The liver is the largest internal organ of the human body, weighing approximately 1.5 kg. Embryologically it develops from the foregut and it spans the upper right and part of left abdominal quadrants. Anatomically the liver consists of four lobes: two larger ones (right and left) and two smaller ones (quadrate and caudate).
Histologically speaking, it has a complex microscopic structure, that can be viewed from several different angles. Physiologically speaking, the liver also performs many essential functions and it is your best friend when you are enjoying some beers with your friends. This article will examine every histological component of the liver, its macroscopic and microscopic vascular supply, and the biliary system.
The liver performs several important functions in the human body, such as given below:
- Plasma protein synthesis - albumins, lipoproteins, glycoproteins, prothrombin, fibrinogen
- Vitamin storage and modification - vitamins A, D, and K
- Iron storage and metabolism - transferrin, haptoglobin, hemopexin, ferritin
- Drugs and toxins degradation
- Bile production
- Carbohydrate metabolism
The liver consists of the following major histological components:
- Parenchyma, which is represented by hepatocytes
- Stroma, which is a continuation of the surrounding capsule of Glisson. It consists of connective tissue and contains the vessels. The capsule is also covered by a layer of mesothelium, arising from the peritoneum covering the liver. The connective tissue of the stroma is type III collagen (reticulin), which forms a meshwork that provides integrity for the hepatocytes and sinusoids.
- Sinusoids, which are capillaries travelling between hepatocytes
- Spaces of Disse (perisinusoidal spaces), which are located between the hepatocytes and the sinusoids.
In histological terms, the liver consists of a large number of microscopic functional units that work in unison to ensure the overall, proper activity of the entire organ. There are three possible ways of describing one such unit, as given below:
- Classic lobule
- Portal lobule
- Liver acinus
The classic lobule is the traditional description and the one that you have most likely heard of the most. It consists of hexagonal plates of hepatocytes stacked on top of each other. Within each plate, the hepatocytes radiate outwards from a central vein. As they extend towards the periphery, the hepatocytes are arranged into strips, similar to the spokes of a cartwheel. Hepatic sinusoids travel between the strips of hepatocytes, draining into the central vein.
One portal canal is located at each corner of the hexagonal classic lobule, making a total of six for each lobule. These portal canals are composed of the portal triads, which are surrounded by loose stromal connective tissue. A periportal space (space of Mall), where lymph is produced, is sandwiched between the connective tissue of the portal canals and the hepatocytes.
While connective tissue is present around the portal canals, the interlobular quantity is very small in humans. This can make routine histological visualizations of the classic lobule difficult.
While the classic lobule view focuses on the blood supply and hepatic mass arrangement, the portal lobule view underlines the exocrine function of the liver i.e. bile secretion. In this case, each functional unit is a triangle, having a central axis through a portal canal and the imaginary vertices through the three different but closest portal canals surrounding it. The area covered by the triangle represents the hepatic regions that secrete bile into the same bile duct.
The focus of this description is the perfusion, metabolism and pathology of hepatocytes, providing a more accurate description of the physiology of the liver. A liver acinus functional unit is in the shape of an oval. The short axis is represented by a shared border between two adjacent lobules together with the portal canals. The long axis is an imaginary line between two adjacent central veins.
Each liver acinus can be divided into three zones:
- Zone 1 - It is the one closest to the short axis, hence to the portal canals and supply of arterial blood. The hepatocytes in zone 1 receive the highest amount of oxygen.
- Zone 2 - It is the one located between zones 1 and 3.
- Zone 3 - It is the one furthest from the short axis but closest to the central vein, hence the hepatocytes receive the least amount of oxygen.
These large and polyhedral (six surfaces) cells make up 80% of the total cells of the liver. They can contain between two and four nuclei, which are large and spherical, occupying the centre of the cells. Each nucleus has at least two nucleoli. The typical lifespan of a hepatocyte is five months. The adjacent hepatocytes leave a very small space between them known as bile canaliculi which are almost 1.0-2.0 μm in diameter. The cell membranes near these canaliculi are joined by tight junctions.
The cytoplasm is acidophilic in routine H&E staining, dotted with basophilic regions represented by rough endoplasmic reticulum (rER) and ribosomes. In addition, hepatocytes contain the following organelles:
- Smooth endoplasmic reticulum (sER), which is essential in toxin degradation and conjugation, as well as cholesterol synthesis.
- Mitochondria (up to 1000/cell)
- Golgi network, which is composed of approximately 50 small Golgi units. They contain granules with very low density lipoprotein and bile precursors.
- Peroxisomes, which contain oxidases and catalases. These enzymes are responsible for detoxification reactions taking place in the liver, for example, that of alcohol.
- Glycogen deposits, which are lost in during H&E preparations, leaving irregular stained areas.
- Lipid droplets
- Lysosomes, which are responsible for iron storage under the form of ferritin.
Perisinusoidal Space (Space of Disse)
This space is situated between the layers of hepatocytes and the sinusoidal endothelial cells. The hepatocytes extend villi into the perisinusoidal space, increasing the extent and rate of material exchange, together with the microvilli.
The perisinusoidal space contains a specific type of cell called Ito, or hepatic stellate, cells. Their role is the storage of hepatic vitamin A inside lipid droplets, which is subsequently released as retinol. However, Ito cells are also responsible for hepatic fibrosis, since they are the ones secreting large amounts of collagen during liver injury.
The liver, as an organ, receives blood from two different sources. The major one is via the hepatic portal vein (75%), which carries venous blood from the intestines, pancreas and spleen. Despite the lack of oxygen, this blood contains high amount of nutrients, endocrine secretions, broken down erythrocytes, but also ingested toxins. The second major source is via the hepatic artery (25%), which brings oxygenated blood to the liver.
Together with the bile duct, the hepatic portal vein and hepatic artery form the portal triad. Those structures supply blood to the sinusoids and the hepatocytes, subsequently draining into the central vein followed by the sublobular veins. The second drainage pattern is via the hepatic veins, which end up in the inferior vena cava.
Interlobular vessels connect the portal triads and sinusoids, transporting the blood into the latter. The hepatic sinusoids have a discontinuous epithelium due to the presence of fenestrae and gaps between endothelial cells and constitute a low-resistance vascular channel. A basement membrane is also absent. The sinusoids appear as pale spaces between the hepatocytes in routine hematoxylin and eosin (H&E) staining. The endothelial cells display flat and condensed nuclei, with poorly stained cytoplasm.
The name of the blood vessels travelling through the portal canals are called interlobular vessels. They send blood into the sinusoids, either directly if they are really small, or by branching into distributing vessels first, which in turn empty into the sinusoids via inlet vessels. From the sinusoids, the blood drains into the central vein, which occupies the central axis of the classic liver lobule. The endothelial cells forming the central veins are surrounded by a small quantity of connective tissue fibers.
As they travel through the parenchyma, the central veins become larger, subsequently emptying into the sublobular veins. The endothelial lining of the sublobular veins is surrounded by a high quantity of connective tissue fibers, consisting of a layer of both collagenous and elastic fibers. Several sublobular veins then converge into larger and valveless hepatic veins, which ultimately empty into the inferior vena cava.
The sinusoids also receive arterial blood from the hepatic arteries. The latter have a thick muscular wall and also supply the connective tissue and various structures in the portal canals.
In addition, sinusoids contain a specific cell type called Kupffer cell, containing ovoid nuclei. These monocyte derivatives of the mononuclear phagocytic system are part of the sinusoid lining from which they extend processes into the lumen. Therefore, Kupffer cells continuously sample the blood travelling through the sinusoids, phagocytosing antigens, microorganisms, and damaged red blood cells.
This is a system consisting of channels that carries bile from the source, this being the hepatocytes, all the way to the gallbladder and intestines. The epithelial cells lining this system are called cholangiocytes. They range in shape from cuboidal in small ductules, to columnar in large ductules. Cholangiocytes have several histological features, such as:
- Few organelles
- Presence of tight junctions between the cells
- Microvilli on their apical domains
- Primary cillium
The hepatocytes secrete bile into the bile canaliculi, which are the smallest channels of the biliary tree. The secretion into these canaliculi is an active process. They partially loop around the hepatocytes and become the canals of Hering close to the portal canal.
These canals are lined by both hepatocytes and cuboidal cholangiocytes. The flow of bile is opposite to that of the blood and the canals of Hering are capable of contracting and assisting this flow towards the portal canal. The canals of Hering also posses hepatic stem cells, which represent the source of hepatocytes and cholangiocytes.
The canals of Hering flow into intrahepatic bile ductules in the periportal space (of Mall), which are completely lined by cholangiocytes. In turn, the intrahepatic bile ductules flow into interlobular bile ducts, which are lined by cuboidal to columnar cholangiocytes and form part of the portal triad. As these ducts travel towards the porta hepatis, they increase in diameter and become invested inside dense connective tissue composed of elastic fibers. Finally, these interlobular ducts join to form the right and left hepatic ducts, which in turn merge to form the common hepatic duct. This duct is lined by columnar epithelial cells. The cystic duct branches from the common hepatic duct, carrying bile to and from the gallbladder.
This condition is characterised by aggregates of regenerated hepatic cells that are separated by bands of scar tissue (deposited collagen tissue). These two processes take place in response to some extent of hepatocyte destruction, resulting in their damage and subsequent death. Some causes include:
- Chronic alcoholism
- Hepatitis B or C infection
- Certain autoimmune conditions
- Some genetic metabolic diseases that result in an excessive storage of copper and iron
The scar tissue negatively impacts the blood flow from the sinusoids to the hepatocytes, resulting in a decrease in function. As a result, portal hypertension develops because the blood cannot drain from the portal vein.
This condition classically manifests itself as a yellow discoloration of tissues, which is due to excessive levels of bilirubin (hyperbilirubinaemia) and deposited bile pigments. Jaundice can have a variety of causes, two common ones being hepatic and biliary tract diseases.
If the ability of the liver to excrete conjugated bilirubin is exceeded, prehepatic jaundice takes place. This type is related to diseases characterised by a high amount of red blood cell breakdown, like sickle cell anaemia (a major source of bilirubin is red blood cell breakdown).
If the liver is damage such that it cannot effectively metabolise and excrete bilirubin, hepatic jaundice occurs. In contrast to the prehepatic type, this kind of jaundice exhibits both conjugated and unconjugated hyperbilirubinaemia.
Posthepatic (obstructive) jaundice is due to a chemical blockage in the biliary system, mostly due to gallstones.