The liver is located in the right upper abdominal quadrant underneath the diaphragm and mostly behind the rib cage.

The liver is located in the right upper quadrant of the abdomen behind the lower part of the rib cage (Fig. 8-2). Cranially its superior surface is in contact with the diaphragm. From the clinical point of view these anatomic facts are important for the following reasons:

Figure 8-2 The location of the liver. The liver is located in the right upper quadrant of the abdomen and is mostly covered by the rib cage. A, Its size can be determined by percussion or even better by ultrasound. B, The biopsy needle is usually introduced through the intercostal spaces.

The size and the shape of the liver are relatively constant but may change under pathologic conditions.

The liver is roughly conical in shape. It consists of a larger right lobe that forms the base of the pyramid and a smaller left lobe that forms the apex of the pyramid. The falciform ligament on the diaphragmatic surface of the liver forms the border between these two lobes. Each major lobe can be subdivided into smaller segments, each of which has a separate blood supply. This subdivision is not important functionally, but it is of paramount importance to surgeons engaged in partial hepatectomy.

The size of the liver depends on body size. On average, top to bottom it has a span of less than 13 cm when measured in the midcostal line. The size of the liver can be estimated by percussion, or by combining percussion and auscultation. Unfortunately these techniques lack precision and reproducibility. More accurate measurements can be made by ultrasonography or radiologic imaging. Ultrasonography may be also used to determine whether the liver has a normal shape and smooth surface, is irregularly shaped, or contains irregular masses. These abnormalities are visible in computed tomography (CT) scans as well.

Pathologically altered livers can be of normal size, enlarged, or reduced in size.

The liver has relatively limited mobility and is linked through the bile ducts with the intestine.

The liver is enclosed by folds of the peritoneum, which together with the falciform ligament keep it fixated in the subdiaphragmatic position. The peritoneum covering the liver is known as Glisson’s capsule. On the visceral side of the liver the peritoneum covers the hilar structures (i.e., the gallbladder) and forms the lesser omentum surrounding the portal vein, hepatic artery, and the extrahepatic biliary ducts (Fig. 8-3).

Figure 8-3 Anatomy of the liver. The liver is covered by the Glisson’s capsule, a layer of peritoneum that also forms the lesser omentum. In the hilum of the liver the most important structures are the hepatic artery, portal vein, and the extrahepatic bile duct, which connects the liver to the duodenum. The confluence of the common bile duct and the pancreatic duct results in the formation of the ampulla of Vater, which is enveloped by the smooth muscles of the sphincter of Oddi.

The extrahepatic biliary ducts begin as the main hepatic ducts, which fuse into a common hepatic duct. The common bile duct joins the cystic duct, and from that point downward it is called the common bile duct, or ductus choledochus. It passes through the head of the pancreas, at which point it usually joins with the main pancreatic duct to terminate in the duodenum at the ampulla of Vater.

The bile flow from the liver into the duodenum depends on a balance between the production and the need for bile. The flow is primarily regulated by the sphincter of Oddi, which forms smooth muscle layers around the choledochus, pancreatic duct, and the ampulla of Vater. The sphincter of Oddi has sympathetic and parasympathetic innervation, the former causing its relaxation and the latter its contraction. Cholecystokinin, a polypeptide hormone produced by intestinal cells, promotes bile flow into the duodenum by causing relaxation of the sphincter of Oddi simultaneously with the contraction of the gallbladder.

The sphincter of Oddi has three functions: (1) regulation of the flow of bile and pancreatic juices into the duodenum, (2) prevention of reflux of duodenal contents into the bile duct and pancreas, and (3) promotion of filling of the gallbladder with hepatic bile.

During feeding the sphincter of Oddi is relaxed, allowing the diluted hepatic bile to enter into the duodenum. Between the meals the sphincter of Oddi is contracted and the bile from the common hepatic bile duct cannot enter into the duodenum; instead it is redirected into the gallbladder where it is concentrated and stored. The gallbladder is not essential for the excretion of bile as evidenced by the fact that it can be removed surgically without significant consequences.

The liver has a dual blood supply.

The liver is full of blood, and under normal circumstances the blood accounts for 30% of the total weight of the liver. The liver could be considered as a blood reservoir because normally it contains approximately 15% of the total circulating blood. This reservoir may expand under certain conditions: in circulatory shock or chronic heart failure the blood content of the liver can increase dramatically.

