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The liver has many complex functions that are summarized in Table 28–1. Several will be touched upon briefly here.
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METABOLISM & DETOXIFICATION
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It is beyond the scope of this volume to touch upon all of the metabolic functions of the liver. Instead, this chapter will focus on those aspects most closely aligned to gastrointestinal physiology. First, the liver plays key roles in carbohydrate metabolism, including glycogen storage, conversion of galactose and fructose to glucose, and gluconeogenesis, as well as many of the reactions covered in Chapter 1. The substrates for these reactions derive from the products of carbohydrate digestion and absorption that are transported from the intestine to the liver in the portal blood. The liver also plays a major role in maintaining the stability of blood glucose levels in the postprandial period, removing excess glucose from the blood and returning it as needed—the so-called glucose buffer function of the liver. In liver failure, hypoglycemia is commonly seen. Similarly, the liver contributes to fat metabolism. It supports a high rate of fatty acid oxidation for energy supply to the liver itself and other organs. Amino acids and two carbon fragments derived from carbohydrates are also converted in the liver to fats for storage. The liver also synthesizes most of the lipoproteins required by the body and preserves cholesterol homeostasis by synthesizing this molecule and also converting excess cholesterol to bile acids.
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The liver also detoxifies the blood of substances originating from the gut or elsewhere in the body (Clinical Box 28–1). Part of this function is physical in nature—bacteria and other particulates are trapped in and broken down by the strategically located Kupffer cells. The remaining reactions are biochemical, and mediated in their first stages by the large number of cytochrome P450 enzymes expressed in hepatocytes. These convert xenobiotics and other toxins to inactive, less lipophilic metabolites. Detoxification reactions are divided into phase I (oxidation, hydroxylation, and other reactions mediated by cytochrome P450s) and phase II (esterification). Ultimately, metabolites are secreted into the bile for elimination via the gastrointestinal tract. In this regard, in addition to disposing of drugs, the liver is responsible for metabolism of essentially all steroid hormones. Liver disease can therefore result in the apparent overactivity of the relevant hormone systems.
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SYNTHESIS OF PLASMA PROTEINS
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The principal proteins synthesized by the liver are listed in Table 28–1. Albumin is quantitatively the most significant, and accounts for the majority of plasma oncotic pressure. Many of the products are acute-phase proteins, proteins synthesized and secreted into the plasma on exposure to stressful stimuli (see Chapter 3). Others are proteins that transport steroids and other hormones in the plasma, and still others are clotting factors. Following blood loss, the liver replaces the plasma proteins in days to weeks. The only major class of plasma proteins not synthesized by the liver is the immunoglobulins.
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CLINICAL BOX 28–1 Hepatic Encephalopathy
The clinical importance of hepatic ammonia metabolism is seen in liver failure, when increased levels of circulating ammonia cause the condition of hepatic encephalopathy. Initially, patients may seem merely confused, but if untreated, the condition can progress to coma and irreversible changes in cognition. The disease results not only from the loss of functional hepatocytes, but also shunting of portal blood around the hardened liver, meaning that less ammonia is removed from the blood by the remaining hepatic mass. Additional substances that are normally detoxified by the liver likely also contribute to the mental status changes.
THERAPEUTIC HIGHLIGHTS The cognitive symptoms of advanced liver disease can be minimized by reducing the load of ammonia coming to the liver from the colon (eg, by feeding the nonabsorbable carbohydrate, lactulose, which is converted into short-chain fatty acids in the colonic lumen and thereby traps luminal ammonia in its ionized form). However, in severe disease, the only truly effective treatment is to perform a liver transplant, although the paucity of available organs means that there is great interest in artificial liver assist devices that could clean the blood.
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Bile is made up of the bile acids, bile pigments, and other substances dissolved in an alkaline electrolyte solution that resembles pancreatic juice (Table 28–2). About 500 mL is secreted per day. Some of the components of the bile are reabsorbed in the intestine and then excreted again by the liver (enterohepatic circulation). In addition to its role in digestion and absorption of fats (Chapter 26), bile (and subsequently the feces) is the major excretory route for lipid-soluble waste products.
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The glucuronides of the bile pigments, bilirubin and biliverdin, are responsible for the golden yellow color of bile. The formation of these breakdown products of hemoglobin is discussed in detail in Chapter 31, and their excretion is discussed in the following text.
