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Structure and function of the liver, biliary tract, and pancreas 

Structure and function of the liver, biliary tract, and pancreas
Chapter:
Structure and function of the liver, biliary tract, and pancreas
Author(s):

Alexander Gimson

and Simon M. Rushbrook

DOI:
10.1093/med/9780199204854.003.1519
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Essentials

Liver and biliary tract

The liver, sited in the right upper quadrant of the abdomen, comprises eight segments, each of which is a complete functional unit with a single portal pedicle and a hepatic vein. Within the functional segments, the structural unit is the hepatic lobule, a polyhedron surrounded by four to six portal tracts containing hepatic arterial and portal venous branches from which blood perfuses through sinusoids, surrounded by walls of hepatocytes that are a single cell thick and lined by specialized endothelial cells with ‘windows’ (fenestrae), to the centrilobular region and the central hepatic veins. Bile secreted through the canalicular membrane of the hepatocyte collects in biliary canaliculi, from which it passes through the biliary tract into the gut.

The liver secretes bile, which aids digestion by emulsifying lipids, and has a central role in metabolism of (1) bilirubin, from haem; (2) bile salts, the principal mechanism for clearance of cholesterol; (3) carbohydrates, e.g. maintenance of blood glucose within a narrow range; (4) amino acids and ammonia, e.g. control of the plasma concentration of amino acids, and clearing portal venous ammonia generated within the gut lumen; (5) proteins, most circulating plasma proteins being produced by hepatocytes; and (6) lipid and lipoproteins.

Pancreas

The pancreas lies in the retroperitoneum and is composed of (1) an exocrine portion centred on acini, producing an alkaline secretion containing digestive enzymes including serine proteases (e.g. trypsinogen, chymotrypsin, which act at various cleavage points), exopeptidases (e.g. carboxypeptidases A and B, which cleave C-terminal amino acids) and lipolytic enzymes, draining through a ductal system into the duodenum; and (2) the islets of Langerhans, which secrete insulin (also glucagon, somatostatin, and pancreatic polypeptide).

Liver and biliary tract

The liver weighs 1.2 to 1.5 kg and has a highly vascular architecture. The classic descriptions of liver anatomy demonstrating the complexity of different parenchymal and nonparenchymal elements have a long history, but only recently have they been united with an increasing understanding of the intricate functional organization and physiological compartmentalization of liver structure. This has had a profound effect on our understanding of the control of physiological processes and the development of liver surgery. A grasp of the hepatic anatomy is key to an appreciation of these complex functional arrangements.

Morphological anatomy

This describes the classic structure of the liver into two lobes, right and left, and the accompanying vascular structures, lymphatics, and biliary tract.

The liver, situated in the right upper quadrant of the abdomen, is covered by Glisson’s capsule, a visceral continuation of the peritoneum. Three ligaments attach to surrounding structures—the falciform ligament anterior and superiorly, and the two posterior triangular ligaments which enclose the retrohepatic vena cava and the small bare area of the liver. Inferiorly Glisson’s capsule attaches to the lesser curve of the stomach and at the hepatic hilus encases the hepatic pedicle consisting of hepatic artery, portal vein, and common hepatic bile duct.

Hepatic lobes

The two major lobes, right and left, and two accessory lobes, quadrate and caudate, are defined by points of surface anatomy (Fig. 15.19.1a). The larger right lobe comprises the dome of the liver under the diaphragm and is limited anteriorly and medially by the falciform ligament and posteriorly by the right border of the inferior vena cava. The quadrate lobe inferiorly abuts on to the antrum of the stomach and first part of the duodenum and is bordered by the posterior transverse hilar fissure, the gallbladder fossa laterally, and the umbilical fissure medially. The caudate lobe lies posterior and superior to the quadrate lobe limited by the vena cava and the ligamentum venosum. Finally, the left lobe has the umbilical fissure medially and the falciform ligament anteriorly.

Fig. 15.19.1 (a) Lobar anatomy and relations. (b) Hilar, portal biliary tract, and pancreatic anatomy.

Fig. 15.19.1
(a) Lobar anatomy and relations. (b) Hilar, portal biliary tract, and pancreatic anatomy.

Vascular anatomy

The portal vein, hepatic duct, and hepatic artery form the hepatic pedicle with the bile duct anterior in the free edge of the lesser omentum and the portal vein posteriorly (Fig. 15.19.1b). The latter is formed by the confluence of the superior mesenteric vein and the splenic veins running posteriorly in the pedicle, dividing into left and right branches to supply each lobe. The left gastric vein also drains into the portal vein and may, in the presence of portal hypertension, be a major feeding vessel for gastro-oesophageal varices.

The hepatic artery arises from the coeliac axis as the common hepatic artery before dividing into a gastroduodenal and the main hepatic artery. There are several common anatomical variants of the arterial supply of the liver, which are of no functional significance but which are of importance in liver transplantation and during surgical resection. The standard division into single left and right hepatic arteries is present in approximately 70% of cases (Fig. 15.19.1b), but common variants include a separate second right hepatic artery (10%), separate right and left hepatic arteries (8%), and origin of the main hepatic artery off the superior mesenteric artery (2.5%). Variants of the left hepatic arterial supply also occur, with a separate left hepatic artery arising from the left gastric artery in 10% of cases.

