cytoplasm. The mitochondria also have a double membrane the inner being invaginated to form grooves or cristae. An enormous number of energy-providing processes take place within them, particularly those involving oxidative phosphorylation. They contain many enzymes, particularly those of the citric acid cycle and those involved in ß-oxidation of fatty acids. They can transform energy so released into adenosine diphosphate (ADP). Haem synthesis occurs here.

       The rough endoplasmic reticulum (RER) is seen as lamellar profiles lined by ribosomes. These are responsible for basophilia under light microscopy. They synthesise specific proteins, particularly albumin; those used in blood coagulation and enzymes. They may adopt a helix arrangement, as polysomes for co-ordination of this function. Glucose-6-phosphatase is synthesised. Triglycerides are synthesised from free fatty acids and complexed with protein to be secreted by exocytosis as lipoprotein. The RER may participate in glycogenesis. The smooth endoplasmic reticulum (SER) forms tubules and vesicles. It contains the microsomes. It is the site of bilirubin conjugation and frozen compounds. Steroids are synthesised, including cholesterol and the primary bile acids, which are conjugated with amino acid glycine and taurine. Enzyme inducers as phenobarbital increase the SER. Peroxisomes are distributed near the SER and glycogen granules. Their function is unknown.

       The lysosomes are dense bodies adjacent to the bile canaliculi. They contain many hydrolytic enzymes, which, if released, could destroy the cell. They are probably intracellular scavengers, which destroy organelles with shortened lifespans. They are the sites of deposition of ferritin, lipofuscin, bile pigment and copper. Pinocytic vacuoles may be observed in them. Some peri-canalicular dense bodies are termed microbes.

       The Golgi apparatus consists of a system of particles and vesicles again lying near canaliculus. It may be regarded as a ‘packaging’ site before excretion into the bile. This entire group of lysosomes, microbes and Golgi apparatus is a means of sequestering any material, which is ingested, and not to be excreted, secreted or stored for metabolic processes in cytoplasm. The Golgi apparatus, lysosomes and canaliculi are concerned in cholestasis. The intervening cytoplasm contains granules of glycogen, lipid and fine fibrils. The cytoskeleton supporting the hepatocytes consists of microtubules, microfilaments and intermediate filaments. Microtubules contain tubulin and control subcellular mobility, vesicle movement and plasma protein secretion. Microfilament are made up of actin are contractile and are important for the integrity and motility of the canaliculus, and for bile flow. Intermediate filaments are elongated-branched filaments comprising cytokeratins. They extend from the plasma membrane to the peri-nuclear area and are fundamental for stability and spacial organisation of the hepatocyte.

Sinusoidal cells: The sinusoidal cells (endothelial cells, Kupffer cells, fat storing cells and pit cells) form a functional and a histological unit together with the sinusoidal aspect of the hepatocyte.

Endothelial cells: They line the sinusoids and have fenestrae, which provide a graded barrier between sinusoids and space of Dissė. The Kupffer cells are attached to the endothelium.

The fat storing cells: They lie in the space of Dissė between the hepatocyte and the endothelial cells.

Kupffer cells: These are highly mobile macrophages attached to the endothelium. They are peroxidase staining and have a nuclear envelope. They phagocytose large particles and contain vacuoles and lysosomes. They are derived from blood monocytes and have only limited capabilities of division. They phagocytose by endocytosis (pinocytosis or phagocytosis) which may be absorptive (receptor-mediated) or fluid phase (non-receptor-mediated). The Kupffer cell has specific membrane receptors for ligands including Fc portion of immunoglobulin and C3b components of complement, which are important for antigen presentation.

       With generalised infections or trauma, Kupffer cells become activated. They specifically endocytose endotoxin and in response secrete a series of factors such as tumour necrosing factor (TNF), interleukins, collagenase and lysosomal hydrolase. These increase discomfort and sickness. It also mediates the uptake of IgM containing immune complexes.

       Endothelial cells. These sessile cells form a continuous wall to the lumen of the sinusoids. Fenestrae (0.1µm in diameter) (sieve plates) determine the exchange of fluids and the size of the particulate matter to and from the space of Dissė and the hepatocyte. Endothelial cells have lobular gradients. Scanning electron microscopy has shown, particularly in zone 3 in alcoholic patients, a striking reduction in the number of fenestrae with formation of basal lamina.

