Liver anatomy and histology

Ali Al-Alwani
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1. The liver Ali Al-Alwani & Saja Al rikabi 117 i-6

2. The Structure The liver is the largest mass of glandular tissue in the body and the largest internal organ, weighing approximately 1,500 g and accounting for nearly 2.5% of adult body weight It is located in the upper right and partially in the upper left quadrants of the abdominal cavity, protected by the ribcage .The liver is enclosed in a capsule of fibrous connective tissue (Glisson’s capsule); a serous covering (visceral peritoneum) surrounds the capsule, except where the liver adheres directly to the diaphragm or the other organs. The liver is anatomically divided by deep grooves into two large lobes (the right and left lobes) and two smaller lobes (the quadrate and caudate lobes) the liver has both endocrine and exocrine functions, however, the same cell (the hepatocyte ) in the liver is responsible for the formation of bile—the liver’s exocrine secre tion—and its numerous endocrine products. In addition, hepatocytes convert noxious substances into nontoxic materials that are excreted in bile.

3. General Hepatic Structure and Vascular Supply The liver is completely enveloped by peritoneum, which forms a simple squamous epithelium covering over the dense, irregular connective tissue capsule (Glisson’s capsule) of the gland. Glisson’s capsule is loosely attached over the entire circumference of the liver except at the porta hepatis, where it enters the liver, forming a conduit for the blood and lymph vessels and bile ducts. the bulk of the liver is composed of uniform parenchymal cells, the hepatocytes. The superior aspect of the liver is convex, whereas its inferior region presents a hilum-like indentation , the porta hepatis. The liver has a dual blood supply, receiving oxygenated blood from the left hepatic artery and the right hepatic artery (25%) and nutrient-rich blood via the portal vein (75%). Both vessels enter the liver at the porta hepatis. Blood leaves the liver at the posterior aspect of the organ through the hepatic veins, which deliver their contents into the inferior vena cava. Bile also leaves the liver at the porta hepatis, by way of the right and left hepatic ducts, to be delivered to the gallbladder for concentration and storage. Hepatocytes are arranged in hexagon-shaped lobules (classical lobules) about 2 mm in length and 700 μm in diameter. These lobules are clearly demarcated by slender connective tissue elements (known as portal tracts) in animals such as the pig and the camel. However, because of the scarcity of connective tissue and the closely packed arrangement of the lobules in humans, the boundaries of the classical lobules can only be approximated. Where three classical lobules are in contact with each other, the connective tissue elements are increased, and these regions are known as portal areas(triads)

4. The Three Concepts of Liver Lobules

5. Hepatic Sinusoids and Hepatocyte Plates Hepatic sinusoids are lined with a thin discontinuous endothelium. The discontinuous sinusoidal endothelium has a discontinuous basal lamina that is absent over large areas. The discontinuity of the endothelium is evident in two ways: • Large fenestrae, without diaphragms, are present within the endothelial cells. • Large gaps are present between neighboring endothelial cells. Hepatic sinusoids differ from other sinusoids in that a second cell type, the stellate sinusoidal macrophage, or Kupffer cell, is a regular part of the vessel lining. Plates of hepatocytes, no more than two cells thick prior to the age of 7 years and one cell thick after that age, radiate from the central vein toward the periphery of the classical lobule . The spaces between the plates of hepatocytes are occupied by hepatic sinusoids, and the blood flowing in these wide vessels is prevented from coming in contact with the hepatocytes by the presence of an endothelial lining composed of sinusoidal lining cells. Resident macrophages, known as Kupffer cells, are associated with the sinusoidal lining cells in the sinusoids . Frequently, phagosomes of Kupffer cells contain endocytosed particulate matter and cellular debris, especially defunct erythrocytes that are being destroyed by these cells. Electron micrographs of Kupffer cells display numerous filopodia-like projections, mitochondria, some RER, a small Golgi apparatus, and an abundance of lysosomes and late endosomes. Because these cells do not make intercellular junctions with the neighboring cells, it has been suggested that they may be migratory scavengers