The liver has a dual blood supply. The hepatic artery, a branch of the hepaticoduodenal artery originating from the celiac axis, provides the arterial blood, which accounts for 25% to 30% of the total hepatic blood supply. The portal vein, a large valveless vein draining the venous blood from the intestines, stomach, pancreas, and spleen, brings in the remaining 70% to 75% of the blood. The venous blood leaves the liver through the hepatic veins, which drain into the inferior vena cava.

On entering the liver at the porta hepatis the portal vein and the hepatic artery divide into progressively smaller and smaller branches until they reach the portal tracts in the hepatic lobule, or acinus. From the portal tract the blood enters into the sinusoids and is finally collected into the terminal hepatic venule. From terminal hepatic venules the blood flows into the larger veins, which finally form the main hepatic vein. The hepatic vein is connected to the lower vena cava, through which the hepatic venous blood reaches the right atrium.

The portal vein and its branches are a low-pressure blood flow system. Blood pressure varies from 3 to 10 mm Hg, depending on several factors including posture and respiratory phase. Coughing, Valsalva maneuver, or compression of the abdomen may also temporarily increase the portal pressure. These physiologic and short-term elevations of portal blood pressure must be distinguished, however, from portal hypertension, which is defined as persistent elevation of portal blood pressure over 12 mm Hg.

In most instances portal hypertension is a consequence of liver disease. If the blood cannot be drained from the portal system through the liver and the portal blood pressure exceeds 20 mm Hg, anastomoses, or collaterals, develop between the portal and systemic venous system. These anastomoses develop through the dilatation and reopening of small veins that normally connect the portal and systemic venous systems. Under normal circumstances these small veins contain very little blood, but in portal hypertension they transform into congested, tortuous, widely opened venous channels that can be visualized by angiography. These anastomotic collaterals most often develop in the area of the lower esophagus and gastric fundus, internal hemorrhoidal veins and retroperitoneum, and the periumbilical veins (Fig. 8-4). The dilatation of periumbilical veins is traditionally called caput Medusae, in reference to the Gorgon from Greek mythology whose hair was made of snakes.

Figure 8-4 Portal hypertension. Portal vein obstruction leads to the formation of collaterals between the portal and systemic venous system.

Hepatocytes perform most complex liver functions.

Hepatocytes, or liver cells, are polarized cells interconnected along their apical sides with intercellular junctions. Tight junctions are important for the maintenance of liver cell polarity; they also ensure the structural stability of liver cell cords. In the midportion of the apical surface two adjacent liver cells form intercellular canaliculi, which are filled with bile secreted by the hepatocytes. The cell surface that does not have tight junctions is called the basolateral side. It delimits the space of Disse, which on the other side is separated from the lumen of the sinusoids by endothelial and Kupffer cells (Fig. 8-5).

Figure 8-5 Liver cell. The liver cell is polarized and has an apical side, containing the biliary canaliculus, and a basolateral domain, which abuts the sinusoids. The sinusoids are lined by fenestrated endothelial cells and phagocytic Kupffer cells. Between the liver cells and endothelial cells of the sinusoids is the narrow space of Disse.

Hepatocytes have numerous functions, and it has been estimated that each moment some 70 metabolic functions are performed simultaneously in every liver cell. These functions can be classified into several categories as follows:

Sinusoids are essential for the normal exchange of metabolites between the blood and liver cells.

The vascular system of the liver consists of branches of the hepatic artery, hepatic vein, and portal vein. These three systems all communicate with one another through the sinusoids, which receive the blood from the hepatic artery and portal vein and drain into the hepatic vein. All these arteries and veins are lined by a continuous layer of endothelial cells, in contrast to the sinusoids, which have a discontinuous endothelial layer. Such fenestration of sinusoids facilitates the passage of metabolites and other substance from the liver cells into the blood and vice versa.

In addition to the endothelial cells, the sinusoids contain scattered Kupffer cells, which act as fixed macrophages. These cells have major scavenger functions and participate in the removal of particulate material, bacteria, and immune complexes from the circulation. Inside the spaces of Disse are scattered the stellate cells of Ito, which have a capacity to store lipids and, if properly stimulated, also synthesize collagenous extracellular matrix. These cells play a major role in the formation of fibrous tissue in liver cirrhosis.

The liver produces large amounts of lymph.