Venous drainage of the liver is through the three main hepatic veins, right, left, and middle, the latter two coalescing before joining the inferior vena cava. The caudate lobe drains separately through an array of small spigelian veins directly into the inferior vena cava. The functional anatomy of the liver (see below) describes the relationship between the main divisions of the portal vein and their draining hepatic veins running in the right, left, and main scissures (Fig. 15.19.2).

Fig. 15.19.2 Functional anatomy of the liver with Couinaud’s segments.

Fig. 15.19.2
Functional anatomy of the liver with Couinaud’s segments.

Biliary anatomy

Biliary canaliculi drain into left and right hepatic bile ducts forming the common hepatic duct until entry of the cystic duct, after which it is designated the common bile duct and has a diameter of less than 8 mm. The left hepatic duct follows a nearly horizontal course, partially extrahepatic. Anatomical variants are again quite frequent, and are surgically important, the most common being drainage of the cystic duct directly into the right hepatic duct. The common bile duct passes behind the first part of the duodenum, through pancreatic tissue to the ampulla of Vater joining drainage of the pancreatic duct (Fig. 15.19.1b). The gallbladder lies in a shallow depression in the underside of the liver, may contain up to 50 ml of bile, and is connected to the cystic duct with a spiral valve.

Lymphatics

The liver has a high blood flow and a highly permeable microcirculation. The consequent production of interstitial fluid, intrahepatic lymph, is formed in the perisinusoidal space of Disse between the hepatocytes and sinusoidal lining endothelium. Lymphatic vessels drain via the portal tracts, closely applied to the hepatic arterial branches, to the hilum and thence to the thoracic duct. A smaller proportion drains with the hepatic veins and some interstitial fluid drains through Glisson’s capsule into the peritoneum. Lymph flow acts to drain from the liver that interstitial fluid and protein that forms inevitably through microvascular filtration. The lymph flow rate in mammalian liver is approximately 0.5 ml/kg of liver per minute, making up 25 to 50% of thoracic duct lymph flow, and may be increased either by elevated microvascular pressure (hydrostatic pressure) through increased hepatic venous pressure or increased inflow pressure, or by reduced transcapillary oncotic pressure.

Nervous system

Both sympathetic and parasympathetic efferent innervation of the liver are described, an anterior plexus around the hepatic artery and posterior around the portal vein. Sympathetic stimulation increases glucose release and glycogenolysis, and reduces oxygen consumption, ammonia uptake, and bile formation. Hepatic vascular resistance also rises as does portal pressure and there is rapid expulsion of blood out of the liver into the systemic circulation. An intrinsic nervous system with a wide variety of neurotransmitters, including noradrenaline, prostanoids, neuropeptide Y, substance P, and vasoactive intestinal peptide, is closely located to smooth muscle cells, fibroblasts, endothelial lining cells, and biliary epithelium within the liver and may be involved in chemoreception and osmoreception.

Extrinsic nervous regulation of hepatic physiological processes seems to be of minor importance as there is no apparent impairment of liver metabolism or bile formation following orthotopic liver transplantation. It may be more relevant during pathophysiological stress: the existence of a hepatorenal reflex is patients with cirrhosis has been postulated whereby an increase in sinusoidal pressure is associated with increased efferent renal sympathetic activity and reduced renal blood flow. In animal models of chronic liver disease, the metabolic consequences of sympathetic nerve stimulation are impaired but the haemodynamic responses exaggerated.

Functional anatomy

Following the initial descriptions by Cantlie in 1898, there has been an increasing appreciation of the importance of the functional anatomy of the liver, the culmination of which was the description by Couinaud of the present eight liver segments that underpins all modern hepatic surgery. Each segment is a complete functional unit with a single portal pedicle and a hepatic vein (Fig. 15.19.2). There are four portal pedicles, two for each lobe, each supplying a sector of the liver, divided from each other by the three hepatic veins lying in a right, middle, and left scissure. This separates the liver into a right and left liver, different from lobes, with independent vascular supply and biliary drainage. Within each sector of the liver there are further subdivisions into segments. The caudate lobe (segment 1) has its own venous drainage, manifest during the Budd–Chiari syndrome with thrombosis of hepatic veins when all venous drainage attempts to pass through this segment with consequent lobar hypertrophy.

The left liver consists of the left posterior sector of segment 2 alone, and a left anterior sector of segment 3 medially and segment 4 laterally separated by the umbilical fissure. The right liver comprises a posterior sector of segment 7 superiorly and segment 6 inferiorly and an anterior sector of segment 5 inferiorly and segment 8, being most of the dome of the liver, superiorly (Fig. 15.19.2).