6. Perisinusoidal Space (Space of Disse) The sinusoidal lining cells are separated from the hepatocytes by a narrow space of Disse (perisinusoidal space), and plasma escaping from the sinusoids has free access to this space. Microvilli of the hepatocytes occupy much of the space of Disse; the extensive surface area of the microvilli facilitates exchange of materials between the bloodstream and the hepatocytes. Hepatocytes do not come into contact with the bloodstream; instead, the space of Disse acts as an intermediate compartment between them. The perisinusoidal space contains type III collagen fibers (reticular fibers) that support the sinusoids, as well as a limited amount of type I and type IV collagen fibers, a basal lamina is absent. Occasionally, nonmyelinated nerve fibers and stellate-shaped hepatic stellate cells (also known as Ito cells and fat storing cells) have been noted in this space. It is believed that hepatic stellate cells store vitamin A, manufacture and release type III collagen into the space of Disse, secrete growth factors required by the liver for generating new hepatocytes, and form fibrous connective tissue to replace hepatocytes damaged by toxins. In addition, pit cells, which display short pseudopodia and cytoplasmic granules, have been noted in the perisinusoidal space of mice and rats. These cells, believed to be natural killer cells, are also assumed to be in the human liver.

7. Hepatic Ducts The system of hepatic ducts is composed of cholangioles, canals of Hering, and bile ducts leading to larger and larger bile ducts that finally culminate in the right and left hepatic ducts. Bile canuliculi anastomose with one another, forming labyrinthine tunnels among the hepatocytes. As these bile canaliculi reach the periphery of the classic lobules, they merge with cholangioles, short tubules composed of a combination of hepatocytes and low cuboidal cells, and occasional oval cells. Bile from cholangioles enters the canals of Hering, slender branches of the interlobular bile ducts, that radiate parallel to the inlet arterioles and inlet venules. Interlobular bile ducts merge to form increasingly larger conduits, which eventually unite to form the right hepatic duct and the left hepatic duct. The extrahepatic system of bile ducts is described later. Most of the cells of the canals of Hering are composed of low cuboidal cells, but interspersed among them are some ovoid cells that are capable of proliferation. The progeny of these oval cells may give rise to cuboidal cells of the bile duct system as well as to hepatocytes. The cuboidal epithelial cells of the cholangioles, canals of Hering, and interlobular bile ducts secrete a bicarbonate-rich fluid similar to that produced by the duct system of the pancreas. The formation and release of this alkaline buffer are controlled by the hormone secretin, produced by diffuse neuroendocrine system (DNES) cells of the duodenum. This fluid acts, with fluid from the pancreas, to neutralize the acidic chyme that enters the duodenum.

8. Hepatocytes Hepatocytes are 5- to 12-sided polygonal cells, approximately 20 to 30 μm in diameter, that are closely packed together to form anastomosing plates of liver cells, one cell in thickness. These cells exhibit variations in their structural, histochemical, and biochemical properties, depending on their location within liver lobules

9. Domains of Hepatocyte Plasmalemma The plasma membranes of hepatocytes are said to have two domains: lateral and sinusoidal.

10. Hepatocyte Organelles and Inclusions Hepatocytes constitute only 60% of the total cell number, they compose about 75% of the weight of the liver. These cells manufacture primary bile, which is modified by the epithelial cells lining the bile ducts and gallbladder and becomes bile. Approximately 75% of the hepatocytes have a single nucleus, and the remainder have two nuclei. The nuclei vary in size, the smallest ones (50% of the nuclei) being diploid and the larger ones being polyploid, with the largest nuclei reaching 64 N. Hepatocytes actively synthesize proteins for their own use as well as for export. Thus, they have an abundance of free ribosomes, RER, and Golgi apparatus . Each cell houses several sets of Golgi apparatuses, located preferentially in the vicinity of bile canaliculi. . Liver cells also have a rich complement of endosomes, lysosomes, and peroxisomes. The complement of smooth endoplasmic reticulum (SER) of hepatocytes varies not only by region but also by function. Cells in zone 3 of the liver acinus have a much richer endowment of SER than those in the periportal area. Moreover, the presence of certain drugs and toxins in the blood induces an increase in the SER content of liver cells because detoxification occurs within the cisternae of this organelle.