Hepatic lymph is formed as plasma passes into the extravascular spaces of Disse. In contrast to capillaries, which in other organs allow the passage of only 0.01% of the plasma volume into the lymphatic channels, in the sinusoids 0.3% of the total hepatic blood is transformed into the lymph. From the spaces of Disse this lymph is drained into the main lymphatic channels running parallel to the branches of the portal vein toward the hilum. From the porta hepatis the lymph enters cysterna chyli, mixing with the lymph from the intestines and the lower extremities. Cirrhosis with intrahepatic scarring or a surgical procedure in the hepatic hilum may interfere with the outflow of the lymph from the liver. These changes block and thus redirect the flow of the lymph, which seeps into the peritoneum, thus contributing to the formation of ascites.

The biliary ducts and the gallbladder are lined by cuboidal to cylindrical cells specializing in the excretion of bile.

The biliary excretory system begins with intercellular bile canaliculi on the apical (intercellular) surface of the hepatocytes (Fig. 8-6). From these canaliculi the bile flows into minor bile ducts in the portal tracts as well as medium-sized and larger (septal) bile ducts draining the bile toward the hepatic bile ducts in the porta hepatis. All bile ducts are lined by cuboidal to cylindrical cells lying in a polarized manner on a basement membrane. Similar polarized cells line the major extrahepatic bile ducts all the way to the papilla of Vater. These cells produce some components of the bile and are also important for the maintenance of bile outflow from the liver. The cells lining the gallbladder resemble those in the bile ducts. However, gallbladder cells are unique in that they can actively absorb sodium and chloride from the bile. The resorption of sodium chloride is followed by a passive outflow of water and concentration of bile.

Figure 8-6 Biliary system. Liver cells secrete bile into the canaliculi, from which it flows into progressively larger and larger ducts.

Connective tissue extends along the bile ducts and blood vessels all the way to the portal tracts in the center of hepatic acini.

Connective tissue forms the liver capsule, and from the surface it extends into the parenchyma along the blood vessels and bile ducts. The ultimate part of this connective tissue skeleton is the strands of collagen in the portal tracts. The acinus itself does not contain banded collagenous stroma beyond the limits of the portal tract. This boundary is called the limiting plate. The skeleton of acini consists of the delicate matrix produced by the endothelial and interstitial cells.

Liver cells are arranged into functional units called lobules or acini.

All hepatocytes are interchangeable among themselves and thus all of them can perform all hepatic functions. Under normal circumstances the function of each hepatocyte nevertheless depends on it location in the hexagonal microscopic unit called the lobule or acinus (Fig. 8-7).

Figure 8-7 Comparison of the acinar (A) and the lobular (B) concept of hepatic microarchitecture. THV, terminal hepatic venule.

(From Underwood JCE, [ed]: General and Systemic Pathology, 4th ed. Edinburgh, Churchill Livingstone, 2004, p. 402.)

According to 19th century histologic teaching, the concept of lobule is based on the idea that hepatocytes are arranged around a small central hepatic vein. Sinusoids and liver cell plates radiate from the central veins, forming a hexagonal unit demarcated on its periphery with portal tracts. Portal tracts containing the bile ducts and the terminal branches of the hepatic artery and portal vein are surrounded by fibrous tissue. The blood flows into the portal tracts through the lobular sinusoids, toward the central vein, and from there into the larger branches of the hepatic vein out of the liver. The bile flows in the opposite direction from the center of the lobule toward its periphery.

The concept of acinus points out some of the misconceptions related to the concept of the lobule. For example, the so-called central hepatic vein has a very thin wall and is actually a venule. From a hemodynamic point of view it is not located centrally but rather at the periphery of the functional unit and is more appropriately called the terminal hepatic venule (THV).

According to the concept of acinus, which is a reverse image of the lobule, the blood enters the functional unit through the centrally located portal tract and flows through the sinusoids toward several peripherally located THVs. Pressure gradients are formed as the blood flows from the center to the periphery, and bile flows from the periphery to the center.

The hepatocytes located along these pressure gradients have different functions, probably determined by the oxygen supply (which is higher around the portal tracts than around the THV) and the concentration of nutrients and metabolites. The acinus can be thus divided into three functional zones: (1) periportal zone 1, (2) perivenular zone 3, and (3) zone 2 in between zones 1 and 3. Furthermore it was shown that the falling blood pressure from the center of the acinus toward its periphery is accompanied by a decreasing concentration of oxygen in hepatic blood and a decreased concentration of various metabolites and toxins. For example, ammonia is mostly extracted from portal blood as soon as it enters into the acinus (zone 1) so that very small amounts of this substance reach the perivenular periphery of the acinus. The hepatocytes of zone 1 are more active in oxidative phosphorylation and gluconeogenesis than those in zone 3. Perivenular hepatocytes, adapted to relative hypoxia, tend to engage more in anaerobic glycolysis and lipogenesis.