Structural organization

Within the functional segments of the liver the structural unit is the hepatic lobule, a polyhedron (2 mm × 0.7 mm) surrounded by four to six portal tracts containing hepatic arterial and portal venous branches from which blood perfuses through sinusoids, surrounded by walls of hepatocytes that are a single cell thick and lined by specialized endothelial cells with ‘windows’ (fenestrae), to the centrilobular region and the central hepatic veins (Fig. 15.19.3).

Fig. 15.19.3 Hexagonal lobule with portal venous branches and hepatic microcirculatory subunit—sinusoids.

Fig. 15.19.3
Hexagonal lobule with portal venous branches and hepatic microcirculatory subunit—sinusoids.

The portal vein branches give off numerous terminal portal venules that run around the lobules in the interlobular septa accompanied by arterioles and bile ductules, and subsequently branch into inlet venules which each supply a hepatic microcirculatory subunit consisting at the base of numerous interconnected sinusoids and, at the apex, the central vein (Fig. 15.19.3).

Sinusoids

Sinusoids are specialized capillaries without a basement membrane and lined with endothelial lining cells through which proteins of low molecular weight may percolate into the space of Disse. The sinusoidal membrane of the surrounding hepatocytes is covered by microvilli that increase the surface area sixfold (Fig. 15.19.4). Within the sinusoids, Kupffer cells and liver-associated lymphocytes may be found, and within the space of Disse, the hepatic stellate cells (also called Ito, fat storage, or perisinusoidal cells), which respectively make up 2%, 0.2%, and 1.4% of the lobular parenchyma (Table 15.19.1).

Fig. 15.19.4 Hepatic sinusoid, sinusoidal cells, and functional spaces.

Fig. 15.19.4
Hepatic sinusoid, sinusoidal cells, and functional spaces.

Table 15.19.1 Hepatic parenchymal cellular elements and physiological functions

Cell type

Percentage of parenchyma

Surface receptors

Cellular functions

Hepatocytes

94

Asialoglycoprotein receptors, IL-6, cytokine receptors, albumin, transferrin, mannose, annexin, MHC class 1, Fas ligand

Maintain glucose, amino acid, ammonia, and bicarbonate homeostasis. Bile acid synthesis and transport. Synthesis of most plasma proteins. Processing of absorbed nutrient fuels and xenobiotics. Lipoprotein metabolism. Processing of hormones and signal mediators

Endothelial lining cells

2.5

Scavenger receptor, Fc IgM, MHC class II (CD4), CD58, thrombospondin receptor

Acts as physical barrier lining to sinusoids allowing passage of molecules via fenestrations up to 100 nm or numerous pinocytotic vesicles. Receptor-mediated uptake of HDL, LDL by scavenger receptor. May express numerous adhesion molecules marginating leucocytes and lymphocytes to sites of inflammation

Kupffer cells

2

KP-1, (CD68), Fc and complement receptors, VCAM, ICAM-1

Phagocytosis of numerous particles including cellular debris, denatured albumin, bacteria, complement. After stimulation, release inflammatory mediators: oxygen radical species, nitric oxide, proteases, TNF-α‎, IL-1, -6, -10, TGF-β‎, prostanoids, interferons

Stellate, fat storage, or Ito cells

1.4

Retinoid, cytokine receptors, platelet-derived growth factor, TGF-β‎, endothelin receptor

Vitamin A storage. Under a wide range of stimuli, including TNF-α‎, TGF-β‎, acetaldehyde, CCL4, prostanoids, cytokines, and oxygen species, transform into myofibroblasts. Secrete extracellular matrix proteins after activation (collagen, fibronectin, laminin, chondroitin sulphate, hyaluronic acid) resulting in fibrogenesis. Activated transformed stellate cells control sinusoidal blood flow

Pit cells

0.1

CD2, CD18

Natural killer cell activity that may be directed against tumour cells and virus-infected cells and occurs without prior activation

Biliary canaliculi

Bile secreted through the canalicular membrane of the hepatocyte collects in biliary canaliculi, which pass around hepatocytes until draining through the short canal of Hering into the bile ductule. Cholangioles are lined by three or four cells that eventually become cuboidal epithelium.

The volume and flow rate of bile are low; secretion into the duodenum is controlled by gallbladder contraction and sphincter of Oddi tone. Agents that cause gallbladder contraction, including cholecystokinin, secretin, and motilin, also relax the sphincter of Oddi (Table 15.19.2). Factors modulating biliary motility have received increased attention recently with the realization that the syndrome of biliary dysmotility may be the cause of biliary-type pain in some cases. Changes in gallbladder motility may also be important in gallstone pathogenesis.