11. Histophysiology of the Liver The liver has both exocrine and endocrine roles as well as the protective function of detoxification of toxins and elimination of defunct erythrocytes. Bile Manufacture Bile, a fluid manufactured by the liver, is composed of water, bile salts, phospholipids, cholesterol, bile pigments, and IgA Bile salts constitute almost half of the organic components of bile. Most of the bile salts are resorbed from the lumen of the small intestine, enter the liver via the portal vein, are endocytosed by hepatocytes, and are transported into the bile canaliculi for subsequent rerelease back into the duodenum (enterohepatic recirculation of bile salts). The remaining 10% of bile salts are manufactured de novo in the SER of hepatocytes by the conjugation of cholic acid, a metabolic byproduct of cholesterol, to either taurine (tauricholic acid) or glycine (glycocholic acid). Bilirubin, a water-insoluble, yellowish green pigment, is the toxic degradation product of hemoglobin. As defunct erythrocytes are destroyed by macrophages in the spleen and by Kupffer cells in the liver, bilirubin is released into the bloodstream and is bound to plasma albumin. In this form, known as free bilirubin, it is endocytosed by hepatocytes. The enzyme glucuronyltransferase, located in the SER of the hepatocyte, catalyzes the conjugation of bilirubin with glucuronide to form the water-soluble bilirubin glucuronide (conjugated bilirubin).

12. Lipid Metabolism Chylomicrons released by surface-absorbing cells of the small intestine enter the lymphatic system and reach the liver through branches of the hepatic artery. Within hepatocytes they are degraded into fatty acids and glycerol. The fatty acids are subsequently desaturated and are used to synthesize phospholipids and cholesterol or are degraded into acetyl coenzyme A. Two molecules of acetyl coenzyme A are combined to form acetoacetic acid. Much of the acetoacetic acid is converted into β- hydroxybutyric acid and some into acetone. These three compounds—acidoacetic acid, β- hydroxybutyric acid, and acetone—are known as ketone bodies. Phospholipids, cholesterol, and ketone bodies are stored in hepatocytes until their release into the space of Disse. In addition, the liver manufactures VLDLs, which are also released into the space of Disse as droplets 30 to 100 nm in diameter. Carbohydrate and Protein Metabolism Additional responsibilities of the liver include the maintenance of normal blood glucose levels, deamination of amino acids, and the synthesis of many blood proteins. Approximately 90% of the blood proteins are manufactured by the liver . These proteins and related products include: Factors necessary for coagulation (such as fibrinogen, factor III, accelerator globulin, and prothrombin) Proteins required for the complement reactions Proteins that function in transport of metabolites Albumins All of the globulins except gamma (γ) globulins All of the nonessential amino acids that the body requires

13. Vitamin Storage Vitamin A is stored in the greatest amount in the liver, but vitamins D and B12 are also present in substantial quantities. The liver contains enough vitamin stores to prevent deficiency of vitamin A for about 10 months, vitamin D for about 4 months, and vitamin B12 for more than 12 months. Degradation of Hormones and Detoxification of Drugs and Toxins The liver endocytoses and degrades hormones of the endocrine glands. The endocytosed hormones are transported into the bile canaliculi in their native form to be digested in the lumen of the alimentary canal or are delivered into late endosomes for degradation by lysosomal enzymes. Drugs, such as barbiturates and antibiotics, and toxins are inactivated by microsomal mixed-function oxidases in hepatocytes. These drugs and toxins are usually inactivated in the cisterna of the SER by methylation, conjugation, or oxidation. Occasionally, detoxification occurs in peroxisomes rather than in the SER. Immune Function Hepatocytes complex IgA with secretory component and release the secretory IgA into the bile canaliculi. Kupffer cells, which are derived from monocyte precursors, are long-lived cells that are located within the hepatic sinusoids and adhere to the luminal surface of endothelial cells. Kupffer cells have Fc receptors as well as receptors for complement and thus can phagocytose foreign particulate matter. The importance of these cells is appreciable because blood from the portal vein contains a considerable number of microorganisms that enter the bloodstream from the lumen of the alimentary canal. These bacteria become opsonized in the lumen or mucosa of the gut or in the bloodstream. Kupffer cells recognize and endocytose at least 99% of these microorganisms. Kupffer cells also remove cellular debris and defunct erythrocytes from the blood.