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Liver Sieve Research Group - Background

The Liver
Internal Structure
Lobular Structure
Sinsoidal Structure
Liver Sinusoidal Endothelial Cells (LSEC)
Other Liver cells

The Liver

Liver structure and ultra structure.

In the adult human, the liver is a large organ weighing around 2000 grams, which receives a large portion of the body's total blood flow. It is strategically placed to receive venous blood from mainly the intestines and the spleen, before passing it back to the heart. It is essential for continued health, as it has over 5000 different functions currently assigned to it.

The liver parenchymal cells (called hepatocytes) account for around 90% of the liver's volume, but the architecture of the liver is more complex than is often realised, with the sinusoidal cells of the liver also playing essential roles in liver function. An indication of the importance of the liver is given by its inherent capacity for regeneration. Over 70% of a healthy liver can be removed and in the right circumstances it will grow back (regenerate) to its original size. It is also the only organ in the body that appears to be almost immortal.

Liver Vasculature
Total blood flow through the liver is approximately 1.5 litres per minute. Unlike other organs the liver receives mostly venous blood from the gut, although this is supplemented with arterial blood by the hepatic artery.

Venous blood from the gut enters via the portal vein before exiting the liver via the inferior vena cava. This venous blood has a low oxygen tension (80% saturated) and a low pressure of 8-10 mm Hg. Oxygenated blood is also delivered to the liver from the hepatic artery which contributes around one quarter of the livers blood.

Bile and Lymph
The liver has other vessels, besides those transporting blood. The lymph system delivers serum that leaks into the extracellular spaces back to the blood via the thoracic duct. The bilary system takes bile produced by each hepatocyte and channels it back to the bile duct, which then empties bile into the intestine.

Internal Structure

Within the liver incoming vessels, (portal vein and hepatic artery)form a branched network that delivers blood to the primary functional unit (the liver lobule). The portal veins, hepatic arteries and bile ducts run alongside each other, until they reach the lobule where they connect to the sinusoids. The structure at this point is the the portal tract. Each portal tract consists of a portal vein delivering venous blood and a hepatic artery delivering oxygenated blood. These combine to flow into the fine blood vessels (sinusoids). The centre of the lobule has a hepatic venule draining the sinusoids into the hepatic veins and finally to the inferior vena cava.

Lobular Structure

The liver contains about one million of these lobular units which are approximately 2-3 mm across. In each lobule are several thousand one mm long sinusoids (capillaries) . These over one billion sinusoids are all in parallel, thus the blood flow is very slow and the interface between it and the hepatocyets is ideal for the exchange of metabolites

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(a cast of a lobule and its myriad 1mm long sinusoids)

A model of the Hepatic Microcirculatory Subunit
Two models of liver structure have been proposed, the lobular and the acinar model. The lobular model regards the primary unit as portal tracts flowing into the central vein. However, in most species there are connections between adjacent lobules. The acinar model is based upon metabolic differences and has no distinct morphological boundaries. The portal tract is at its centre and a line between the surrounding terminal hepatic venules (central veins) deliminates the outer boundary. Within the acinus are three metabolic zones, with zone 1 being closest to the portal tract and zone 3 closer to the hepatic vein. A further subdivision of the loble into hepatic microcirculatory subunits (HMS) has been proposed with several units to each lobule and connecting sinusoids bridging between adjacent sinusoids.

Portal vein -->portal tract -->sinusoids -->central veins -->vena cava

Sinusoidal Structure

Liver Sinusoidal and Hepatocytes Diagram

These sinusoids form a three dimensional network of vessels around the liver parenchymal cells (hepatocytes). Hepatocytes are arranged in plates one cell thick, so are in effect bathed in blood. Sinusoids range from around 4 um in diameter at the portal end of the lobule (zone 1) to 5 um at the hepatic vein).

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SEM of a small portion of a liver lobule showing sinusoids (S) containing some seven micron diameter erythrocytes (E) and separated by cords of hepatocytes (H). The hepatocytes (H) on one side about the sinusoids (S) while on the opposite line the bile canaliculi (B)(magnification x2,000)

An estimate of the total length of sinusoids in the human liver can be calculated from the blood volume of the human liver and the sinusoidal diameter. These calculations suggest a total sinusoidal length of approximately 1,500 km (but it should be noted that these 1mm long sinusoids are all in parallel not in series).

