OVERVIEW OF THE LIVER AND ITS FUNCTIONS

The liver is a large, multilobed organ located in the abdominal cavity whose function is intimately associated with that of the gastrointestinal system. The liver serves as the first site of processing for most absorbed nutrients and also secretes bile acids, which as we learned in Chapter 29, plays a critical role in the absorption of lipids from the diet. In addition, the liver is a metabolic powerhouse, critical for disposing of a variety of metabolic waste products and xenobiotics from the body by converting them to forms that can be excreted. The liver stores or produces numerous substances needed by the body, such as glucose, amino acids, and plasma proteins. In general, key functions of the liver can be divided into three areas: (1) contributions to whole-body metabolism, (2) detoxification, and (3) excretion of protein-bound/lipid-soluble waste products. In this chapter we discuss the structural and molecular features of the liver and the biliary system that subserve these functions, as well as their regulation. However, although the liver contributes in a pivotal way to the maintenance of whole-body biochemical status, a complete discussion of all of the underpinning reactions is beyond the scope of the present text. We will confine our discussion primarily to hepatic functions that relate to gastrointestinal physiology.

The Liver and Detoxification

The liver serves both as a gatekeeper, by limiting the entry of toxic substances into the bloodstream, and as a garbage disposal, by extracting potentially toxic metabolic products produced elsewhere in the body and converting them to chemical forms that can be excreted. The liver fulfills these functions, in part, because of its unusual blood supply. Unlike all other organs, the majority of blood arriving at the liver is venous in nature and is supplied via the portal vein from the intestine (Fig. 31-1). As such, the liver is strategically located to receive not only absorbed nutrients but also potentially harmful absorbed molecules such as drugs and bacterial toxins. Depending on the efficiency with which these molecules are extracted by hepatocytes and subjected to so-called first-pass metabolism, little or none of the absorbed substance may make it into the systemic circulation. This is a major reason why not all pharmaceutical agents can achieve therapeutic concentrations in the bloodstream if administered orally.

Figure 31-1 Typical blood flow through the splanchnic circulation in a fasting adult human.

The liver has two levels at which it removes and metabolizes/detoxifies substances originating from the portal circulation. The first of these is physical. Blood arriving in the liver percolates among cells of macrophage lineage, known as Kupffer cells. These cells are phagocytic and are particularly important in removing particulate material from portal blood, including bacteria that may enter blood from the colon even under normal conditions. The second level of defense is biochemical. Hepatocytes are endowed with a broad array of enzymes that metabolize and modify both endogenous and exogenous toxins so that the products are, in general, more water soluble and less susceptible to reuptake by the intestine. The metabolic reactions involved are broadly divided into two classes. Phase I reactions (oxidation, hydroxylation, and other reactions catalyzed by cytochrome P-450 enzymes) are followed by phase II reactions that conjugate the resulting products with another molecule, such as glucuronic acid, sulfate, amino acids, or glutathione, to promote their excretion. The products of these reactions are then excreted into bile or returned to the bloodstream to ultimately be excreted by the kidneys. We will return to the precise mechanisms involved in the detoxification of some key metabolic waste products later.

Role of the Liver in Excretion

The kidneys play an important role in the excretion of water-soluble catabolites, as discussed in the renal section. Only relatively small water-soluble catabolites can be excreted by the process of glomerular filtration. However, larger water-soluble catabolites and molecules bound to plasma proteins, including lipophilic metabolites and xenobiotics, steroid hormones, and heavy metals, cannot be filtered by the glomerulus. All these substances are potentially harmful if allowed to accumulate, so a mechanism must exist for their excretion. The mechanism for excretion involves the liver, which excretes these substances in bile. Hepatocytes take up these substances with high affinity by virtue of the presence of an array of basolateral membrane transporters, and the substances are subsequently metabolized at the level of microsomes and in the cytosol (Table 31-1). Ultimately, substances destined for excretion in bile are exported across the canalicular membrane of hepatocytes via a different array of transporters. The features of bile allow solubilization of even lipophilic substances, which can then be excreted into the intestine and ultimately leave the body in feces.

Table 31-1 Key Transporters of Hepatocytes

STRUCTURAL FEATURES OF THE LIVER AND BILIARY SYSTEM

Hepatocytes, the major cell type in the liver, are arranged in anastomosing cords that form plates around which large volumes of blood circulate (Fig. 31-2). The liver receives a high blood flow that is disproportionate to its mass, which ensures that hepatocytes receive high quantities of both O₂ and nutrients. Hepatocytes receive more than 70% of their blood supply at rest via the portal vein (rising to more than 90% in the postprandial period).

Figure 31-2 Diagrammatic representation of a hepatic lobule. Plates of hepatocytes are arrayed radially around a central vein. Branches of the portal vein and hepatic artery are located on the periphery of the lobule and form the “portal triad” together with the bile duct. Blood from the portal vein and hepatic artery percolates around the hepatocytes via the sinusoids before draining into the central vein.

(Modified from Bloom W, Fawcett DW: A Textbook of Histology, 10th ed. Philadelphia, Saunders, 1975.)

The plates of hepatocytes that constitute the liver parenchyma are supplied by a series of sinusoids, which are low-resistance cavities supplied by branches of both the portal vein and the hepatic artery. The sinusoids are unlike the capillaries that perfuse other organs. During fasting, many sinusoids are collapsed, but more can gradually be recruited as portal blood flow increases during the period after a meal when absorbed nutrients are transported to the liver. The low resistance of the sinusoidal cavities means that blood flow through the liver can increase considerably without a concomitant increase in pressure. Eventually, the blood drains into central branches of the hepatic vein.

The sinusoids are also unusual in the endothelial cells that line their walls (Fig. 31-3). Hepatic endothelial cells contain specialized openings, known as fenestrations, that are large enough to permit the passage of molecules as big as albumin. Sinusoidal endothelial cells also lack a basement membrane, which might otherwise pose a diffusion barrier. These features allow access of albumin-bound substances to the hepatocytes that will eventually take them up. The sinusoids also contain Kupffer cells. Beneath the sinusoidal endothelium and separating the endothelium from the hepatocytes is a thin layer of loose connective tissue called the space of Disse, which likewise poses little resistance to the movement of molecules even as large as albumin in health. The space of Disse is also the location of another important hepatic cell type, the stellate cell. Stellate cells serve as storage sites for retinoids and in addition are the source of key growth factors for hepatocytes. Under abnormal conditions, stellate cells are activated to synthesize large quantities of collagen, which contributes to the hepatic dysfunction.

Figure 31-3 Interrelationships of the major cell types in the liver.

Hepatocytes are also the origination point for the biliary system. Although hepatocytes are considered to be epithelial cells with basolateral and apical membranes, the spatial arrangement of these two cell domains differs from that seen in simple columnar epithelium, such as that lining the gastrointestinal tract. Rather, in the liver the apical surface of the hepatocyte occupies only a small fraction of the cell membrane, and the apical membranes of adjacent cells oppose each other to form a channel between the cells known as the canaliculus (Fig. 31-3). The role of canaliculi is to drain bile from the liver, and these canaliculi drain into biliary ductules, which are lined by classic columnar epithelial cells known as cholangiocytes. Ultimately, the biliary ductules drain into large bile ducts that coalesce into the right and left hepatic ducts to permit exit of bile from the liver. These, in turn, form the common hepatic duct, from which bile can flow into either the gallbladder, via the cystic duct, or the intestine, via the common bile duct (Fig. 31-4), on the basis of prevailing pressure relationships.

Figure 31-4 Functional anatomy of the biliary system.