Liver

THE LIVER

The liver is located in the peritoneal cavity below the diaphragm. The liver is the largest internal organ of the body and can reach 1,500g in adults. It is also the largest gland of the body and serves both exocrine and endocrine functions. The metabolic functions of the liver are numerous.

The liver has an abundant blood supply and in particular receives venous blood from the small intestine (mesenteric veins and hepatic portal vein), which contains all the food components absorbed from the intestine with the exception of the lipids.

Histological organization of the liver

The liver has four lobes. The basic morphofunctional units are hepatic lobules, which number approximately one million. In some animals, such as the pig, the lobules have a hexagonal appearance as seen in sections. The diameter of each lobule is about 1-2mm. A thin layer of connective tissue surrounds each lobule. Overall there is very little connective tissue in the liver. At the center of each lobule is a central vein. Each lobule has a vascular supply of arterial blood (from branches of the hepatic portal artery) and venous blood (from branches of the hepatic portal vein) from specific areas at the angles of the hexagon. These areas are known as portal areas as they receive arterial and venous blood from the porta of the liver.

Portal areas

The structures found in each portal area are :

branch of the hepatic portal vein (the largest vessel in the portal area, bringing about 70% of the afferent blood)
branch of the hepatic artery (arteriole supplying about 30% of the afferent blood)
bile ductule (epithelial structure, through which bile produced by the liver cells is secreted)
lymph vessels (the liver is the source of 35-50% of all lymph in the body under resting conditions). These lymph vessels are sometimes difficult to detect in standard histological preparations owing to the thinness of the walls and collapse of the lumen.

The structures of the portal area are surrounded by loose connective tissue (part of Glisson's capsule). In cases where the borders of the lobules are difficult to detect, the portal area provides a useful landmark or reference point.

The arterial and venous blood flows centripetally in each lobule (from the portal areas to drain in the central vein), whereas the bile flows centrifugally towards the portal areas.

The main cells of the lobules are epithelial cells known as the hepatocytes. These are sometimes referred to as parenchymal cells. The hepatocytes are derived from the embryonic endoderm. The hepatocytes in each lobule are arranged in radial hepatic plates. The blood flows between the hepatic plates in large sinusoids and as a result all the hepatocytes have a rich blood supply.

Hepatic sinusoids

The sinusoids are discontinuous and fenestrated.

The four main cell types of the sinusoids are :

Endothelial cells
Kupffer cells
Fat-storing (Ito) cells
Pit cells (NK cells)

Endothelial cells

The endothelial cells lack any basal lamina and their structural support comes from reticular fibers in the space (Space of Disse) separating the endothelial layer from the hepatocytes. The Space of Disse is visible in histological preparations as a gap between the free edge of hepatocytes and the endothelial cells.

Kupffer cells

The Kupffer cells are fixed macrophages, which belong to the Mononuclear Phagocyte System. They are associated with the endothelial cells and possess cellular processes, which extend via the spaces between endothelial cells into the lumen of the sinusoid. The location and phagocytic function of Kupffer cells can be easily demonstrated if a vital dye, such as Trypan blue, is injected into the peritoneal cavity or into a blood vessel; within a short time, the dye is engulfed into the cytoplasm of Kupffer cells. Kupffer cells also take part in the breakdown of aged erythrocytes. In addition, the Kupffer cells can detect and engulf bacteria in the blood and lead to their breakdown.

Fat-storing cells

These are also known as lipocytes or Ito cells. They are typically found in the Space of Disse and have the ability to accumulate lipid droplets. They are the main source of vitamin A storage in the body and also play a role in wound healing (hepatic fibrogenesis).

Pit cells

These are mobile cells found in the Space of Disse that belong to the immune system. They are believed to be a form of Natural Killer cells (NK cells) or Lymphokine-activated Killer cells (LAK cells).

Histology of hepatocytes

Hepatocytes are large (20-30mm) polyhedral epithelial cells with large central regular nuclei. About 25% of all the hepatocytes have two nuclei (binucleate), and there are several instances (up to 10%) of polyploid hepatocytes with very large nuclei (more than one set of chromosomes).