Table 15.19.2 Physiological effects of neurotransmitters and hormones on biliary function

Contraction

Relaxation

Gallbladder motility

Acetylcholine

Secretin

Cholecystokinin

Glucagon

Motilin

Vasoactive intestinal peptide

β‎-Adrenergic agents

Pancreatic polypeptide

Endorphins

Sphincter of Oddi

Secretin

Cholecystokinin

Motilin

Vasoactive intestinal peptide

β‎-Adrenergic agents

Pancreatic polypeptide

Cellular elements

Hepatocytes are arranged in unicellular plates (Remak’s plates) that branch and divide around sinusoids, and are covered by specific membranes at each surface: sinusoidal (70% of surface area) for exchange of material between the Disse space and intracellular compartment (endo- and exocytosis); canalicular membrane (15%) for exchange with the smallest of biliary canaliculi or hemicanals; and lateral membrane (15%) separated from the former by tight junctions and involved in intercellular transport between hepatocytes. There is abundant smooth and rough endoplasmic reticulum, numerous mitochondria, and glycogen. There is an extensive cytoskeleton. Other cells making up 6% of all parenchyma include sinusoidal-lining endothelial cells, Kupffer cells, hepatic stellate cells (Ito cells, fat-storing cells), and pit cells (intrahepatic lymphocytes) (Table 15.19.1). These cells each differ in morphology, patterns of function, reactions to stimuli and disease, and expression of surface molecules and receptors. Interplay between these cells is critical, with communication via tight junctions allowing complex modulation of hepatocyte growth and function by sinusoidal lining cells. Parenchymal cells may clear mediators, including cytokines, secreted by endothelial lining and Kupffer cells. Waves of cellular activity may pass down the length of sinusoids. Importantly some cells show heterogeneity of function relative to their zonal location. Periportal hepatocytes differ from perivenous cells in both the direction of carbohydrate metabolism and ammonia/glutamine synthesis. Ito cells show zonal differences in desmin and cytokeratin staining, vitamin A storage, and α‎-smooth muscle actin.

Endothelial lining cells

These cells are central to the processes that control entry and exit trafficking of molecules from the sinusoidal flow into the Disse space. Fenestrae with a diameter of 100 nm, occupying up to 8% of the sinusoidal surface, act as a physical barrier to access of parenchymal cells by large molecules including lipids, cholesterol, vitamin A, and possibly some viruses. Endothelial cells also possess numerous specialized endocytotic mechanisms, some linked to specific receptors including mannose, transferrin, caeruloplasmin, modified high-density lipoprotein (HDL), low-density lipoprotein (LDL), glucosaminoglycans, and hyaluronic acid. Nonspecific endocytosis of molecules and small particles up to 0.1 µm also occurs. Endothelial cells are also capable of expressing a range of surface adhesion molecules including E- and P-selectins, intercellular adhesion molecule 1 (ICAM-1), and lymphocyte function-associated antigen-4 (LFA-4) that enhance polymorphonuclear leucocyte and lymphocyte adherence, activation, and migration towards sites of inflammation.

Kupffer cells

These cells represent part of the mononuclear phagocyte system and are adherent to the sinusoidal surface of endothelial lining cells, predominantly in a periportal distribution. Covered with numerous microvilli and with a number of intracytoplasmic vesicles, their main function is to phagocytose a range of particulate material including cellular debris, senescent red blood cells, parasites, bacteria, endotoxin, and tumour cells. Phagocytosis is via a range of mechanisms including coated pits, macropinocytotic vesicles, and phagosomes aided by opsonization of particles by fibronectin or opsonin. Kupffer cells may be activated by molecules including Escherichia coli endotoxin, interferon-γ‎, tumour necrosis factor α‎ (TNFα‎), and arachidonic acid as well as zymosan and phorbol myristate to release a range of inflammatory mediators that include oxygen radical species, nitric oxide, proteases, TNFα‎, interleukins 1, 6, and 10 (IL-1, -6, -10), transforming growth factor β‎ (TGFβ‎), prostanoids, and interferon-α‎ and -γ‎. Some of these may act in an autocrine or paracrine loop to further activate other Kupffer cells. These inflammatory products have a range of effects including significant modulation of parenchymal cell function (down-regulation of albumin synthesis and up-regulation of acute-phase protein gene expression), and induction of adherence of polymorphonuclear leucocytes and lymphocytes to endothelial lining cells due to enhanced expression of endothelial adhesion molecules.

Hepatic stellate cells

Stellate cells (Ito cells, fat-storing cells) have a similar morphology to fibroblasts with the addition of fat droplets, and are located within the Disse space. A fine branching array of cytoplasmic processes circle sinusoids under the endothelial cells. Stellate cells contain most of the body’s stores of vitamin A. Retinoids are taken up from chylomicrons by specific receptors on hepatocytes and stellate cells and stored within the latter. These cells are central to the process of hepatic fibrogenesis, responding to mediators released by parenchymal and Kupffer cells, causing transformation into myofibroblasts. TGFβ‎ initiates this process, stimulating production by the transformed stellate cell of extracellular matrix products (collagen types I, III, and IV, fibronectin, laminin, chondroitin sulphate, and hyaluronic acid) in addition to products for matrix degradation (collagenase, metalloproteinase, and its inhibitor TIMP-1). Activation of stellate cells is also an important mechanism for control of sinusoidal perfusion, through cytoskeletal actin within branching cellular processes beneath the endothelium.

Pit cells

Similar to large granular lymphocytes and located in clefts within endothelial lining cells, pit cells have natural killer cell properties with spontaneous activity against tumour cells in the absence of prior activation. They may also play a role in hepatic regeneration.