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BILIRUBIN METABOLISM & EXCRETION
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Most of the bilirubin in the body is formed in the tissues by the break down of hemoglobin (see Chapter 31 and Figure 28–4). The bilirubin is bound to albumin in the circulation. Most of it is tightly bound, but some of it can dissociate in the liver, and free bilirubin enters liver cells via a member of the organic anion transporting polypeptide (OATP) family, and then becomes bound to cytoplasmic proteins (Figure 28–5). It is next conjugated to glucuronic acid in a reaction catalyzed by the enzyme glucuronyl transferase (UDP-glucuronosyltransferase). This enzyme is located primarily in the smooth endoplasmic reticulum. Each bilirubin molecule reacts with two uridine diphosphoglucuronic acid (UDPGA) molecules to form bilirubin diglucuronide. This glucuronide, which is more water-soluble than the free bilirubin, is then transported against a concentration gradient most likely by an active transporter known as multidrug resistance protein-2 (MRP-2) into the bile canaliculi. A small amount of the bilirubin glucuronide escapes into the blood, where it is bound less tightly to albumin than is free bilirubin, and is excreted in the urine. Thus, the total plasma bilirubin normally includes free bilirubin plus a small amount of conjugated bilirubin. Most of the bilirubin glucuronide passes via the bile ducts to the intestine.
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The intestinal mucosa is relatively impermeable to conjugated bilirubin but is permeable to unconjugated bilirubin and to urobilinogens, a series of colorless derivatives of bilirubin formed by the action of bacteria in the intestine. Consequently, some of the bile pigments and urobilinogens are reabsorbed in the portal circulation. Some of the reabsorbed substances are again excreted by the liver (enterohepatic circulation), but small amounts of urobilinogens enter the general circulation and are excreted in the urine.
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When free or conjugated bilirubin accumulates in the blood, the skin, scleras, and mucous membranes turn yellow. This yellowness is known as jaundice (icterus) and is usually detectable when the total plasma bilirubin is greater than 2 mg/dL (34 μmol/L). Hyperbilirubinemia may be due to (1) excess production of bilirubin (hemolytic anemia, etc; see Chapter 31), (2) decreased uptake of bilirubin into hepatic cells, (3) disturbed intracellular protein binding or conjugation, (4) disturbed secretion of conjugated bilirubin into the bile canaliculi, or (5) intrahepatic or extrahepatic bile duct obstruction. When it is due to one of the first three processes, the free bilirubin rises. When it is due to disturbed secretion of conjugated bilirubin or bile duct obstruction, bilirubin glucuronide regurgitates into the blood, and it is predominantly the conjugated bilirubin in the plasma that is elevated.
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OTHER SUBSTANCES CONJUGATED BY GLUCURONYL TRANSFERASE
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The glucuronyl transferase system in the smooth endoplasmic reticulum catalyzes the formation of the glucuronides of a variety of substances in addition to bilirubin. As discussed above, the list includes steroids (see Chapter 20) and various drugs. These other compounds can compete with bilirubin for the enzyme system when they are present in appreciable amounts. In addition, several barbiturates, antihistamines, anticonvulsants, and other compounds cause marked proliferation of the smooth endoplasmic reticulum in the hepatic cells, with a concurrent increase in hepatic glucuronyl transferase activity. Phenobarbital has been used successfully for the treatment of a congenital disease in which there is a relative deficiency of glucuronyl transferase (type 2 UDP-glucuronosyltransferase deficiency).
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OTHER SUBSTANCES EXCRETED IN THE BILE
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Cholesterol and alkaline phosphatase are excreted in the bile. In patients with jaundice due to intrahepatic or extrahepatic obstruction of the bile duct, the blood levels of these two substances usually rise. A much smaller rise is generally seen when the jaundice is due to nonobstructive hepatocellular disease. Adrenocortical and other steroid hormones and a number of drugs are excreted in the bile and subsequently reabsorbed (enterohepatic circulation).
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AMMONIA METABOLISM & EXCRETION
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The liver is critical for ammonia handling in the body. Ammonia levels must be carefully controlled because it is toxic to the central nervous system (CNS), and freely permeable across the blood–brain barrier. The liver is the only organ in which the complete urea cycle (also known as the Krebs-Henseleit cycle) is expressed (Figure 1–20). This converts circulating ammonia to urea, which can then be excreted in the urine (Figure 28–6).
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Ammonia in the circulation comes primarily from the colon and kidneys with lesser amounts deriving from the breakdown of red blood cells and from metabolism in the muscles. As it passes through the liver, almost all of the ammonia in the circulation is cleared into the hepatocytes. There, it is converted in the mitochondria to carbamoyl phosphate, which in turn reacts with ornithine to generate citrulline. A series of subsequent cytoplasmic reactions eventually produce arginine, and this can be dehydrated to urea and ornithine. The latter returns to the mitochondria to begin another cycle, and urea, as a small molecule, diffuses readily back out into the sinusoidal blood. It is then filtered in the kidneys and lost from the body in the urine.