The cytoplasm of the hepatocytes is typically fairly acidophilic (many mitochondria present), with areas of basophilia (rough endoplasmic reticulum). The hepatocytes are unusual in that they possess abundant rough endoplasmic reticulum (RER) and smooth endoplasmic reticulum (SER) in the same cells. The RER is associated with protein synthesis, whereas the SER is associated with steroid metabolism.

Golgi bodies of the hepatocytes are well developed

Lipid droplets are commonly found in the cytoplasm. These increase in number and size after alcohol ingestion and also after treatment with steroid drugs such as glucocorticoids.

Lysosomes are common in hepatocytes, especially in the vicinity of the bile canaliculi and are sometimes referred to as peribiliary bodies.

Peroxisomes (formerly called microbodies) are also common in hepatocytes. These are membrane-bound organelles, typically 0.2-0.8mm in diameter, which can be identified at the ultrastructural level by the presence of crystalline nucleoids. The peroxisomes contain enzymes such as catalase, urate oxidase, d-amino oxidase and gamma-hydroxy acid oxidase. The peroxisomes play a role in protecting the cells from effects of peroxides, which may cause irreversible damage.

Glycogen deposits in the cytoplasm can be shown with periodic acid-Schiff staining. At the ultrastructural level the glycogen is seen to be in the form of rosettes.

Bile canaliculi

The membranes between adjacent hepatocytes are modified to form small channels, known as bile canaliculi, through which the bile secreted by the hepatocytes initially passes. The bile canaliculi possess microvilli and are sealed by tight junctions to prevent bile leakage. The bile canaliculi form a complex anastomosing network, which in the portal areas open into Hering canals, lined with cuboidal epithelium, and into the portal bile ductules. The network of bile canaliculi in hepatic lobules can be demonstrated in histochemical preparations of liver processed for ATP-ase enzymatic activities.

FUNCTIONS OF HEPATOCYTES

Hematopoietic function

In embryos the liver functions as an haemopoietic organ and is active in producing blood cells (erythrocytes and leukocytes). At week 10 the liver is about 10% of fetal weight. The hematopoietic function lasts until month 7 of fetal development. Histological examination of the fetal liver shows large nests of forming blood cells between the hepatocytes and the walls of blood vessels.

METABOLIC FUNCTIONS

Deamination of amino acids. The liver is responsible for the breakdown of amino-acids. The hepatocytes have all the necessary enzymes of the urea cycle. The urea is transported to the kidneys prior to excretion in the urine.
Synthesis of plasma proteins. The hepatocytes are the main source of important plasma proteins such as: albumin, globulin, fibrinogen, prothrombin. Unlike other protein synthesizing and secreting cells of the body, the hepatocytes are unusual in that they lack protein storage granules.
Carbohydrate metabolism. The hepatocytes play major roles in glucose homeostasis. Excess carbohydrates can be stored as glycogen deposits, which can be reconverted to glucose according to need (glycogenesis and glycogenolysis). The hepatocytes are also the main site of gluconeogenesis (formation of glucose from amino-acids or lipids) in times of stress such as starvation.
Lipid metabolism. The hepatocytes are the site synthesis and secretion of serum lipoproteins. They also play major roles in cholesterol and steroid metabolism and in the metabolism of the fat-soluble vitamins (vitamins A and D).
Drug detoxification. The hepatocytes are important in the detoxification of lipid-based drugs. The SER is responsible for the "conjugation" process involved in the inactivation of the drugs.
Lymph synthesis. The liver produces large quantities of lymph (50% of protein-rich lymph).
Bile synthesis. The hepatocytes synthesize bile, which plays a role in the emulsification of fats prior to lipid absorption into the lacteals of the villi of the small intestine. Pigments resulting from the breakdown of aged erythrocytes, such as bilirubin, are excreted in the bile.

Synthesis of serum lipoproteins

Up to 50% of the protein-rich lymph is derived from the liver. Fatty acids from the blood are taken up by the hepatocytes and become esterified in the smooth endoplasmic reticulum (SER) to form triglycerides. Proteins are synthesized in the rough endoplasmic reticulum (RER). The proteins combine with the triglycerides in the Golgi bodies to form lipoproteins, which are packaged into small membrane-bound structures, prior to secretion to the blood.