       Fat storing (Ito) cells. These stellate sessile cells lie with the space of Dissė. They may contain fat. When empty, ultrastructurally they resemble fibroblast. They store excess vitamin A and other retinoids, also other fat-soluble vitamins. In the presence of hepatocyte damage, Ito cells migrate to zone 3 where they change into myofibroblasts which secrete collagen type I, II, IV and laminin. They may regulate sinusoidal blood flow and hence contribute to portal hypertension. Collagenization of the space of Dissė results in decreased access of protein-bound substrates to the hepatocyte.

       Pit cells. These are highly mobile, natural killer lymphocytes attached to endothelium. They show characteristic granules and rod cored vesicles. Pit cells show spontaneous cytotoxicity against tumour and virus infected hepatocyte.

Extra cellular matrix: This is obvious when there is liver disease, but also exists in a subtle form even in normal liver. In or around the space of Dissė, all major constituents of a basement membrane can be found including type IV collagen, laminin, heparin sulphate, protoglycan and fibronectin. All cells impinging on the sinusoids can contribute to this matrix. The matrix within Dissė space influences hepato-cellular function, affecting expression of tissue-specific gene such as albumin. It may be important in liver regeneration.

Altered hepatic microcirculation and disease: In the liver disease, particularly in the alcoholic, the liver microcirculation may be altered by collagenization of the space of Dissė, formation of a basal lamina beneath the endothelium and modification of the endothelial fenestration. All these processes are maximal in zone 3. They contribute to deprivation of nutriments intended for the hepatocyte and to the development of portal hypertension.

Adhesion molecules: In hepatic inflammation lymphocyte are often the cells infiltrating the liver. There are interactions between the receptors on the leucocyte surface, lymphocyte function associate antigen (LFA-1) and an intracellular adhesion molecule (ICAM-1 or 2). ICAM-1 is expressed strongly on sinusoidal lining cells and weekly on portal and hepatic endothelium in normal liver. Induction of ICAM- 1 on epithelium, vascular endothelium and peri-venular hepatocytes is found in post transplant rejection. Expression of this adhesion molecule on the bile duct has been found in primary biliary cirrhosis and primary sclerosing cholangitis.

       The relative function of the cells in the periphery of acini (zone 3) adjacent to terminal hepatic veins are different from those in circulatory area adjacent to terminal hepatic vein artery and portal veins (zone 1).

       Kerbs’ cycle enzymes are found in highest concentration in zone 1 where as glutamine synthetase is perivenous. Oxygen supply is an obvious difference; cells in zone 3 receive their oxygen supply last and are particularly prone to anoxic liver injury. Drug metabolising P450 enzymes are present in greater amounts in zone 3. This is particularly so after enzyme induction, for instance with phenobarbital.

       Hepatocytes in zone 3 receive a higher concentration of any toxic product of drug metabolism. They also have a reduced glutathione concentration. This makes them particularly susceptible to hepatic drug reactions.

       Hepatocytes in zone 1 receive blood with a higher bile salt concentration and therefore are particularly important in bile salt dependent bile formation. Hepatocytes in zone 3 are important in non bile salt dependent bile formation. There are also zonal differences in hepatic transport rate of substance from sinusoids to canaliculus.

       The cause of metabolic difference between the zone varies. For some functions (gluconeogenesis, glycolysis, ketogenesis) it appears to be dependent upon the direction of blood flow along the sinusoid. For other (cytochrome P450) the gene transcription rate differs between perivenous and periportal hepatocytes. The differential expression of glutamine synthetase across the acinus is already established in foetal liver.

Sinusoidal membrane traffic: The sinusoidal plasma membrane is a receptor rich and metabolically dynamic domain, which is separated from the bile canaliculus by a lateral domain, which participates in cell-cell interaction. Receptor-mediated endocytosis (RME) is responsible for transfer of large molecules such as glycoproteins, growth factor and carrier proteins (transferrin). These ligands bind to receptors on the sinusoidal membrane, the occupied receptors cluster into a coated (Catharine) pit and endocytosis proceeds.

Bile duct epithelial cells: These can be isolated from rat liver and grown in short term culture. Studies show receptor mediated endocytosis of epidermal growth factor by the cells and exocytosis under the control of secretin. The metabolism of bile acids in biliary epithelium differs considerably compared with hepatocyte.