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(magnification x10,000 showing sinusoids (s), red blood cells (e), kuppfer cell (k), lymphocyte (l), Bilecannaliculus (b), hepatocytes (h), hepatocyte microvilli (m))

The diameter of a sinusoid is such that a red blood cell (approximately 7 um in diameter) needs to deform the gossimer thin endothelium to pass through. This creates a massaging effect on the sinusoidal wall by the red blood cells, as proposed by Wisse in 1988. This massage helps move materials between the blood and the hepatocytes.

Liver Sinusoidal Endothelial Cells (LSEC)

The walls of the sinusoid are formed by thin endothelial lining cells (the endothelium). Behind the endothelium is the space of Disse, which is filled with a loose matrix that separates the endothelium from the hepatocytes. Therefore the space of Disse lies between the blood vessel (sinusoid) and the hepatocytes. The hepatocytes have microvilli on their surface which increase the surface area exposed in the space of Disse by around 6 times. This allows more efficient exchange between hepatocytes and blood plasma within the space of Disse.

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The "Liver sieve".. a scanning electron micrograph of a portion of the luminal surface of the fenestrated endotherlial lininf of a liver sinusoid. The 100nm diameter fenestrae or pores block the chylomicron (C) from passing through to the space of Disse and hepatocytes but allow passage of the smaller chylomicron remnants (r)(original magnification x 30,000) Picture courtesy of Eddie Wisse

Direct communication between the hepatocytes and the plasma in the sinusoids, is through small holes (fenestrae) in the walls of these vessels. This fenestrated endothelium acts as a liver sieve, preventing large objects such as red blood cells, from passing into the space of Disse, but allows blood proteins and small lipoproteins to pass through.

Under the scanning electron microscope, fenestrae have an average diameter of 100nm, however transmission studies suggest that this is a result of shrinkage of tissue during processing. A diameter of about 150nm close to the portal vein and 175 nm at the central vein have been measures by transmission electron microcopy.

Fenestrae

The fenestrae are often clustered in groups throughout the endothelium, called sieve plates. Sieve plates occur more frequently in sinusoids close to the portal vein. The diameters and frequency of occurrence of fenestrae also varies within the liver. Rather than report the number and size of holes separately, the ratio of the area occupied by holes over the total area measured (porosity), is commonly used as a measurement.

Fenestrae in the wall of sinusoids close to the portal vein have a porosity of 5.5% and 7.4% in the region of the hepatic vein. This results from a slightly increased diameter and decreased frequency of fenestrae in the portal area. This change has been suggested to be a result of the oxygen gradient within the sinusoid, but we hypothesize that it could result from the matrix gradient found in the space of Disse from portal to the hepatic zones.

Bile ducts
There is another drainage system present in the liver with its flow in the opposite direction to the blood. The liver hepatocytes produce bile, by extracting proteins, cholesterol and salts from the blood. Bile is secreted into small grooves on the surface of the hepatocytes called bile cannaliculiae. These cannaliculae have very fine microvilli lining them. Bile is then collected into bile ducts which join and transport their contents to the biliary tree, gall bladder and eventually the duodenum.

Lymph
Liver also connects with the lymph system which among other functions, returns fluid and protein that leaks from vessels back into the bloodstream. Plasma (high protein lymph) from the blood in sinusoids moves through the fenestrae of the endothelial cells into the space of Disse (between the hepatocytes and the sinusoidal vessel). From here it can flow back along the vessels to connect with the lymphatic vessels. Liver lymph drains into the thoracic duct which empties lymph back into the blood.

Liver Function
The liver has a myriad of functions to perform, in many ways acting as a metabolic factory for the rest of the body. The liver synthesizes blood clotting factors, converts glycogen to glucose, produces albumin and other proteins and produces lipoproteins. It also stores retinol (Vitamin A), fats, glycogen and lipids. Liver removes chylomicron remnants, proteins, immune complexes bilirubin, cholesterol and many other products from the blood.

Detoxification
The LESC also make up the body's largest reticulo-endothelial system (RES) removing much waste material from the blood. The liver's hepatacites are responsible for detoxification of nearly all of the drugs and chemicals that the body sees. This includes the many toxins present in the diet and also toxins produced by bacteria in the gut. Most medical and recreational drugs are also metabolised within the liver. Alcohol is the best well known of the recreational drugs, while Paracetomol is a good example of a medicinal compound metabolised by liver.

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