Bile secretion

Bile secretion begins in the fetus from about week 12 of gestation.
The components of bile are water and bile salts (sodium glycocholate and sodium taurocholate). The bile, which is excreted via the bile duct to the duodenum, is responsible for the emulsification of fats. Synthesis of the bile salts takes place in the SER, where there is conjugation of the amino acids glycine and taurine with cholic acid.

The bile also serves as a vehicle for the excretion of components of aged erythrocytes. The breakdown of erythrocytes (by Kupffer cells of the liver, or macrophages of the spleen) results in the heme pigment being converted to biliverdin, which is converted to bilirubin. Bilirubin, which is water-insoluble, is conjugated with glucuronic acid in the SER of hepatocytes to form water-soluble bilirubin glucuronide, which is secreted in the bile. In the duodenum the bilirubin is converted by bacteria to urobilinogen, which is reabsorbed in the distal small intestine and recaptured in the liver. About 90% of the bile is recycled, with about 10% de novo formation. The bile provides the characteristic dark color of the feces.

Metabolic zones in the hepatic lobules

It is possible to divide the lobules into areas of differing metabolic activity. The most peripheral areas of the lobules, have the richest blood supply (greatest oxygenation, more metabolites). This peripheral area is called the zone of permanent function. The middle zone of the lobules has reduced metabolic activities and is known as the zone of intermediate function. The most central zone, closest to the central canal, has the least metabolic function and is known as the zone of permanent repose or inactivity. This is reflected in the much greater numbers and activities of mitochondria in the peripheral (perilobular) zone as compared to the inner (centrolobular) zone.

If an experimental animal is well fed, the glycogen accumulates in the hepatocytes of the peripheral zone and only later to a lesser degree in the hepatocytes of the middle zone. The hepatocytes of the inner zone show virtually no accumulation of glycogen. If the animal is then starved, the glycogen first disappears from the middle zone and only later from the most peripheral zone.

Various concepts of lobules

Lobules of exocrine glands typically have their main secretory duct located in the center of the lobule.
The classical (hexagon-shaped) lobule, in contrast, has its secretory ducts (bile ductules) at the periphery.

It is possible to consider an arrangement similar to that of other exocrine glands with centrally located secretory ducts in the lobules. This concept is known as the portal lobule composed of a triangular arrangement stretching between three central veins. The portal lobule lacks clearly defined borders.

A further concept of hepatic lobules, based on functional areas is the acinus (of Rappaport). The borders of the acinus are not clearly defined, but are based on physiological areas. The acinus is a diamond-shaped structure in which physiological zones are defined. This concept is important in the understanding of several histopathological conditions.

Regeneration

Parenchymal cells of the liver have a remarkable capacity for regeneration. If up to 60% of the liver is removed surgically from an experimental animal, the liver tissue can regenerate and return to its original dimensions within a relatively short time.

Many chemicals are cytotoxic to liver cells. These include chlorinated hydrocarbons (pesticides) and a range of common organic solvents and anaesthetics (carbon tetrachloride, xylene, chloroform, ether).

THE GALLBLADDER

The function of the gallbladder is to provide a storage site for bile (synthesized in the liver). The bile also becomes more concentrated in the gallbladder owing to ion-transporting activities of the epithelium lining the lumen.

Simple, columnar, homogeneous epithelium lines the lumen. The epithelium typically has many folds, however, when the gallbladder is filled with bile, these folds disappear.

The layers of the gallbladder consist of:

Mucosa consisting of columnar epithelium and lamina propria. The cytoplasm of the epithelial cells has weak acidophilic characteristics. The nuclei tend to be oval and situated in the more basal part of the cells
Muscularis consisting of smooth muscle, which is found in longitudinal, transverse and oblique directions
Perimuscular dense connective tissue layer
Serosa, which covers part of the organ only.

Lipids reaching the duodenum signal the release of the polypeptide hormone, cholecystokinin (CCK) from endocrine cells of the mucosa into the blood. The cholecystokinin has receptors in the wall of the gallbladder, which result in the contraction of the smooth muscle and the release of the bile via the bile duct on to the duodenum.

PANCREAS

The pancreas is a compound gland with both exocrine and endocrine functions. Unlike the liver, the exocrine and endocrine functions are from different cells.