Physiological processes

Hepatic blood flow

The liver receives approximately 25% of cardiac output, one-third from the hepatic artery and two-thirds from the portal vein with a plasma flow at rest of 1600 ml/min in women and 1800 ml/min in men. Hepatic blood flow increases after feeding and with expiration and decreases with standing, inspiration, and sleep. In contrast to other organs, metabolic autoregulation of blood flow is not observed. Changes in hepatic oxygen consumption do not seem to control hepatic blood flow. Vascular autoregulation of hepatic arterial blood flow mediated by adenosine is present, but may not be of great physiological importance. Hepatic arterial resistance increases with increasing hepatic venous pressure due to a stepwise myogenic response in the hepatic artery to increased pressure. There is an important reciprocity between portal venous and hepatic arterial flow with a reduction in portal venous input being associated with significant compensatory decrease in hepatic arterial resistance and rise in arterial flow. The mechanism for this relationship is unproven but may be due to adenosine-mediated arterial vasodilatation.

The portal venous system is passive, without pressure-dependent autoregulation, and the major physiological factors controlling flow are those modulating supply to the intestines and spleen. The sites of portal venous resistance are not fully defined in humans but may be at sinusoidal or postsinusoidal levels. The significant capacitance of the hepatic circulation, with blood comprising up to 20% of liver volume, is reflected in the important role of the liver and splanchnic circulation in acting as a blood reservoir. Sympathetic nerve stimulation may reduce hepatic blood volume by up to 50%.

Sinusoidal perfusion

Blood pressure in sinusoids ranges from 4.8 to 1.7 mmHg, with flows of 270 to 410 ml/s. There is likely to be considerable heterogeneity of the unidirectional sinusoidal flow, control for which can be considered as either passive (haemodynamic) or active. Passive control mechanisms include: (1) the arterial input pressure and flow at the level of the arteriosinous twig at the origin of the sinusoid; and (2) changes in right atrial pressure, central venous pressure, and hepatic venous pressure that are transmitted to the sinusoid from the centrilobular veins. Active control mechanisms include: (1) the presence of ‘functional’ sphincters at the inlet and outlet of the sinusoid due to indentations by the cell bodies of sinusoidal lining cells, which under different physiological stimuli may change dimension and alter sinusoidal perfusion; (2) plugging by leucocytes, which are less compressible than erythrocytes and may under physiological stimuli adhere to endothelial lining cells; (3) activation of Kupffer cells within sinusoids and release of other vasoactive mediators including nitric oxide, cytokines, and prostanoids; and (4) transformation of hepatic stellate cells into activated contractile myofibroblasts that constrict the sinusoidal lumen. Sinusoidal flow will also affect the transendothelial traffic into and out of the Disse space by the processes of forced sieving and endothelial massage that may affect, respectively, the passage of lipoprotein particles and the appropriate mixing of the interstitial fluid. Therefore, sinusoidal flow is likely to have a profound effect on numerous hepatic metabolic functions and clearance of xenobiotics.

Bile formation

The formation of bile by hepatocytes and its modification by bile ductular epithelium serves many functions (Table 15.19.3). In humans the daily production of 600 ml of bile is made up of 75% of canalicular origin and 25% from ductules. Bile is formed by osmotic filtration, with the secretion of the two primary bile salt anions, taurine and glycine conjugates of cholic acid and chenodeoxycholic acid, across the canalicular membrane by an active transport mechanism against a concentration gradient of 5000:1 (Fig. 15.19.5). Negatively charged intercellular tight junctions prevent back diffusion of these anions, allowing the selective passage of cations, predominantly sodium, and to a smaller extent potassium, calcium, and magnesium, followed by the passive transit of water, transcellularly or between cells. The resulting bile salt-dependent bile flow makes up 50% of canalicular bile flow, with the remaining bile salt-independent flow resulting from the active secretion of bicarbonate and glutathione.

Table 15.19.3 Physiological functions of bile

Digestion

Neutralization of duodenal pH

Bile salt activation of lipase, formation of micelles

Emulsification, lipolysis, and solubilization of fat

Absorption of fat-soluble substances

Excretion, including xenobiotics

Cholesterol

Bilirubin

Drugs

Environmental toxins

Heavy metals

Mucosal immunity

Secretory IgA

Fig. 15.19.5 Bile salt metabolism and enterohepatic pathway. NTCP, Na-taurocholate cotransporters; conjugated bile salt uptake from portal blood. OATP, organic anion transporter; bile salt, organic anion, and amphipathic solutes uptake. BSEP, bile salt export pump; ATP-dependent bile export—bile salt-dependent bile flow. MDR1, multidrug resistance; organic cation, xenobiotic export. MDR2, bilirubin glucuronide export; bile salt-independent bile flow. MDR3, multidrug resistance; translocation of phosphatidylcholine. GSHT, glutathione transporter; gluthathione transport independent of bile flow.