The concept of the acinus explains several clinicopathologic findings, some of which can be appreciated by liver biopsy and deserve to be mentioned here:

Glycogen accumulates in the liver of infants who lack glucose-6-phosphatase.

The glucose taken up from blood is stored in the liver in the form of glycogen. Glycogen stores (70–80 g) are sufficient to meet the body’s demand during 24 hours of fasting, after which gluconeogenesis from amino acids becomes the primary source of glucose. In children who have von Gierke’s disease, or glycogenosis type I, the hepatocytes lack glucose-6-phosphatase and therefore cannot form glucose to be exported into the blood (Fig. 8-8). Such children suffer from hypoglycemia. At the same time glucose-1-phosphate accumulates, promoting glycogen accumulation in liver cells and resulting in hepatomegaly. Compensatory metabolic changes lead to hyperlipidemia and lactic acidosis.

Figure 8-8 Glycogen accumulation in glycogenosis type I. Deficiency of glucose-6-phosphatase (glucose-6-P) leads to the accumulation of glucose-1-phosphate (glucose-1-P), promoting deposition of unused carbohydrates in the form of glycogen.

Lipids can accumulate in liver cells due to increased supply and influx, increased endogenous lipogenesis, lowered utilization, or decreased excretion.

Lipids are transported by blood to the liver from food absorbed in the intestines or from fat stores and other tissues (Fig. 8-9). The fat absorbed from food in the intestines is packaged into chylomicrons, which enter the intestinal lymph and from there enter the blood. During the passage of such blood through the small blood vessels of the skeletal muscle and fat tissue, the endothelial lipoprotein lipase acts on the chylomicrons, resulting in the formation of glycerol, free fatty acids, and cholesterol-enriched chylomicron remnants. Most of the glycerol and fatty acids thus formed are absorbed by muscle cells and fat cells, whereas the chylomicron remnants reach the liver and are taken up through the low-density lipoprotein (LDL) and LDL-related receptors.

Figure 8-9 Lipid metabolism in the liver. Free fatty acids (FFAs) and chylomicron remnants derived from the fat absorbed in the intestine from food, the FFAs derived from the endogenous peripheral fat stores, and the lipid contained in circulating lipoproteins enter into the liver. In the liver FFAs can be esterified, used up through oxidation, stored in the form of triglycerides, or used for the formation of structural phospholipids. Lipids can be secreted as lipoproteins or as ketone bodies or excreted in bile. Lipids can be also formed in the liver from carbohydrates and proteins.

Free fatty acids liberated from chylomicrons but not taken up by other tissues also end up in the liver. In addition to these exogenous lipids the lipid pool inside the hepatocytes also contains endogenously formed cholesterol and lipids that have arrived into the liver through the endogenous LDL receptor-mediated uptake. These lipids may be further metabolized as follows:

Fatty liver (steatosis) can be induced by increasing the supply of lipids by overeating. Obesity, diabetes, and alcoholism are also associated with overabundance of lipid influx into the liver. Alcohol mobilizes free fatty acids from peripheral fat tissue stores, but it also promotes the esterification of intrahepatic fatty acids into triglycerides, and it inhibits the synthesis of the apoproteins essential for synthesis and export of VLDLs. Starvation and protein-deficient malnutrition may cause fatty liver due to inadequate synthesis and export of lipoproteins. The most important causes of fatty liver are listed inTable 8-1.

Table 8-1 Common Causes of Fatty Liver

Protein synthesis is a major function of liver cells.

Liver cells synthesize proteins for endogenous purposes but also for export. Proteins for exogenous purposes are synthesized in the cisterns of the rough endoplasmic reticulum, glycosylated or folded, and actively secreted into the blood. Most of the plasma proteins are synthesized in the liver. Liver disease results in marked reduction of plasma protein synthesis, which is usually associated with significant pathophysiologic changes. For example, hypoalbuminemia occurs in chronic liver disease, resulting in diminished oncotic pressure of the plasma and predisposing to edema formation.

Abnormal synthesis of some proteins may also cause structural changes in hepatocytes, which are visible by light and electron microscopy. The best example is α1-antitrypsin (AAT) deficiency, an autosomal recessive disorder characterized by the inability of liver cells to excrete AAT. The defect lies in the abnormal folding of the AAT in the cisterns of the rough endoplasmic reticulum of hepatocytes, which cannot then complete the synthesis of the protein and retains the abnormal intermediate product inside the cytoplasm in the form of round globules (Fig. 8-10). Deficiency of AAT predisposes the affected person to cirrhosis but also to pulmonary emphysema.

Figure 8-10 α₁-Antitrypsin (AAT) deficiency. Genetic mutation interferes with the folding of the AAT in the cisterns of rough endoplasmic reticulum (RER), inhibiting the transfer of proteins from the rough endoplasmic reticulum to the Golgi apparatus. The abnormal AAT accumulates in the form of round aggregates inside the RER.

Amino acids are metabolized to urea and ammonia, which may be toxic.

Amino acids absorbed from the intestines in surplus to the needs of the body as well those that are released after normal cell turnover are used for the production of energy, for the synthesis of new proteins, or for ketogenesis or glucogenesis, or are metabolized further into urea (Fig. 8-11). Urea is excreted in urine and feces. Urea that is excreted in kidneys leaves the body, but the urea excreted into the intestine is again cleaved by urease-containing bacteria, and the newly formed ammonia is absorbed into the portal circulation and sent back to the liver. Approximately 10 to 20 g of nitrogen are produced every 24 hours in an average adult and excreted.

Figure 8-11 Metabolism of amino acids. Amino acids entering the liver cell are used for energy production, new protein synthesis, glucogenesis, or ketogenesis. Unused amino acids are degraded through the urea cycle. Urea is excreted in the urine or into the intestines. In the intestines urease-rich bacteria metabolize urea into ammonia, which is recirculated to the liver.

Chronic liver disease leads to decreased synthesis of serum albumin and hypoalbuminemia.

Albumin is the most abundant serum protein, but it occurs also in interstitial fluids. In an adult the total body pool of albumin is approximately 300 g, of which 40% is inside the circulating blood and 60% in the extravascular pool. Its normal blood concentration is 3.5 to 5 g/dL, and the liver must produce about 12 g of albumin a day to keep it in that range.

Since the liver is the only source of albumin, chronic destructive liver disease and especially cirrhosis manifest with hypoalbuminemia. Hypoalbuminemia is therefore one of the best indicators of reduced hepatic synthetic capacity. Not every patient with chronic liver disease, and even many with cirrhosis, demonstrates hypoalbuminemia. The half-life of albumin in the plasma is 21 days, and thus even if production ceases it takes some time before the concentration in the serum drops below the normal range. Furthermore, the loss of liver synthetic function is usually in part compensated for by adaptive reduction in the degradation of albumin. However, demonstrable hypoalbuminemia is a reliable sign of chronic liver insufficiency.

Hypoalbuminemia may be aggravated in patients with portal hypertension by excessive leakage of albumin from the blood into the ascites fluid or the lymph away from its normal flow through the liver. Hypoalbuminemia may also be partly related to poor nutrition, which is especially common in cirrhotic patients who are chronic alcoholics. Finally, bear in mind that albumin is a “negative acute-phase reactant”; that is, the liver reduces the synthesis of albumin in response to many acute and chronic diseases. Since patients with advanced cirrhosis usually feel sick, this is yet another reason why they might have hypoalbuminemia.

Cirrhosis is associated with prolonged prothrombin time and a bleeding tendency.

Prothrombin time (PT) is a functional test that measures the intrinsic and common coagulation pathways. The normal PT is 12 minutes, and it depends on a normal plasma concentration of prothrombin and factors VII, IX, and X. The synthesis of these factors is vitamin K-dependent and occurs exclusively in the liver. In massive acute liver injury caused by acute viral infection or toxins, as well as in chronic liver diseases such as cirrhosis, PT is prolonged. Impaired absorption of fat due to defective bile synthesis and excretion may affect the absorption of fat-soluble vitamins, such as vitamin K, thus contributing to the reduced production of coagulation factors.

Serum levels of ceruloplasmin are reduced in Wilson’s disease.

Ceruloplasmin is a serum protein involved in the transport of copper. Like most other serum proteins it is synthesized by the liver. In Wilson’s disease, an inborn error of copper metabolism, serum levels of ceruloplasmin are markedly reduced. Although the reasons for this phenomenon are unknown, low ceruloplasmin concentration is a reliable sign of Wilson’s disease, especially if associated with a high concentration of copper in liver biopsy specimens or urine.

Acute and chronic diseases stimulate the liver to secrete acute-phase reactants.

Various inflammatory diseases, as well as chronic debilitating diseases such as cancer, may stimulate the liver to synthesize a variety of proteins known as acute-phase reactants. This group of proteins includes the C-reactive protein; a number of serum transport proteins, such as transferrin and ceruloplasmin; some coagulation factors, such as fibrinogen; and enzyme inhibitors, such as antichymotrypsin. Interleukins produced by the inflammatory cells are the mediators of this liver response, but its purpose remains unknown.

C-reactive proteins (CRPs) can be estimated indirectly by a widely used test—the erythrocyte sedimentation rate (ESR). In this test, a calibrated tube is filled with venous blood and allowed to settle for 1 and 2 hours. The extent of separation of the red blood cells from the plasma is measured in millimeters and expressed as the observed ESR value.

C-reactive protein, the main acute-phase reactant, is routinely measured in clinical practice and provides the same information as ESR, meaning that it indicates whether the patient has some systemic disease or demonstrates a focus of inflammation in the body. C-reactive protein is a elevated in patients who have myocardial infarction, but its serum concentration falls during recovery. Persistently high values for serum CRP or their rise after normalization is a good predictor for the recurrence of myocardial ischemia following an infarction.

Among acute-phase reactants produced by the liver, the serum amyloid A precursor is also worth mentioning. This protein, if produced in large quantities, may be deposited in the kidneys, liver, adrenals, spleen, and other organs in the form of amyloid, thereby causing systemic amyloidosis. This disease may have a protean manifestation, but overall it has a poor prognosis and cannot be cured with our present means.

The liver detoxifies drugs and toxins.

The liver is the major site of drug metabolism and detoxification of toxins. Some drugs are ingested in an inactive form and become active only after conversion into an active form in the liver. Lipid-soluble drugs are made water-soluble by the cytochome P450 family of enzymes. During this process P₄₅₀ unmasks or introduces into the drugs polar groups such as —OH or —NH₂. Thereafter many of these drugs can be excreted by the kidneys, whereas others need to be further conjugated to make them less lipophilic. This conjugation includes binding to glucuronic, sulfuric, or acetic acid. Glucuronidation is the most common form of drug conjugation in the liver. Glucuronidation of drugs is inefficient in neonates; many drugs cannot therefore be inactivated and are potentially toxic during the neonatal period. Detoxification of drugs is defective in patients who have cirrhosis; thus the blood concentration of many antibiotics, psychopharmaceuticals, and hypoglycemics may remain high for prolonged periods in such patients.

The liver degrades and neutralizes ammonia, thus disabling its toxicity.

Cirrhosis and massive liver necrosis may reduce the capacity of the liver to remove ammonia formed from the degraded amino acids. In cirrhotic patients with portal hypertension the blood bypasses the liver through the portal-systemic anastomoses, further contributing to body’s inability to remove ammonia. If the portal hypertension-related esophageal varices rupture and the patient has a massive bleed, the swallowed blood becomes yet another source of ammonia. Blood is a protein-rich fluid, and when it arrives into the intestines, the proteins are degraded into amino acids and further into ammonia. Hyperammonemia resulting from any of these complications of cirrhosis has a potentially toxic effect on the brain and is considered to play an important pathogenetic role in hepatic encephalopathy (Fig. 8-12).

Figure 8-12 Hepatic encephalopathy. A, Normal liver. Amino acids absorbed from the intestines are metabolized by the liver, and the potentially toxic ammonia is converted into urea and excreted into the intestines or urine. Ammonia formed in the intestines through the action of bacteria is neutralized by the liver as well. B, Cirrhosis. The liver cannot degrade the ammonia entering the portal vein system from the intestines. Furthermore, the portocaval anastomoses provide venues for the ammonia-containing portal blood to bypass the liver. Thus, the systemic circulation is flooded with extra ammonia, which is toxic and can induce hepatic encephalopathy.

The liver inactivates and degrades hormones.

Many hormones act on the liver. For example, glucagon and insulin regulate the uptake and metabolism of glucose in the liver. Many hormones are inactivated or degraded by the liver. All steroid hormones, such as corticosteroids, aldosterone, and sex hormones, are inactivated and degraded in the liver. The liver is involved in the metabolism of parathyroid and thyroid hormone, insulin, and many others.

Bilirubin derived from the heme component of the hemoglobin is bound to albumin and carried to the liver.

Approximately 4 mg/kg of bilirubin is formed daily, mostly from the heme component of hemoglobin released from effete red blood cells (Fig. 8-13). A smaller part of the newly formed bilirubin (15% to 20%) is derived from ineffective hematopoiesis and heme-containing enzymes such as P₄₅₀ oxidoreductases or other porphyrins.

Figure 8-13 Bilirubin formation and excretion.

Biliribin formed from heme is water-insoluble. It must attach to albumin to be transported to the liver for further processing and excretion in the bile. Since it has not been conjugated in the liver it is also known as unconjugated bilirubin. Owing to the links to albumin it cannot enter into the urine and it does not cross the normal blood–brain barrier.

Unconjugated bilirubin is elevated in the serum in conditions that lead to increased hemolysis, such as autoimmune hemolytic anemia, hereditary spherocytosis, or sickle cell anemia. Ineffective hematopoiesis, as in megaloblastic anemia caused by vitamin B₁₂ or folic acid deficiency, may also cause unconjugated hyperbilirubinemia (i.e., prehepatic jaundice).

Bilirubin taken up by hepatocytes is conjugated to glucuronide.

The bilirubin–albumin complex binds to the basolateral side of hepatocytes. It dissociates from albumin and is actively transported across the plasma membrane into the cytoplasm of liver cells. At least three distinct mechanisms participate in this process. In the cytoplasm bilirubin is transferred into the endoplasmic reticulum, most likely by direct membrane-to-membrane transfer. In the endoplasmic reticulum bilirubin is then conjugated through the action of uridine disphosphate (UDP) and uridine glucuronyltransferase (UGT) into monoglucuronides and diglucuronides and readied for excretion (Fig. 8-14).

Figure 8-14 Intrahepatic processing of bilirubin. The unconjugated bilirubin bound to albumin is delivered in the blood to the liver, where it binds to the cell surface thus dissociating from albumin. Bilirubin enters into the liver cells and is transferred to the endoplasmic reticulum. Inside the endoplasmic reticulum bilirubin is bound to glucuronic acid through the action of uridine glucuronosyltransferases (UGTs). Water-soluble bilirubin monoglucuronides and diglucuronides, which account for 80% of the total conjugated bilirubin, are transported into the bile canaliculi by enzymes such as multidrug resistance protein 2 (MRP2).

UGT is a large family of enzymes that are active in many organs. In the liver UGT1A1 performs most of the glucuronidation of bilirubin. Hence it is to no surprise that mutations of the gene encoding UGT1A1 account for most hereditary unconjugated hyperbilirubinemias. The most important among these diseases are the Gilbert and Crigler-Najjar syndromes.

Uptake and conjugation of bilirubin in hepatocytes may be affected by many forms of hepatocellar injury and various drugs. Functional immaturity of hepatocytes combined with increased hemolysis of fetal red blood cells in the early postnatal period accounts for neonatal physiologic jaundice.

Bilirubin is excreted into the bile canaliculi in a water-soluble form.

Bilirubin monoglucuronides and diglucuronides are water-soluble and are readily excreted into the bile. Conjugated bilirubin is transported across the plasma membrane by canalicular organic anion transporter multidrug resistance protein 2 (MRP2). Mutation of the gene for the ATP-binding cassette (ABC) of the canalicular organic anion transporter protein MRP2 results in Dubin-Johnson syndrome, which is characterized by conjugated hyperbilirubinemia and mild jaundice but no other major problems.

Bilirubin reaches the intestine through the bile ducts.

Bilirubin in bile has an average concentration of 0.2%, yet it gives the bile its typical yellow-brown color. Bile flows from the intercellular canaliculi into the bile ducts in the portal tracts and from there through larger bile ducts to the hilum of the liver and into the common bile duct. Obstruction of bile ducts causes regurgitation of bilirubin into the blood and conjugated hyperbilirubinemia. Clinically it manifests as obstructive jaundice. The most important causes of obstructive jaundice are illustrated in Figure 8-15.

Figure 8-15 Extrahepatic obstructive jaundice. The diseases causing jaundice are classified as neoplastic or non-neoplastic.

Bilirubin is transformed in the intestines by bacteria into urobilinogen.

Bacteria in the intestines hydrolyze the conjugated bilirubin into free bilirubin, which is further reduced into several pyrroles known as urobilinogen. Most of the urobilinogen is excreted in feces, but approximately 20% is reabsorbed and through the enterohepatic recirculation returns to the liver. Part of reabsorbed urobilinogen is excreted in the urine, accounting for its yellowish color.

The liver cells produce bile and excrete it into the bile ductules.

Bile is a complex bicarbonate-rich fluid produced by the liver cells and excreted through the biliary ducts into the intestines. Approximately 450 mL of canalicular bile is produced daily, which is supplemented with about 150 mL of ductular secretion to account for a total of 600 mL.

The bile is a complex fluid that consists principally of water (97%) and the following solutes:

The concentration of various solutes in the bile varies enormously. Primary biliary acids, cholic and chenodeoxycholic acids, account for 10% to 50% of organic solutes of bile, whereas phospholipids account for 10% to 20%, cholesterol for 3% to 10%. The relationship between these three components determines whether cholesterol remains in a soluble form or precipitates. Proteins account for 3% to 5%, and bilirubin for 0.3% to 2% of organic solutes.

Primary bile acids are produced in the hepatocytes from cholesterol and conjugated to glycine or taurine (Fig. 8-16). Once excreted from the liver cells, bile acids combine with cholesterol and phospholipids to form micelles, which are important for the emulsification and subsequent absorption of fat in the small intestine. Bile ductular cells secrete mucus, composed of proteins and carbohydrates, as well as water and minerals.

Figure 8-16 Recirculation of bile.

Primary bile acids are almost completely reabsorbed together with some urobilinogen in the terminal ileum and recirculated back to the liver (“enterohepatic circulation of biliary acids”). Small amounts of primary bile acids that reach the colon are transformed by bacteria into secondary bile acids, deoxycholic acid and lithocholic acid. Secondary bile acids are mostly lost in the feces, but some are reabsorbed and recirculated to the liver. At any point in time 85% of the total bile acid pool is either in the intestines or in the gallbladder. Thus the liver must replace only a small portion of the total bile acid pool, which is good because the liver has a limited capacity for bile acid production.

A large portion of this hepatic bile is extruded into the duodenum during the meals (Fig. 8-17). Between meals the sphincter of Oddi contracts and redirects the bile flow into the gallbladder, where it is concentrated by a removal of water and stored until needed.

Figure 8-17 Bile flow during feeding and fasting. A, During feeding the sphincter of Oddi is relaxed and bile flows into the intestine. The gallbladder contacts, adding the concentrated bile to the newly synthesized bile flowing out of the liver. B, During fasting the sphincter of Oddi is contracted and the flow of bile in the common bile duct is redirected into the gallbladder, where it is stored and concentrated.

Bile acid concentration can be measured in the serum, and although it changes in various liver diseases, the methods for measuring bile acid concentration in the serum are rather cumbersome. Accordingly, this biochemical test is not widely used in practice.

The liver diseases affect the excretion of bile.

The bile produced by pathologically altered livers differs from normal bile, which might affect the absorption of fats from the intestine. Long-term changes in the composition of bile are associated with steatorrhea and deficiencies in fat-soluble vitamins A, D, E, and K.

Vitamin K deficiency contributes to the prolongation of PT and may account in part for the bleeding tendency of patients who have cirrhosis.

Changes in the composition of bile may predispose to formation of gallstones.

The solutes found in bile remain in a soluble form as long as the relative concentration of cholesterol, bile salt, and lecithin remains in the normal range (Fig. 8-18). Changes in the composition of bile and the presence of substances that promote “nucleation of bile” (e.g., bacteria) may lead to the formation of gallstones.

Figure 8-18 Phase diagram for plotting different mixtures of bile salt, lecithin, and cholesterol. Mixtures containing 4% to 10% of solids (e.g., point A in the curved area) are nonlithogenic. Any mixture that is out of that zone (e.g., point B) is potentially lithogenic.

(From Andreoli TE, Carpenter CCJ, Griggs RC, Loscalzo J: Cecil Essentials of Medicine, 6th ed. Philadelphia, Saunders, 2004, p. 425.)

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