than funneling bile into the intestine, BECs are actively involved in bile production by performing both absorptive and secretory functions via various membrane transport mechanisms including channels (e.g. water channels and chloride channels), transporters (e.g. ileal BA transporter), and exchangers (e.g. Cl−/HCO3− or Na+/H+ exchangers). The large cholangiocytes are located at the level of interlobular and major bile ducts and they express several different ion channels and transporters at the basolateral or apical domain; they are believed to be mostly involved in secretin/cyclic AMP‐regulated bile secretion. Smaller bile duct branches include terminal cholangioles and ductules or canals of Hering; the latter is a channel located at the ductular–hepatocellular junction, lined partly by hepatocytes and partly by cholangiocytes, and represents the physiologic link between the biliary tree and the hepatocyte canalicular system extended within the lobule. Their secretory function is believed to be mostly regulated by intracellular calcium. More recently, other important biological properties restricted to cholangiocytes lining the smaller bile ducts have been reported, especially with regard to their plasticity (the ability to undergo limited phenotypic changes), reactivity (the ability to participate in the inflammatory reaction to liver damage), and ability to behave as liver progenitor cells.
The hepatic sinusoidal endothelial cells (HSECs) represent 20% of the total liver cells. Unlike capillary endothelial cells, HSECs do not form intracellular junctions and simply overlap one another. They can secrete prostaglandins and cytokines [2]. They are also responsible for maintaining a cell niche that favors the quiescence of HSCs.
The Kupffer cells are specialized tissue macrophages and account for up to 90% of the total population of fixed macrophages in the body. These are macrophages attached to the endothelial lining of the sinusoid, in greater numbers in the periportal areas. They are responsible for removing old and damaged blood cells or cellular debris, bacteria, viruses, parasites, and tumor cells.
The HSCs, also known as Ito cells or lipocytes, are mesenchymal cells and represent the major storage site of retinoids in healthy livers. They lie within the subendothelial space, and their long cytoplasmic extensions have close contact with parenchymal cells and sinusoids, where they may regulate blood flow and hence influence portal hypertension. HSC activation is the central event in hepatic fibrosis. During hepatocyte injury, HSCs proliferate, migrate to zone three of the acinus, change to a myofibroblast‐like phenotype, and produce collagen and laminin.
Finally, the pit cells represent the natural killer (NK) cells of the liver and are located within the sinusoids. Pit cells show spontaneous cytotoxicity against tumor‐ and virus‐infected hepatocytes.
Hepatic Metabolism
The liver is the site of many metabolic pathways. It stores and makes available many nutrients as energy sources. In turns, the metabolic function of the liver is regulated by hormones secreted by the pancreas, adrenal gland, and thyroid.
Bilirubin Metabolism and Transport
Bilirubin is an end‐product of heme catabolism. Two enzymes are involved in bilirubin formation: the microsomal heme oxygenase converts heme to biliverdin and a cytosolic reductase subsequently reduces biliverdin to bilirubin.
The majority (up to 85%) of heme is derived from hemoglobin and only a small fraction from other heme‐containing proteins such as cytochrome P450, myoglobin and immature bone marrow cells. Bilirubin formed in the monocytic–macrophage cell system of liver, spleen and bone marrow and some of the bilirubin formed in the hepatocytes from hepatic heme are released into plasma where bilirubin is bound to albumin at high‐affinity binding sites. In normal conditions, only a minimal amount of bilirubin is unbound in plasma. An increase in free bilirubin would allow the pigment to enter tissues where it can have toxic effects; this is what is observed in neonates with defective conjugation and in Crigler–Najjar syndrome, when diffusion of unbound bilirubin into the brain can cause kernicterus.
In normal conditions, bilirubin is efficiently taken up by the liver whereas the albumin remains in plasma. In the liver, bilirubin is bound initially to glutathione‐S‐transferase, then glucuronidated and excreted into bile. Microsomal bilirubin uridine diphosphate glucuronosyltransferase (UGT) is the enzyme that converts unconjugated bilirubin to conjugated bilirubin monoglucuronide and diglucuronide. Biliary excretion of the glucuronide is mediated by the adenosine triphosphate (ATP)‐dependent multidrug resistance protein (MRP)‐2 and this is the rate‐limiting factor in the transport of bilirubin from plasma to bile. Bilirubin diglucuronide is not reabsorbed from the small intestine; in the colon it may be hydrolyzed by bacterial β‐glucuronidases, producing urobilinogens and urobilin, which are excreted in the stool or urine.
Carbohydrate Metabolism
The liver plays a key role in carbohydrate metabolism. It maintains carbohydrate stores by synthesizing glycogen and generating glucose from precursors such as lactate, pyruvate, and amino acids. Glycogen stored in the liver is the main source of rapidly available glucose for the whole organism. In the fed state, glycogen synthesis occurs preferentially in the perivenous hepatocytes whereas in the fasting state, glucose release via glycogenolysis and gluconeogenesis initially occurs in periportal hepatocytes. The liver glycogen stores contain up to a 2‐day supply of glucose, after which glucogenesis occurs mainly from lactate. In acute liver failure, the blood glucose level may drop whereas this is infrequent in chronic liver disease, where it is more common to observe hyperglycemia and insulin resistance. This may be related to decreased glucose uptake by muscle and reduced glycogen storage in the liver and muscle.
Lipid Metabolism
A major role of the liver in lipid metabolism is to synthesize large quantities of cholesterol and phospholipids, many of which are packaged with lipoproteins and made available to the rest of the body. Free cholesterol also derives from the uptake of chylomicron remnants and lipoproteins from the circulation. BAs are synthesized from free cholesterol, and both BA and cholesterol are secreted into bile. Bile provides a major route for cholesterol excretion.
The rate‐limiting step of cholesterol synthesis is the conversion of 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG‐CoA) to mevalonate by the enzyme HMG‐CoA reductase, which is located almost exclusively in periportal cells. Synthesis is increased in biliary duct obstruction, terminal ileal resection, biliary or intestinal lymph fistula, and with medications such as colestyramine, corticosteroids and thyroid hormones. Cholesterol synthesis is inhibited by BAs, cholesterol feeding, fasting, and medications such as fibrates, nicotinic acid, and statins.
During chronic cholestasis, such as in primary biliary cholangitis and primary sclerosing cholangitis (PSC) but also in acute cholestasis, cholesterol serum levels are increased. This is mainly secondary to retention of cholesterol normally excreted in bile but also to increased hepatic synthesis of cholesterol, reduced plasma lecithin‐cholesterol acyltransferase activity, and regurgitation of biliary lecithin, which produces a shift of cholesterol from pre‐existing tissue cholesterol into the plasma. In patients with severe chronic cholestasis who are however malnourished, for example in premature ductopenic variant of primary biliary cholangitis (PBC) or in carcinomatous biliary obstruction, the serum cholesterol may be lower. Elevated cholesterol levels are clinically associated with skin xanthomas and xanthelasma. Hypercholesterolemia is not consistently associated with subclinical atherosclerosis in PBC, but should be treated if other risk factors for cardiovascular disease are also present.
In addition, the liver has other roles in lipid metabolism such as oxidizing triglycerides to produce energy; synthesizing lipoproteins; and converting excess carbohydrates and proteins into fatty acids and triglyceride, which are then exported and stored in adipose tissue.