Fig. 15.19.5
Bile salt metabolism and enterohepatic pathway. NTCP, Na-taurocholate cotransporters; conjugated bile salt uptake from portal blood. OATP, organic anion transporter; bile salt, organic anion, and amphipathic solutes uptake. BSEP, bile salt export pump; ATP-dependent bile export—bile salt-dependent bile flow. MDR1, multidrug resistance; organic cation, xenobiotic export. MDR2, bilirubin glucuronide export; bile salt-independent bile flow. MDR3, multidrug resistance; translocation of phosphatidylcholine. GSHT, glutathione transporter; gluthathione transport independent of bile flow.

Bile in biliary ductules is further modified by reabsorption of glucose, amino acids, and bile salts, as well as active secretion. Reabsorption of bile salts, the cholehepatic shunt pathway, occurs after their protonation in bile with the generation of further bicarbonate into bile stimulating bile flow. Active secretion of bicarbonate and chloride within ductules is mediated by the secretin receptor and the cystic fibrosis transmembrane receptor. Gallbladder epithelium further modifies and concentrates bile by an active anion transport process.

Bile salt conjugates secreted from hepatocytes into bile are deconjugated in the jejeunum and ileum with reabsorption and reuptake by the liver—this enterohepatic circulation conserves bile acids and maintains their high concentration within bile. The 5% of bile acids passing through the ileocaecal valve are fully deconjugated by colonic bacteria and reabsorbed as the secondary bile acids deoxycholic acid and lithocolic acid, which are in turn secreted as taurine and glycine conjugates.

Metabolic processes

Hepatic metabolic processes have a central role in protein, carbohydrate, and lipid metabolism and fuel economy, orchestrating a diverse interplay between central splanchnic and peripheral organs. Interruption to these processes results in the major metabolic consequences of acute and chronic liver disease. Modulation of these metabolic processes can occur at a number of levels. Transport of molecules across membranes and through cells is an important control mechanism as are rate-limiting enzyme levels, controlled at a number of transcriptional and translational points. There is important zonal heterogeneity of hepatocyte function, with periportal zone 1 cells with a higher oxidative capacity and larger mitochondria involved in gluconeogenesis, β‎-oxidation of fatty acids, amino acid catabolism, ureagenesis, cholesterol synthesis, and bile secretion, whereas perivenular cells are more involved with glycolysis, lipogenesis, ammonia clearance with glutamine synthesis, detoxification, and biotransformation.

Bilirubin metabolism

(see Chapter 15.20)

The first step in the production of bilirubin is the formation of biliverdin IXa by the action of haem oxidase on haem-containing proteins including catalases, cytochromes as well as haemoglobin in senescent red cells, with the release of carbon monoxide and Fe2+. Biliverdin convertase within the cytosol reduces biliverdin to unconjugated bilirubin (Fig. 15.19.6). Both biliverdin convertase and haem oxidase are predominantly found within reticuloendothelial cells.

Fig. 15.19.6 Metabolism of haem and bilirubin with clearance through canalicular membrane to bile.

Fig. 15.19.6
Metabolism of haem and bilirubin with clearance through canalicular membrane to bile.

Bilirubin is transported within plasma bound with high affinity to albumin. A few substances may displace bilirubin from albumin, including sulphonamides and fatty acids. Unbound bilirubin, which is insoluble in water, is present only in nanogram quantities but may cause significant cellular toxicity in neonates and in the Crigler–Najjar syndrome.

Bilirubin uptake by hepatocytes occurs via an organic anion-binding protein receptor. Within the hepatocyte the unbound bilirubin is transported by organelles and a number of transport proteins including glutathione-S-transferase (ligandin) to the endoplasmic reticulum. This reduces back diffusion into sinusoids of the lipid-soluble unbound bilirubin. Glucuronidation to the mono- and diglucuronides renders bilirubin water soluble. Secretion across the canalicular membrane occurs at the canalicular multispecific membrane organic anion transporter.

Bile salt metabolism

In addition to their role in digestion, bile acids are the principal mechanism for clearance and metabolism of cholesterol, which acts as a substrate for their synthesis and in turn promotes biliary cholesterol secretion as lamellar vesicles. The first step in bile acid synthesis is rate limiting and involves cholesterol 7α‎-hydroxylase. Transcriptional control of the cholesterol 7α‎-hydroxylase gene has been demonstrated with thyroxine and glucocorticoids increasing, and glucagon decreasing, gene expression. Preformed (nondietary) cholesterol and bile acids may also control this enzyme. The close association between bile acid and cholesterol metabolism is reflected in the often parallel activation of 7α‎-hydroxylase and HMG-CoA reductase, which is of critical importance in bile acid synthesis. The two major bile acids, cholic acid (60% of bile acid pool) and chenodeoxycholic acid are secreted into bile as taurine and glycine conjugates. The transport receptors for both uptake into hepatocyte and transport across the canalicular membrane are controlled at both transcriptional and post transcriptional levels by multiple factors including bile acids, cytokines and hormones. Nuclear receptors such as the farnesoid X and liver X receptor also regulate transcription.

Carbohydrate metabolism

(Fig. 15.19.7)

Fig. 15.19.7 Carbohydrate metabolism and pathways for glycolysis and glycogenesis.

Fig. 15.19.7
Carbohydrate metabolism and pathways for glycolysis and glycogenesis.

The liver has a central role in maintaining blood glucose within a narrow margin. During fasting, hepatic glucose release is contributed to by both glycogenolysis (33%) and gluconeogenesis (67%) from lactate, pyruvate, glycerol, and the glucogenic amino acids alanine and glutamine (Fig. 15.19.7). This process is regulated by at least four levels: (i) hormonal control, with glucagon accounting for up to two-thirds of basal fasted glucose output, and cortisol, growth hormone, and catecholamines also contributing; (ii) the supply of substrates, fatty acids, lactate, pyruvate, and amino acids for hepatic gluconeogenesis; (iii) metabolic regulation of hepatic enzyme activity; and (iv) the degree of hepatocellular hydration. The direction of gluconeogenesis or glycogenolysis is controlled at the level of three paired enzyme cycles—glucose/glucose 6-phosphate, fructose 6-phosphate/fructose 1,6-bisphosphate, and pyruvate/phosphoenolpyruvate. In contrast, after a glucose load, insulin suppresses hepatic glucose release and activates glucose synthetase, while autoregulation of hepatic glucose extraction by glucose itself within the portal venous circulation is an important factor in controlling the distribution of the load between liver and peripheral tissues.

Amino acid and ammonia metabolism

The liver is the most important organ in controlling the plasma concentration of amino acids. During prolonged starvation, hepatic proteolysis stimulated by glucagon increases splanchnic export of amino acids, whereas during the postprandial absorptive state, amino acid uptake is significantly increased. The gluconeogenic amino acids are preferentially extracted and metabolized, whereas the branched chain amino acids valine, leucine, and isoleucine are only cleared in the liver for protein synthesis and are catabolized in the muscle. During sepsis and under the influence of cytokines IL-1, IL-6, and TNFα‎, the liver may significantly enhance gluconeogenesis and protein synthesis of acute-phase reactants (C-reactive protein, serum amyloid A).

The liver has a critical role in clearing portal venous ammonia generated within the gut lumen, by both formation of carbamoyl phosphate and entry into the urea cycle in periportal hepatocytes, and glutamine synthetase-driven glutamine synthesis in perivenous hepatocytes.

Protein synthesis

Most circulating plasma proteins with the exception of immunoglobulins and von Willebrand factor are produced by hepatocytes. The major controlling factors for this constitutive protein secretion are substrate delivery and the degree of hydration of hepatocytes. Acute-phase protein secretion is also specifically controlled by cytokines with a reciprocal relationship to albumin and other carrier protein synthesis.

Lipid and lipoprotein metabolism

(Fig. 15.19.8) (see Chapter 12.6)

Plasma lipoproteins are particles with an outer layer of cholesterol, phospholipids, and apoproteins and an inner core of cholesterol esters and triglycerides. The various lipoproteins differ in the relative proportions of these elements. Dietary derived chylomicrons, consisting of more than 90% triglyceride, are processed within muscle and adipose tissue by lipoprotein lipase, extracting free fatty acids and the remnant, enriched in cholesterol, are extracted by the liver—an exogenous lipid pathway. During carbohydrate feeding, free fatty acids formed within the liver are exported as very-low-density lipoprotein (VLDL) and taken up by muscle and adipose tissue with extraction of free fatty acids, leaving intermediate-density lipoprotein and subsequently LDL. Specific LDL receptors on hepatocytes or scavenger receptors on Kupffer cells remove LDL where cholesterol may be utilized for bile salt metabolism or excreted into bile. Peripheral LDL receptors in extrahepatic tissues also extract cholesterol. Export of cholesterol from peripheral tissues in high-density lipoprotein is modified in plasma by lecithin; cholesterol acyltransferase (LCAT) and LDL is formed for further recirculation.

Pancreas

Structure and function

A retroperitoneal organ receiving arterial supply from splenic, superior mesenteric, and gastroduodenal arteries, the pancreas is composed of an exocrine portion centred on acini producing digestive enzymes draining through a ductal system into the duodenum, and the islets of Langerhans which make up 1 to 2% of the whole volume and are predominantly located along arterioles.

Development and congenital anomalies

The pancreas develops from ventral and dorsal buds of the primitive duodenum. With rotation around the duodenum the two portions fuse together and the duct originating from the dorsal portion (duct of Santorini) forms the accessory duct whilst the main drainage of the gland is through the duct of Wirsung to the ampulla of Vater. Failure of ductal fusion, pancreas divisum, in which most of the gland drains through the duct of Santorini to the minor papilla, occurs in approximately 8% of the population, and in a small proportion may lead to recurrent acute pancreatitis. Annular pancreas results from pancreatic tissue remaining wrapped around the duodenum during rotation of the ventral portion. Ectopic pancreatic tissue may occur in a submucosal location within the stomach and duodenum.

Exocrine pancreas

The pancreas secretes up to 2 litres of fluid per day although resting secretion rates are very low (0.3 ml/min). Acini are located in lobules draining into extralobular ducts. Cells lining the ducts secrete bicarbonate, the major anion within pancreatic juice. The acinar cells are pyramidal with the nucleus and endoplasmic reticulum towards the base and zymogen storage granules towards the apex and draining duct. Two classes of proteolytic enzymes are secreted—the serine proteases and the exopeptidases. Serine proteases all require activation either by intestinal endopeptidase in the case of trypsinogen or by trypsin itself in the case of chymotrypsin, elastase, and protease E. Serine protease act at various cleavage points whereas the carboxypeptidases A and B (exopeptidases) cleave C-terminal amino acids. The lipolytic enzymes include phospholipase A2, lipase, and carboxylesterase. Other proteins found in pancreatic secretions include lysosomal proteins, ribonucleases, and amylase.

Control of the secretory process involves hormones as well as sympathetic and parasympathetic nerve fibres. Secretin is the main stimulus to ductal bicarbonate secretion, whereas cholecystokinin, acetylcholine, and to a lesser extent gastrin and neurotensin stimulate zymogen release of digestive enzymes at the apical membrane. Although often described as having cephalic, gastric, and intestinal phases to indicate the origin of the pancreatic stimulus, this distinction is physiologically artificial since the phases run concurrently. Somatostatin and glucagon inhibit pancreatic proenzyme secretion.

Endocrine pancreas

The islets of Langerhans represent an endocrine organ consisting of four cell types: α‎ cells secreting glucagon, β‎ cells secreting insulin, δ‎ cells secreting somatostatin, and PP cells secreting pancreatic polypeptide. The β‎ cells constitute 80% of islet volume and form the central core around which the others cells form a mantle. The principal physiological function of these cells is to maintain stable glucose concentration irrespective of substrate delivery.

The β‎ cells act as a sensor of glucose concentration over a wide range, with rapid equilibration of glucose levels across the cell membrane by the GLUT-2 transporter. The molecular basis for this sensor is considered to be glucokinase, the activity of which closely follows glucose levels. Enhanced glucose metabolism increases ATP/ADP ratios, which in turn blocks potassium ion channels, and the subsequent change in membrane potential allows an influx of calcium that promotes exocytosis of insulin-containing granules. Many other hormones, neuropeptides, and neurotransmitters also modulate glucose-dependent insulin secretion (Table 15.19.4).

Table 15.19.4 Source and metabolic control of pancreatic endocrine function

Source

Stimuli for release

Inhibitors of release

Physiological role

Insulin

B cells

  • Glucose, leucine, inosine, sulphonylureas

  • Secondary stimuli: free fatty acids, arginine, alanine, acetylcholine, glucagon, GIP

Hypoglycaemia, adrenaline, noradrenaline, somatostatin, insulin-like growth factor

  • Increases rate of transport of glucose across cell membrane

  • Enhances glycogen synthesis and inhibits gluconeogenesis; increases protein, triglyceride, and VLDL synthesis in hepatocytes

  • Enhances protein and glycogen synthesis in muscle cells

  • Enhances triglyceride deposition and inhibits lipolysis in adipocytes.

Glucagon

A cells

  • Glucose, catecholamines

  • Secondary stimuli: glutamine, alanine, arginine, vasoactive intestinal peptide

Insulin, somatostatin

  • Stimulates glycogenolysis.

  • Promotes gluconeogenesis from amino acids Increases lipolysis in adipose tissue

Somatostatin

D cells

Glucose, arginine, GIP, glucagon, sulphonylureas

Sympathetic nerve stimulation

  • Suppresses pancreatic exocrine release of insulin and glucagon

  • Reduces gastric motility

  • Inhibits growth hormone-releasing hormone

Pancreatic polypeptide

PP cells

Protein intake, sympathetic nerve stimulation

?

Probable inhibition of pancreatic acinar and ductal secretion

GIP, glucose-dependent insulinotropic polypeptide.

Further reading

Balabaud C, et al. (1988). Light and transmission electron microscopy of sinusoids in human liver. In: Bioulac Sage P, Balabaud C (eds) Sinusoids in human liver; health and disease, pp. 87–110. Kupffer Cell Foundation, Rijswik.Find this resource:

    Erlinger S (1993). Intracellular events in bile acid transport by the liver. In: Tavoloni N, Berk PD (eds) Hepatic transport and bile secretion. Physiology and pathophysiology, pp. 467–75. Raven Press, New York.Find this resource:

      Gumucio JJ (1999). Functional organisation of the liver. In: Bircher J, et al. Oxford textbook of clinical hepatology, pp. 437–46. Oxford University Press, Oxford.Find this resource:

        Kang S, Davis RA (2000). Cholesterol and hepatic lipoprotein assembly and secretion. Biochim Biophys Acta, 1529, 223–30.Find this resource:

        Knook DI, Wisse E (eds) (1982). Sinusoidal liver cells. Elsevier, Amsterdam.Find this resource:

          Tukey RH, Strassburg CP (2000). Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Ann Rev Pharmacol Toxicol, 40, 581–616.Find this resource: