Liver

Development of Liver

The foregut is the first segment of the gut tube within the abdomen. It is attached to the anterior body wall by a ventral/anterior mesentery and to the posterior wall by a dorsal/posterior mesentery, the latter supplying blood from the dorsal aorta via the celiac arterial trunk. Two diverticula extend from the foregut, one dorsally and the other ventrally. The dorsal pancreatic bud extends into the dorsal mesentery while the liver develops from the endodermal cells that line the foregut and extend into the ventral mesentery to create the hepatic diverticulum during the third week. The cells of the hepatic diverticulum proliferate and extend superiorly into the septum transversum, which separates the pericardial cavity from the developing peritoneal cavity. The cells of the mature liver will include cells that originated in both the hepatic diverticulum (hepatocytes) and the septum transversum (Kupffer cells and fibroblasts). As the hepatic diverticulum expands within the septum transversum, its connection to the foregut narrows to become the bile duct, which will carry bile from the liver to the duodenum.

At approximately 30 days of development, another extension of endoderm projects inferiorly from the bile duct. This diverticulum will develop into the gallbladder, and the connection between it and the bile duct will become the cystic duct. Just proximal to the developing gallbladder is yet another diverticulum extending from the bile duct, the ventral pancreatic bud. The two pancreatic buds will fuse to form the mature pancreas, and the gallbladder will become associated with the inferior side of the liver.

The ventral mesentery, including connective tissue from the septum transversum, connects the anterior abdominal wall to the liver and the liver to the stomach. These portions of the ventral mesentery thin out to become the membranous falciform ligament and lesser omentum, respectively. As the septum transversum thins to become the central area of the diaphragm, it leaves a layer of mesothelial cells on the surface of the liver. The superior surface of the liver, however, remains in direct contact with the septum transversum, and the mesothelial cells (also called the visceral peritoneum of the liver) reflect off of the liver and onto the inferior surface of the diaphragm. This leaves a bare area of the liver on its superior surface, “bare” because it is not covered by mesothelial cells.

As the stomach rotates and shifts to the left, the liver enlarges and fills the superior right side of the abdomen. The falciform ligament tethers the liver to the anterior body wall; during embryonic and fetal life, it contains the umbilical vein, which brings oxygenated blood from the placenta through the liver and to the developing heart. The lesser omentum connects the liver to the developing stomach and duodenum; it can be subdivided into the hepatogastric and hepatoduodenal ligaments. The hepatoduodenal ligament contains the common bile duct, as well as the hepatic portal vein and proper hepatic artery.

Development of Liver and Its Venous System

The hepatic diverticulum buds off of the gut tube in close relation to the vitelline veins, located on the ventral floor of the foregut at a site corresponding to the future duodenum. A vascular plexus branching out from the vitelline veins becomes surrounded by the endodermal cells that are developing into the liver. At an early stage, the right and left vitellines feed blood to a plexus within the liver, the hepatic sinusoids. Blood from this plexus leaves the developing liver through a pair of veins that enter the sinus venosus of the heart alongside the right and left umbilical veins coming from the placenta and the common cardinal veins. Subsequently, the right and left vitelline veins form anastomoses between each other: the first within the liver and then two more outside of the liver, lying dorsally and ventrally around the duodenum, so that a vascular ring is formed. Part of this ring will disappear as the distal portion of the vitelline veins and yolk sac dwindle. The remaining portion of the venous trunk that is posterior to the duodenum becomes the portal vein; the portion that remains anterior to the duodenum develops into the superior mesenteric vein, joined by the splenic vein. The veins leading from the liver to the sinus venosus become the hepatic veins, the left of which atrophies, so that blood from the left half of the liver drains into the right vitelline vein. The umbilical veins initially drain exclusively to the sinus venosus by way of the common cardinal veins, but they form anastomoses with the sinusoids bilaterally.

As development proceeds, the umbilical veins lose their connection to the common cardinal veins and eventually the rest of the right umbilical vein atrophies, leaving only the left umbilical vein to carry blood from the placenta to the developing embryo. For a time the venous blood from the placenta passes through the liver to the right vitelline vein. Eventually, a large venous trunk, the ductus venosus, develops and separates from the hepatic sinusoids to carry oxygenated blood to the right atrium of the heart, bypassing most of the liver parenchyma. At this stage, approximately half of the blood from the umbilical vein goes through the ductus and the rest passes through the liver.

As the liver protrudes into the abdominal cavity, it remains in contact with the diaphragm in the bare area, and the attachment to the septum transversum becomes the coronary ligament. At the same time the umbilical vein becomes incorporated within the falciform ligament, running from the umbilicus to the liver. After the postnatal circulation is established, no more blood flows through the umbilical vein, and it becomes the fibrous ligamentum teres, still within the falciform ligament .

Prenatal and Postnatal Circulation

In intrauterine life, fetal blood receives oxygen and nutrients from maternal blood in the placenta. Except during the very early stages when the yolk sac and vitelline veins are still functioning, the umbilical cord supplies blood to the fetus. While the vitelline veins are transformed, the umbilical vein anastomoses with the hepatic sinusoids, so that at one stage (when the fetus is 6 mm long), all of the blood of the umbilical vein passes through the primitive hepatic sinusoids. At the same time, the right umbilical vein and the proximal portion of the left undergo atrophy, and subsequently, the enlarged distal part of the left umbilical vein courses diagonally through the liver in a channel, the ductus venosus , which has formed by rearrangement of early hepatic sinusoids. As the lobes of the liver grow, the ductus venosus comes to lie outside the liver and joins the inferior vena cava, in which the small amount of deoxygenated venous blood from the caudal portions of the fetus is mixed with the oxygen-rich blood coming through the ductus venosus. The mixed blood entering the right atrium hits the interatrial membrane (septum secundum) and is directed through the foramen ovale into the left atrium, keeping the foramen open. In the left atrium the blood mixes with a small amount of nonoxygenated blood from the pulmonary veins, passes into the left ventricle, and then passes into the ascending aorta, where this mixed blood perfuses the coronary, common carotid, and subclavian arteries. A small amount of blood within the right atrium from the inferior and superior venae cavae is diverted into the right ventricle and thereafter into the pulmonary trunk, which supplies the lungs. Because the amniotic fluid is filling the air passageways, the lungs have a high resistance, and very little blood from the pulmonary trunk actually enters the pulmonary arteries and lungs. Most of the blood in the pulmonary trunk is shunted into the descending aorta by way of the ductus arteriosus, where it joins the blood ejected from the left ventricle. In this way, the viscera and lower limbs receive mixed-oxygenation blood, and the heart and brain, organs that are most sensitive to hypoxia, receive blood with higher oxygen content directly from the left ventricle.

After birth, the placental blood flow ceases, the newborn begins breathing, and the oxygen level in the blood rises significantly. These changes induce closure of both the ductus venosus and ductus arteriosus. These channels are obliterated and become fibrous cords, the ligamentum teres and ligamentum arteriosum, respectively. The ligamentum teres terminates at the superior margin of the umbilicus, near the two lateral umbilical ligaments, containing the remnants of the umbilical arteries , spread in the interior abdominal wall toward the internal iliac arteries. During embryonic and fetal life, the two umbilical arteries carried deoxygenated blood from the body through the umbilical cord to the placenta. With the closure of the ductus venosus, oxygenated blood no longer reaches the inferior vena cava, and the liver from birth on is provided with oxygen-rich blood only via the hepatic arteries. With the first respiration, the resistance in the pulmonary vascular tree diminishes, and this pressure drop leads immediately to increased blood flow through the pulmonary arteries and veins and into the left atrium. This closes the valve of the foramen ovale, so that blood is no longer shunted from right to left. The foramen ovale is closed within 1 year in 75% of newborns. The fossa ovalis is an indentation marking the location of the foramen. In the remaining infants, an oblique communication may persist between the right and left atria, which may be demonstrated anatomically but only in rare cases is patent enough to allow mixing of oxygenated and deoxygenated blood. Within 3 months after birth, the ligamentum arteriosum is no longer patent, although it may also sometimes persist, allowing the mixing of blood.

Topography of Liver

The liver is located in the upper right part of the abdomen. In the scheme of dividing the abdomen into nine regions, the liver occupies the right hypochondriac region and the greater part of the epigastric regions. The left lobe of the liver extends, to a variable degree, into the left hypochondriac region. The liver is the largest organ of the body, weighing 1400 to 1600 g in adult males and 1200 to 1400 g in adult females. In normal, healthy individuals, the liver margin extending below the thoracic cage is smooth and offers little resistance to the palpating finger. Downward displacement, enlargement, hardening, and nodular formation or cysts produce definite palpatory findings. Using percussion, one must consider that the lungs overlie the upper portion of the liver and that the liver, in turn, overlaps the intestines and stomach.

The projections of the liver on the body surface have added significance when one is performing a liver biopsy. The projections vary, depending upon the position of the individual as well as the body build, especially the configuration of the thorax. The liver lies close to the diaphragm, and the superior pole of the right lobe projects as far as the level of the fourth intercostal space or the fifth rib, the highest point being 1 cm below the nipple near the lateral body line. The superior limit of the left lobe projects to the upper border of the sixth rib. Here, the left tip of the liver is close to the diaphragm.

The ribs cover the greater part of the liver's right lobe, and a small part of its anterior surface is in contact with the anterior abdominal wall. When a person is standing erect, the liver extends downward to the 10th or 11th rib in the right midaxillary line. Here, the pleura projects downward to rib 10, and the more superficial right lung projects to rib 8. The inferior margin of the liver crosses the costal arch in the right lateral body line approximately at the level of the pylorus (transpyloric line). In the epigastrium the liver is not covered by the thoracic cage and extends approximately three fingers' breadth below the base of the xyphoid process in the midline. Part of the left lobe is covered again by the rib cage.

Over the upper third of the right half of the liver, percussion gives a dull zone, because here the diaphragm, pleura, and lung overlie the liver. Over the middle portion, flat percussion is obtained due to the presence of the liver. Similarly, over the lowest third of the liver, a flat percussion tone is usually heard, except that sometimes intestinal resonance is produced by gas-filled intestinal loops. The border between dullness and flatness moves during respiration and is altered by enlargement or displacement of the liver, and also by possible pathologic conditions within the thoracic cage which may change the percussion qualities of the thoracic organs.

In the horizontal position the projection of the liver moves slightly superiorly, and the percussive area of flatness appears slightly enlarged. The extent of the flat sound, best percussed in the horizontal position, provides information about the size of the organ.

The projections of the liver are altered in some diseases, such as tumor infiltration, cirrhosis, or syphilitic hepar lobatum, and are changed by displacements of the organ or more often by thoracic conditions pushing the liver inferiorly. Subphrenic abscesses, depending upon location and size, also displace the liver inferiorly. Ascites, excessive dilatation of the colon, or abdominal tumors may push the liver superiorly, and retroperitoneal tumors may move it anteriorly. Kyphoscoliosis or a barrel shape of the chest alters the position of the liver. Sometimes the liver is abnormally movable (hepatoptosis), causing peculiar palpatory findings.

Surfaces and Bed of Liver

The liver is a large, wedge-shaped organ molded to the underside of the diaphragm and resting upon the abdominal viscera. Its diaphragmatic surface is divided into a superior part (which includes the cardiac impression ), an anterior part (which extends beyond the diaphragm onto the anterior abdominal wall), a right part, and a posterior part (attached to the diaphragm by the coronary ligament ). The border between the anterior aspect and visceral surface is the inferior margin. Its consistency, sharpness of edge, smoothness of surface, and movement upon respiration provide clinical information. On laparotomy, the inferior margin and the anterior aspect are first exposed. Otherwise, the hepatic surfaces are not separated by distinct margins.

The liver is covered by peritoneum, except for the gallbladder bed, the porta hepatis (entry point of the common hepatic duct, hepatic artery, portal vein, lymphatics, and nerves), adjacent parts surrounding the inferior vena cava, and a space to the right of the inferior vena cava called the bare area, which is in contact with the right suprarenal gland (suprarenal impression) and the right kidney (renal impression). The peritoneal duplications, which extend from the anterior abdominal wall and from the diaphragm to the organ, form the ligaments of the liver, which, along with intraabdominal pressure, help fix the liver in its position. The diaphragmatic peritoneal duplication is the coronary ligament, the upper layer of which is exposed if the liver is pulled away from the diaphragm. The right free lateral margin of the coronary ligament forms the right triangular ligament, whereas the left triangular ligament surrounds and merges with the left tip of the liver, the fibrous appendix of the liver. The space between the upper and lower layers of the coronary ligament is filled with areolar connective tissue. Below the insertion of the lower layer of the right coronary ligament, the hepatorenal space extends posterior to the liver and anterior to the right kidney.

The falciform ligament extends from the liver to the anterior abdominal wall, originating from the middle portion of the coronary ligament. This double layer of peritoneum contains the ligamentum teres (obliterated left umbilical vein), and its insertion on the liver divides the organ into a right lobe and a left lobe. As the falciform ligament crosses the inferior margin of the liver it releases the ligamentum teres, which then enters a fissure on the visceral surface of the liver. Inferiorly, this fissure for the ligamentum teres separates the quadrate lobe from the left lobe of the liver. Beyond the porta hepatis it is continued superiorly as the fissure for the ligamentum venosum (the obliterated ductus venosus of the fetus). The two fissures may be regarded as the left limb of an H-shaped pattern characteristic of the visceral surface of the liver. The right limb is formed by the gallbladder fossa and the groove for the inferior vena cava. The horizontal limb is marked by the porta hepatis, where vessels and bile ducts enter and exit the liver. The quadrate lobe, between the gallbladder and the fissure for the umbilical vein, is in contact with the pylorus and the superior (first) portion of the duodenum (duodenal impression). The caudate lobe lies superior to the porta hepatis, between the fissure for the ligamentum venosum and the inferior vena cava; the inferior projection of the lobe is the papillary process. The visceral surface of the liver reveals further impressions of the organs with which it is in contact: the impressions for the colon and the right kidney, and on the left lobe the impressions for the esophagus and the stomach. The superior surface is related to the diaphragm and forms the domes of the liver.

Lesser Omentum, Variations in Form of Liver

If the inferior margin of the liver is lifted, the lesser omentum is exposed. It is a peritoneal fold extending from the first portion of the duodenum and the lesser curvature of the stomach to the liver, where it is inserted into the fissure of the ligamentum venosum and continues to the porta hepatis. Here, the layers are separated to accommodate the structures running to and from the liver. On the free right edge of the lesser omentum is the thick hepatoduodenal ligament. It forms the anterior boundary of the omental (epiploic) foramen ( of Winslow ) , which is the entrance to the omental bursa. The posterior wall of this cavity is formed by the inferior vena cava and the caudate lobe of the liver. Near the right margin of the lesser omentum is found the common bile duct, which divides into the cystic duct and common hepatic duct. To its left lies the hepatic artery and posterior to both, the portal vein. The nerves and lymph vessels of the liver accompany these structures. The porta hepatis is limited anteroinferiorly by the quadrate lobe and posterosuperiorly by the caudate lobe. On the right side of the porta hepatis, the main hepatic duct branches into the right and left hepatic ducts and they enter the liver. On the left side of the porta hepatis the hepatic artery enters the liver posterior to the branching of the ducts. The forking portal vein enters posterior to the ductal and arterial ramifications.

The shape of the liver varies. Its great regenerative ability, as well as the plasticity of the liver tissue, permits a wide variety of forms, which depend in part upon pressure exerted by neighboring organs and in part upon disease processes or vascular alteration. A greatly reduced left lobe is compensated for by enlargement of the right lobe, which reveals very conspicuous and deep costal impressions. Occasionally, the left lobe is completely atrophic, with a wrinkled and thickened capsule and, microscopically, an impressive approximation of the portal triads, with hardly any lobular parenchyma between them. In the majority of such cases, vascular aberrations have been demonstrated, such as partial obstruction of the lumen of the left branch of the portal vein by a dilated left hepatic duct or obstruction of the bile ducts. This lesion is therefore thought to be the result of a local nutritional deficiency, especially because the nutritional condition of the left lobe is poor to begin with. In other instances, associated with a transverse position of the organ, the left lobe is unduly large. Historically, deformation of the liver sometimes resulted from laced corsets or from tight belts or straps. Such physical forces may flatten and elongate the liver downward with reduction of the superior diaphragmatic surface and sometimes with a peculiar tonguelike extension of the right lobe. In other instances, the corset liver is displaced, and the renal impression is exaggerated. Clinical symptoms (dyspepsia, cholelithiasis, chlorosis) were ascribed to the corset liver, but it is questionable whether this condition actually led to clinical manifestations other than peculiar findings on palpation. Indentations on the liver are normally produced by the ribs, by diaphragmatic insertions, and by the costal arch. In kyphoscoliosis, the rib insertions may become very prominent. Parallel sagittal furrows on the hepatic convexity have been designated as “diaphragmatic” grooves. None of the described variations are considered functionally significant today.

Cellular Elements of Liver

Hepatocytes are the cells that make up the parenchyma of the liver. The cytoplasm of the hepatocytes normally contains various defined particles that can be visualized by histochemical methods. Neutral fat is found in the form of droplets, which are stainable in frozen sections by fat stains but appear as vacuoles after dissolution of fat with the routine use of organic solvents in histologic techniques. The fat droplets or vacuoles in normal liver cells do not exceed 4 microns in diameter. They usually line up on the free margin of the cells, like pearls on a string. Enlargement of the fat droplets is the result of an imbalance between the transport of fat to the liver from either the intestine or the peripheral tissue, or of its formation or catabolism within the liver. The imbalance in fat metabolism may be focal, mainly due to disturbances of the blood flow and local anoxia, or may be diffuse. The fat droplets become gradually larger until the liver cell cytoplasm is studded with droplets of different size; the nucleus, however, still remains in the center. Subsequently, the droplets merge, and one large drop pushes the nucleus to the side. Eventually, large drops of neighboring liver cells coalesce to form fatty cysts, in which the fat is actually extracellular and the remnants of several cells line the cyst.

Glycogen, if previously precipitated by alcohol fixation, appears as fine red particles in the cytoplasm after staining with Best's carmine or periodic acid–Schiff reagent. In routinely fixed and stained sections or biopsy specimens of normal liver, the dissolved glycogen produces a fine, granulated and vacuolated appearance of the cytoplasm. In severe disease of any kind, particularly in the agonal period, the glycogen content becomes markedly reduced, so that, as a rule, in autopsy specimens little glycogen is found. The glycogen content of the liver cells is an index of its functional status. The mitochondria of hepatocytes are stainable with preparations such as Janus green, appearing as globular elements in the center and rod-shaped elements in the periphery of the lobule. They contain, as do all cells of the body, phospholipids and a great number of enzyme systems.

The stellate sinusoidal macrophages (Kupffer cells) assume a wide variety of shapes in the normal liver as an expression of different activity stages, primarily phagocytosis. Some of them are flat, similar to endothelial cells in other organs. Others have a large amount of cytoplasm, which contains various inclusions, not necessarily an expression of disease. Some of these inclusions are bacteria, pigments, red cells, and fat droplets. In various abnormal conditions, the phagocytosis becomes exaggerated, and resting endothelial-like stellate sinusoidal macrophages can rapidly change into the large phagocytic type. These cells typically line the hepatic sinusoids, where they can interact with incoming pathogens or fragments.

The hepatic stellate cells (Ito cells) are also found within the sinusoidal space but play a distinct role in normal liver metabolism. They store vitamin A within lipid inclusions and release it as needed. When the liver is damaged, these cells cease playing a role in vitamin A metabolism and differentiate into cells that are similar or identical to myofibroblasts. They then release types I and III collagen to repair damage to the stroma and parenchyma of the liver, thus becoming involved in the development of cirrhosis by changing the stroma of the liver.

Intrahepatic Structures

Vessel and Duct Distribution, Liver Segments

The intrahepatic distribution of vessels and bile ducts was successfully studied on casts prepared by injecting a chemically impregnable plastic into the vascular and biliary conduits before removing tissue by corrosive agents. The knowledge thus obtained proved to be a valuable asset for the cholangiographic demonstration of the vascular apparatus in vivo but was also of more than theoretical interest in view of the recognition of segmental divisions, similar to those in the lungs, which opened up the possibility of partial hepatectomy or the excision of single metastatic nodules and surgical excision of specific segments. Although the human liver, in contrast to the liver of some animals, fails to display surface lobulation, the parallel course of the branches of the hepatic artery, portal vein, and bile ducts and the appearance of clefts in these preparations of vessels and ducts pointed to a distinct lobular composition. A major lobar fissure extends obliquely inferior from the fossa for the inferior vena cava to the gallbladder fossa, which does not coincide with the surface separation between the right and left lobes running along the insertion of the falciform ligament and the fossa for the ductus venosus. Through this fissure extends one of the main trunks of the hepatic vein, the tributaries of which never follow the distribution of the other vessels but cross the portal vein branches in an interdigitated fashion.

Each lobe is partitioned by a segmental division and is drained by a lobar bile duct of the first order. The right division extends obliquely from the junction of the anterior and posterior surfaces inferiorly toward the lower border of the liver and continues on the inferior surface toward the porta hepatis, dividing the right lobe into an anterior and a posterior segment, each of which is drained by a bile duct of the second order. The left segmental cleft runs on the anterior surface along the attachments of the falciform ligament and on the visceral surface through the fissure of the ligamentum teres and ligamentum venosum. This fissure divides the left lobe into a medial and a lateral segment, but in a significant number of cases it is crossed by bile ducts and vessels. The lateral segment corresponds to the classic descriptions of the left lobe, whereas the aspect of the medial segment on the visceral liver surface corresponds to the quadrate lobe. The four bile ducts of the second order fork into those of the third order, which drain either the superior or the inferior area of the corresponding segments. Thus, the bile ducts and the accompanying vessels can be designated according to the lobes, segments, and areas to which they belong. The anatomically distinct caudate lobe has a vascular arrangement that divides it into a left portion drained by the left lobar duct and a right portion drained by the right lobar duct. The caudate process, connecting the caudate lobe with the right lobe of the liver, has a separate net of vessels, which, in the majority of cases, communicates with branches of the right lobar duct. Neither the caudate lobe nor other parts of the liver provide an effective communication between the right and left lobar duct systems. Intrahepatic anastomoses between intraparenchymal branches of the arteries also have not been found, but in one fourth of the cases interconnections between the right and left systems exist through small extrahepatic or subcapsular anastomosing vessels.

The distribution of draining bile ducts and afferent blood vessels, as described and pictorialized in a schematic fashion, is valid in the majority of instances, but individual variations are met in abundance. They concern, especially, the lateral superior vessels and ducts for the appendix fibrosa. Rudimentary bile ducts are frequent in this region. The incidence of segmental bile duct variation is greater on the right, whereas that of segmental arteries is greater on the left side. Furthermore, the observations of several investigating groups are, in some respects, still at variance.

Arterial Blood Supply of Liver, Biliary System, and Pancreas

As is the case in the gastrointestinal system in general, the arterial supply of the liver, biliary system, and pancreas is incredibly variable. This plate will cover the typical branching pattern, and we will thereafter review the most common variations of the vasculature related to the liver. The celiac trunk is usually a short, thick artery originating from the aorta just below the aortic hiatus in the diaphragm. It extends horizontally and forward above the pancreas, and splits into left gastric, common hepatic, and splenic arteries.

From the celiac trunk, the common hepatic artery passes anteriorly and to the right to enter the right margin of the lesser omentum, in which it ascends. As the common hepatic artery turns superiorly, it gives origin first to the gastroduodenal artery, which supplies arteries to the stomach, duodenum, and pancreas, then usually to the supraduodenal artery, and finally to the right gastric artery. The continuation of the common hepatic artery, after the gastroduodenal artery departs, is thereafter known as the proper hepatic artery. It ascends within the hepatoduodenal ligament (part of the lesser omentum) alongside the common bile duct and hepatic portal vein. The proper hepatic artery ascends anterior to the hepatic portal vein and to the left of the common bile duct. As it nears the liver, it divides into several branches, most commonly into a right hepatic and a left hepatic artery. The right hepatic artery generally passes posterior to the common hepatic duct to enter the cystic triangle (of Calot), formed by the cystic duct, the hepatic duct, and the liver. In a minority of cases, however, the right hepatic artery crosses anterior to the bile duct. All terminal branches of the hepatic artery enter the liver at the porta hepatis, alongside the hepatic portal vein and hepatic bile ducts. The left hepatic artery passes anterior to the left hepatic bile duct and also frequently gives off a large branch, the intermediate hepatic artery, which also passes anterior to the left hepatic bile duct.

Hepatic Artery Variations

It is important to know the textbook branching pattern of the hepatic arteries, but it is equally important to realize that many variations on this pattern exist and one cannot anticipate the branching that may be found in any one individual. These variations occur with equal incidence in the right and left hepatic arteries and are of more than passing surgical significance, mostly because of the liver necrosis that follows their unintended ligation. A replaced artery originates from a source different from that in the standard description and substitutes for the typical vessel. An accessory artery is an extra vessel present in addition to those originating according to standard descriptions. An example of a replacement artery is the origin of the common hepatic artery from the superior mesenteric artery (1). It passes through, or posterior to, the head of the pancreas, and its ligation during a pancreaticoduodenal resection deprives the liver of its arterial blood supply. Under these circumstances, only the left gastric and splenic arteries arise from the celiac trunk. Sometimes, right or left hepatic arteries originate independently from the celiac trunk or fork off from a very short common hepatic artery (2). Under these conditions, the gastroduodenal artery originates from the right hepatic artery. Somewhat frequently, the right hepatic artery, giving off the gastroduodenal artery, originates from the superior mesenteric artery, whereas the left hepatic artery, in turn giving off the intermediate hepatic artery, is derived from the celiac trunk (3). Ligation of the replaced right hepatic artery, especially where it crosses the junction of the cystic and common ducts (for instance, during cholecystectomy) deprives the right lobe of the liver of its blood supply. In contrast, ligation of an accessory right hepatic artery, coming from the superior mesenteric artery (5), is far less significant, because another right hepatic artery runs its typical course. Under these circumstances, two right hepatic arteries may be found in the cystic (Calot) triangle. A replaced right hepatic artery is far more frequent than an accessory one. An aberrant left hepatic artery, originating from the left gastric artery, is, in half of cases, replaced (4) and, in the other half, accessory (6). If it is replaced, only the right hepatic artery comes from the celiac trunk, whereas in the presence of an accessory vessel, the common and proper hepatic arteries take their usual course. Ligation of a replaced left hepatic artery (for instance, during gastrectomy) endangers the blood supply to the left lobe of the liver.

An accessory left hepatic artery may also come from the right hepatic artery (7). In about 12% of cases the right hepatic artery, originating at its typical site of departure, crosses anterior to the common hepatic duct instead of posterior to it (8), a variation worthy of being remembered in the exploration of the duct. The described variations are also significant in the formation of collaterals after obstruction or ligation of an artery. Other variations not described here are less frequent, but their potential existence should not be ignored or discounted when operating in this field.

Cystic Artery and Its Variations

The cystic artery most frequently originates from the right hepatic artery within the cystic triangle of Calot, to the right of the common hepatic duct. However, its frequent variations are of great significance in cholecystectomy and are best recognized by careful dissection of the structures in the triangle. Typically, the artery divides into an anterior branch, going to the free peritoneal surface of the gallbladder, and a posterior branch, going to the nonperitoneal surface and the gallbladder bed. The branches communicate with each other by means of numerous twigs. In about 20% of cases, the cystic artery does not originate in the triangle but arises from the right hepatic artery (1) outside the triangle, from the intermediate (2) or left hepatic artery, or, even less frequently, from the proper hepatic artery (3) before it forks into its branches. In all these instances it crosses the anterior and sometimes the posterior aspect of the common hepatic duct. Rare replacements include an origin from the gastroduodenal artery (4), and even from the celiac trunk (5) or independently from the aorta. In these instances the cystic artery originates inferior to the origin of the cystic duct and crosses anterior to the common bile duct. The cystic artery may also be derived from an aberrant right hepatic artery coming from the superior mesenteric artery, the origin being either within the cystic triangle (6) or outside of it (7). In the latter instance it again crosses anterior to the common hepatic duct.

Double cystic arteries are also frequently encountered, occurring in approximately 25% of cases. Under these circumstances both the superficial, or anterior, branch and the deeper posterior branch may arise within the triangle from the right hepatic artery (8). As a rule, the origin of the posterior branch is much higher in the triangle, whereas the anterior branch may swing caudally around the proximal part of the cystic duct. Less frequently, one or both of the cystic arteries originate outside the triangle. In these cases, the most frequent pattern is an origin of the anterior cystic artery outside the triangle from the right hepatic artery with crossing in front of the bile duct, and origin of the posterior branch to the deeper structures of the gallbladder high within the triangle (9). Rarely, the anterior cystic artery may originate from the gastroduodenal artery (10). For the surgeon it is well to remember that an important vessel may have an inferior origin and accompany the cystic duct, in case the entire cystic artery or its superficial branch starts from the gastroduodenal artery or other intestinal arteries. Double cystic arteries may also arise within or outside of the triangle from an aberrant right hepatic artery (11). The number of possible variations is great, and their incidence is not negligible. It should be emphasized that an artery resembling the cystic artery in its course and paralleling the cystic duct is not necessarily the cystic artery but may be a branch of the proper or right hepatic artery.

Portal Vein Tributaries, Portacaval Anastomoses

The portal vein forms posterior to the head of the pancreas at the height of the second lumbar vertebra by confluence of the superior mesenteric and splenic veins. It runs posterior to the first portion of the duodenum and then in the right border of the lesser omentum to enter the liver at the porta hepatis, where it splits into its hepatic branches. The portal vein receives the left gastric vein, which communicates with the esophageal venous plexus. The latter, in turn, connects with the short gastric veins and the azygos and hemiazygos veins in the lower and middle parts and with various branches of the superior vena cava, such as the brachiocephalic and inferior thyroid veins in the upper part of the esophageal region. The portal vein further accepts the right gastric vein, which with the left gastric vein forms a loop. The left main branch of the portal vein admits the paraumbilical veins and, occasionally, a persisting umbilical vein.

The superior mesenteric vein originates at the root of the mesentery as it receives venous blood from midgut veins such as the middle colic, right colic, ileocolic, jejunal, ileal, and inferior pancreaticoduodenal veins, receiving in addition many small veins. It runs anterior to the third portion of the duodenum and the uncinate process of the pancreas . A foregut vein, the right gastroepiploic vein, coming from the right aspects of the greater curvature of the stomach, also enters the superior mesenteric vein.

The splenic vein usually receives the inferior mesenteric vein just posterior to the body of the pancreas. The inferior mesenteric vein drains hindgut structures; it begins with the superior rectal veins and continues in the posterior abdominal wall, receiving many tributaries, particularly the sigmoid and left colic veins. The splenic vein itself begins at the hilus of the spleen and admits the left gastroomental vein, short gastric veins (both of which communicate with esophageal veins), and pancreatic veins which anastomose with retroperitoneal veins, and therefore with the caval system.

The shortness of the hepatic portal vein discourages mixing of the blood coming from its constituents, so that the right extremity of the liver may chiefly receive blood coming from the superior mesenteric vein. The left lobe may receive blood from the left gastric, inferior mesenteric, and splenic veins, whereas the left part of the right lobe, including the caudate and quadrate lobes, receives mixed blood. These streamlines, demonstrated in experimental animals, are not seen during portal venography and are not certain to occur in the human being. Their existence has been assumed, however, to explain the localization of tumor metastases and abscesses and also the predominance of massive necrosis in acute fatal viral hepatitis in the left lobe, which supposedly does not receive nutrient-rich protective blood from the small intestine.

The portacaval anastomoses have great clinical significance. They dilate when the blood flow in the portal vein and/or through the liver is restrained; they relieve portal hypertension and may be lifesaving in acute portal hypertension but, as in chronic obstruction, may shunt blood from the liver, compromising the liver's vital functions and, therewith, contributing to hepatic insufficiency. Dilatation of the rectal veins results in hemorrhoids, with the attendant danger of hemorrhage, thrombosis, and inflammation. The varicosities of the esophageal veins (and less so of the gastric veins of the stomach) may lead to esophageal hemorrhage, the most dangerous complication of portal hypertension. The various retroperitoneal portacaval anastomoses have less clinical significance. The paraumbilical anastomoses lead to a marked dilatation of the veins in the anterior abdominal wall. If these veins converge toward the umbilicus, they form what is called caput medusae.

Portal Vein: Variations and Anomalies

The anatomy of the portal vein system is less variable than that of the hepatic arteries. However, the variations that do occur in this series of vessels are of paramount importance during shunt operations for portal hypertension. The length of the portal vein varies from 5.5 to 8 cm, with an average of approximately 6.5 cm, the mean diameter being normally 1.09 cm. In cirrhosis, however, the diameter becomes considerably wider. It is of practical importance that in only slightly over 10% of the studied cases no vessel enters the main stem of the portal vein, but in the vast majority, several veins are admitted that may be torn during the dissection for portacaval anastomosis. Dangerous hemorrhage may result, and ligation of these vessels may interfere with the size of the portal vein and the performance of the anastomosis. In more than two thirds of cases, the left gastric vein, which is of major significance as portal drainage from esophageal varices, enters into the left aspect of the portal vein. Otherwise it enters at the junction of the splenic and superior mesenteric veins, and in almost one fourth of cases, it joins the splenic vein. Under all these circumstances, the right gastric vein may enter into the portal vein stem. On its right aspect, the portal vein may admit the superior pancreaticoduodenal vein, and close to the liver the cystic vein, which frequently joins the right side of the portal vein. The usual anatomic description of the formation of the portal vein is found in only about half of cases. In the remainder, the inferior mesenteric vein enters the junction of the splenic and superior mesenteric veins or joins the superior mesenteric vein.

The size of the splenic vein, of major importance in a splenorenal shunt, is said to average less than 0.5 cm between the splenic hilus and the junction with the inferior mesenteric vein. As a rule, the splenic vein is widened to a lesser degree in portal hypertension than is the portal vein. Because the splenic vein is more or less embedded into the head of the pancreas, the many pancreatic venous tributaries are so short that they may be easily torn during a shunt operation, and their ligation creates technical problems.

Of the rare congenital anomalies of the portal vein, the one of surgical significance concerns an abnormal position anterior to the head of the pancreas and the duodenum. Another rare but physiologically interesting anomaly is the entrance of the portal vein into the inferior vena cava. It would indicate that a liver that appears normal in a morphologic sense can function without receiving blood from the portal vein. With this anomaly, the hepatic artery is considerably enlarged. A great rarity is an entrance of the pulmonary vein into the portal vein; this is probably the consequence of some disturbance in the development of the venous systems at an early fetal stage. Another extremely rare variation is the presence of congenital strictures of the portal vein at the porta hepatis, producing severe portal hypertension that may not be relieved by surgical anastomoses.

Lymphatic Drainage of Liver and Bile Tract

The perisinusoidal space (of Disse) separates the sinusoidal wall from the hepatocytes. The spaces are filled by extensions of the hepatocyte cytoplasm and are traversed by fine arcuate reticular fibers, extending from the basement membrane of the capillaries to the hepatocytes, which themselves do not rest on a basement membrane. Through these spaces the exchange of fluid, and especially solids from the liver cells to the sinusoidal lumen and vice versa, takes place. Under normal circumstances the perisinusoidal spaces are almost completely invisible and the arcuate reticular fibers can hardly be separated from the sinusoidal basement membranes. However, in the agonal period, and especially in passive congestion, in anoxia, or in various toxic conditions, hepatic edema sets in, with widening of the sinusoidal spaces, which are filled by a protein-rich fluid. This widening may develop very rapidly, probably as a result of an abnormally increased permeability for serum protein brought about, for instance, by hypoxia. Therefore, in autopsy specimens (even when the liver is normal), as a rule, the perisinusoidal spaces are expanded, whereas in biopsy specimens they are usually invisible. In toxic conditions or congestion, this widening may be markedly exaggerated. The fluid in the perisinusoidal space is the beginning of lymph from deep lymphatic vessels from the liver. This fluid travels in a direction similar to that of the bile, toward nearby portal triads, to join larger lymph vessels that parallel the bile duct, hepatic artery, and hepatic portal vein. Few lymphatics are present in the central canals around the tributaries of the hepatic vein; lymph tends to travel toward the portal triad. Lymph from the more superficial regions of the liver and its capsule drain to superficial lymphatic vessels. The capsule of the liver (Glisson capsule) contains a dense network of lymphatics that communicates with a lymphatic network in the gallbladder bed. These widespread intercommunications make the hepatic lymphatic system a functional unit.

The lymphatic drainage of the liver follows several routes. Superficial lymphatic vessels as well as deep lymphatic vessels from the inferior and anterior region of the liver drain to hepatic lymph nodes, found running alongside the hepatic arteries at the porta hepatis. Additional lymph nodes are found along the proper and common hepatic arteries. Lymphatic fluid drains along these nodes to reach the celiac lymph nodes at the base of the celiac trunk and inferior vena cava. From there, lymphatic vessels proceed to the cisterna chyli, and a few extend directly from the porta hepatis to the thoracic duct. Lymphatic vessels near the bare area of the liver, on the posterior and superior aspects of the organ, drain toward the inferior vena cava as it passes through the diaphragmatic hiatus of the diaphragm. There, lymphatic fluid encounters the phrenic lymph nodes in the vicinity of the thoracic duct.

In addition, a few vessels from the left side of the posterior surface drain to the left gastric lymph nodes and some from the right side of the posterior surface drain directly to the celiac nodes. The lymph vessels from the gallbladder and from most of the extrahepatic bile ducts drain to the hepatic nodes, but a few vessels from the common bile duct also run to the right gastric lymph nodes. Anastomoses of the hepatic lymphatics with duodenal and pancreatic lymphatics are typically noted only in the presence of adhesions.

Innervation of Liver and Bile Tract

The liver, gallbladder, and biliary tract receive their nerve supply from the sympathetic and parasympathetic systems as well as the right phrenic nerve. The sympathetic innervation comes chiefly from the intermediolateral cell column of the 7th to the 10th spinal segments. Axons from these levels exit via the anterior roots, spinal nerves, and white rami communicans to reach and pass through the sympathetic ganglia of the sympathetic trunk. Preganglionic sympathetic axons reach the prevertebral ganglia by way of the thoracic splanchnic nerves and synapse with the nerve cells within the ganglia. Most of the postganglionic sympathetic fibers to the liver probably originate in the celiac ganglia; some of them may start in small ganglia present at the porta hepatis. The parasympathetic innervation is provided by both vagal trunks, the posterior trunk of which traverses, with some branches, the right portion of the celiac plexus but does not form synapses within it. The anterior vagal trunk reaches the liver through the hepatogastric ligament from the anterior surface of the esophagus and stomach.

The preganglionic parasympathetic and postganglionic sympathetic nerves form the anterior and posterior hepatic plexuses. The anterior plexus lies near the hepatic artery; it is composed mostly of fibers from the left portion of the celiac plexus and from the right abdominal branch of the anterior vagal trunk. The posterior plexus, behind the portal veins and the bile ducts, receives fibers from the right celiac ganglion and the posterior vagal trunk. Within the liver, nerves follow the branches of the blood vessels and bile ducts to reach their targets. The innervation of the intrahepatic blood vessels is analogous to that of other blood vessels. In the wall of the bile ducts a nerve fiber network extends close to the epithelium. Apparently the branches of the common hepatic artery are supplied entirely by sympathetic fibers, whereas the muscles of the bile ducts and the gallbladder are innervated by both autonomic nerves. The extrahepatic bile ducts and the gallbladder receive branches from the anterior and posterior hepatic plexuses. Preganglionic parasympathetic axons synapse with postganglionic parasympathetic nerve cells near their target, such as the muscularis of the gallbladder and the smooth muscle of the bile ducts.

Nonpainful, reflexive afferent inputs from the liver, gallbladder, and extrahepatic bile ducts travel to the medulla oblongata by running in a retrograde fashion along the parasympathetic inputs to each organ. They are therefore found within the anterior and posterior vagal trunks and vagus nerves. Afferent nerves that carry visceral pain signals from the liver and extrahepatic biliary system travel along sympathetic fibers to each organ. Therefore they pass along the hepatic arteries, through the thoracic splanchnic nerves and white rami, and then the posterior roots to reach the spinal cord. The phrenic nerve also enters the liver, sometimes joined by sympathetic fibers, with branches distributed to the coronary and falciform ligaments and to the capsule of the liver. Pain elicited in the liver is usually of the dull type, associated with diffuse tenderness over the right upper quadrant of the abdomen and pain in the right shoulder. A beltlike area of skin hypersensitivity, corresponding to the ninth thoracic and first lumbar vertebrae, is generally found on the right side of the body. Acute enlargement of the liver is frequently painful (because of stretching of the capsule and traction on the hepatic ligaments); this condition and the shoulder pain on the right side reflect innervation by the phrenic nerve. Biliary tract pains are felt either as circumscribed tenderness in the gallbladder region or as colicky pain. Pain radiates to the back just below the tip of the right scapula, to the right shoulder, to the substernal area, and sometimes also to the anterior left chest. Involvement of the subserosa produces sharply defined knifelike pain associated with hyperesthesia of the skin.

Congenital and Familial Hyperbilirubinemias

Congenital and familial hyperbilirubinemias can be divided into conjugated and unconjugated hyperbilirubinemias. Unconjugated hyperbilirubinemia results from blockages at the level of uptake of unconjugated bilirubin by the hepatocyte (1) and prior to conjugation (2). Conjugated hyperbilirubinemia occurs from blockage at the point of excretion of bilirubin into the canaliculus (3) or downstream from the point of excretion. Unconjugated bilirubin passes through the liver cell membrane facing the sinusoid, probably without the participation of the Kupffer cell, and is conjugated by the enzyme glucuronyl transferase, with glucuronic acid. This acid is derived from glucose, linked to uridine phosphate, and oxidized to uridine diphosphate glucuronic acid. The promptly reacting bilirubin glucuronide is excreted into the bile.

Bilirubin transport through the liver cell may be partially or completely blocked at any of four sites. Uptake of unconjugated bilirubin by the liver cell may be blocked at the sinusoidal surface by multiple causes, including conditions with reduced hepatic blood flow, such as congestive heart failure and portosystemic shunting. Whether inherited disorders such as Gilbert syndrome do this is less clear.

Gilbert syndrome, the most common disorder of bilirubin glucuronidation, results from a defect in the promoter of the gene that encodes the enzyme uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1), resulting in reduced hepatic bilirubin-UGT activity. The disease is benign but presents as episodes of mild jaundice, which are typically triggered by fasting, hemolysis, intercurrent febrile illness, stress, physical exertion, and other situations that may increase bilirubin production. Despite the episodes of mild jaundice, there is no liver injury and liver enzymes are not increased. The prognosis for patients with Gilbert syndrome is similar to that of the general population.

By contrast, patients who have absence or deficiency of glucuronyl transferase, as found in Crigler-Najjar syndrome, have significant rates of morbidity and mortality. As opposed to Gilbert syndrome, in which the defect is in the promoter region, the defects in Crigler-Najjar syndrome are caused by a variety of alterations to the coding sequences of the UGT1A1 gene. This results in abnormal protein production and absent (type 1 Crigler-Najjar syndrome) or very low (type II Crigler-Najjar syndrome) hepatic UGT1A1 activity. In type I disease, in which levels can reach more than 20 to 50 mg/dL, kernicterus can develop if intervention is not rapid. Short-term treatments, such as phototherapy and plasmapheresis, and long-term treatments, such as liver transplantation, are necessary for afflicted individuals.

Inherited disorders that cause conjugated hyperbilirubinemia involve blocks at the level of the biliary excretion of conjugated bilirubin (3) or downstream of the point of excretion (4). There is an increase in serum conjugated and unconjugated bilirubin. These disorders, including Dubin-Johnson syndrome, Rotor syndrome, progressive familial intrahepatic cholestasis, and benign recurrent intrahepatic cholestasis, are caused by multiple different defects, some which have been identified and others not. Dubin-Johnson syndrome and Rotor syndrome have similar phenotypes characterized by mild fluctuating conjugated and unconjugated hyperbilirubinemia associated with an excellent prognosis. The genetic defect in Dubin-Johnson syndrome is in the multidrug- resistance–associated protein-2 component of the bile transporter. The defect in Rotor syndrome has not been molecularly identified but is thought to be related to a defect in hepatic storage of conjugated bilirubin rather than of excretion into the canaliculi. Dubin-Johnson syndrome is associated with accumulation of a golden-brown pigment in the liver cells which causes the liver to appear black. Progressive familial intrahepatic cholestasis is a heterogeneous group of disorders, characterized by various defects in the secretion of bile acid and other components of bile. With the exception of benign recurrent cholestasis , these disorders, which present in childhood or infancy, are associated with growth failure and progressive liver disease.

The fourth block occurs downstream at the point of secretion of bile into the canaliculi. Two well-described disorders, Alagille syndrome and abnormalities of villin gene expression, result in structural defects in the bile canalicular structure and are associated with chronic cholestasis.

Congenital Anomalies

The development of ductules and bile ducts depends upon organizing influences. Disturbances of development lead to an irregular arrangement of the ducts, resulting in solid nodules or in cysts. Small irregular proliferations of ductules and bile ducts, surrounded by excessive fibrotic tissue, appearing as small white nodules, are a frequent incidental finding in biopsy and autopsy specimens. The narrow cavities form an irregular plexus, usually connected with the biliary system and often containing small bile calculi. The significance of these hamartomas, also called multiple bile duct adenomas, lies in their differentiation from inflammatory lesions.

The same embryologic disturbance leads to cyst formation when the hamartomatous cavities become large or communicate with each other. The large ones are found mostly in adults, indicating that they grow during life. Occasionally, single large cysts are observed, which cause pressure symptoms. More frequent is polycystic disease of the liver, which is, in at least half of cases, associated with polycystic disease of the kidney and, though not so regularly, with pancreatic cysts. Sometimes other anomalies, such as aneurysms of the cerebral arteries, are encountered simultaneously. The lesion is often familiar. Exceptionally, this hepatic involvement may produce upper abdominal pain and a feeling of fullness, without functional impairment. This mostly occurs in the fourth and fifth decades. Malignant degeneration seems to be rare. The health of the patient is primarily influenced by the renal involvement. The hepatic cysts are lined by a cuboidal epithelium, which is often desquamated. Their lumen contains a clear yellow fluid. Other hepatic cysts are parasitic or, less commonly, caused by accumulation of blood, lymph, and bile. Ciliated cysts are derived from misplaced intestinal endoderm, or they may be teratoid.

Riedel lobe is a tonguelike extension of the right lobe, projecting from the anterior margin around the gallbladder. As a rule, the projection is 1 to 2 inches long, irregularly shaped, and narrow at its neck. Exceptionally, it is very long and extends into the pelvis. Sometimes the neck is thinned to a freely movable pedicle, consisting mainly of fibrosed tissue. The liver tissue in the lobe itself is mostly normal, but it may exhibit fibrosis or bile stasis if the blood supply and bile drainage in the pedicle are compromised. The Riedel lobe is either a congenital anomaly or of unknown cause, but it is benign. The main clinical significance of the Riedel lobe lies in unusual palpatory findings in the area of the gallbladder, which can be readily mistaken for a distended gallbladder, tumor in the omentum, or pancreatic cyst. A Riedel lobe can be mistaken on imaging for hepatomegaly.

Liver Functions

The liver, ranking first in size as a parenchymal organ, takes also first position in number, variety, and complexity of functional accomplishments. Only the most essential features of the liver's physiology and those which are of principal interest for the practice of medicine are illustrated and discussed in the following pages of this section. In the accompanying plate an attempt has been made to present a classifying and summarizing survey.

Holding a strategic position between the intestinal and general circulation and harboring, according to its dimensions, a large amount of blood and extracellular fluid, the liver exercises a major influence on the volume of circulating blood and its constituents. The liver acts as a sponge or “flood chamber,” which can be filled or congested, as in failure of the right heart. The “filter action” of the liver also results from its peculiar anatomic location, because all nutrients, and also injurious materials absorbed by the intestines, are brought to the organ via the portal system. The effect of the liver on water and electrolyte balance, though it is regulated mainly by the kidneys, lungs, adrenals, and hypophysis, should not be underestimated, not only because of the large parenchymal mass of the organ but also because all the ingested water and salts pass through the liver before entering other extracellular departments.

The hexagonal, epithelial liver cells have multitudinous and very diversified functions. They are the site of the chemical transformations that make body constituents from foodstuffs or their digested breakdown products and that correlate the three main categories of organic body material, so that the totality of the liver cells becomes a great “metabolic pool” of the organism. The versatility of this central chemical laboratory of the organism, together with the liver's storage capacity for glycogen, proteins, fats, and vitamins, is of the utmost significance for the energy economy of the entire body. The liver stores these organic materials not only for its own need but to satisfy the needs of distant organs. It gives glucose to the blood to maintain the sugar level and to supply energy for all vital phenomena. The liver cells form many of the serum proteins to provide forces for the oncotic pressure of the plasma or to be used as a transport vehicle for water-insoluble compounds or as coagulating factors or to fulfill enzymatic functions and other functions.

The epithelial hepatic cells, furthermore, protect the organism from injurious agents by a variety of detoxification processes, which yield substances deprived of detrimental properties.

The bile, also manufactured by the epithelial cells, contains the characteristic bile pigments, salts of bile acids, cholesterol, and a number of other components. It is excreted into the bile capillaries and leaves the liver through the intrahepatic bile duct system to reach the duodenum via the extrahepatic bile tract.

The Kupffer cells, besides functioning as endothelial cells like others elsewhere in the organism, represent the quantitatively most important part of the reticuloendothelial system. These cells are concerned with the breakdown of hemoglobin to bilirubin, participate in the formation of γ-globulin and immune bodies, and act as scavenger cells that remove by phagocytosis pigments, bacteria, and other corpuscular or macromolecular elements.

The liver's vascular system serves the proper intrahepatic blood distribution by sphincter actions. The two blood supplies (hepatic artery under high pressure and portal vein under low pressure) are harmonized. The hepatic sinusoids differ from other capillaries in that they have a greater permeability for proteins.

Innate Immune System and Liver

The liver serves a central role in the immune system. As the largest solid organ in the body, the liver has a dual blood supply. In addition to the conventional arterial blood supply from the hepatic artery (which is fed by the aorta), the liver is also the main drainage system for the gastrointestinal tract, with about 80% of its blood supply coming from the portal vein. As a result, it is exposed to blood that has a rich supply of bacterial products (including endotoxin), environmental toxins, and food antigens. As the gateway to the systemic blood system, the liver serves important roles as the first line of defense and as an immune modulator. It is estimated that approximately 30% of the total blood flows through the liver every minute, and with this blood is carried all the immune cells, such as lymphocytes, that may circulate throughout the body.

In its essential role as the immune regulator, the unique anatomic structure of the liver is important. In addition to the parenchymal cells, the hepatocytes (which constitute approximately 80% of all the cells in the liver) and the remaining nonparenchymal cells (which include a wide array of cells) are essential to the immune system. These include endothelial cells, stellate cells, Kupffer cells, and lymphocytes. The liver sinusoidal endothelial cells (LESC) form a monolayer between the hepatocytes and the portal blood supply. Unlike traditional veins, the sinusoids in the liver have sievelike fenestrations that allow for greater contact between the cells that come through the sinusoids, such as lymphocytes, as well as other components in the portal blood. In the space of Disse between the sinusoids and the hepatocytes , there are many interactions that may be critical for immune function. LESC, which make up the bulk of the nonparenchymal cells (≈50%), express receptors supporting their role in the immune response, including molecules such as the mannose receptor and scavenger receptor, which promote antigen uptake. They even express major histocompatibility class I and II molecules and costimulatory molecules CD40, CD80, and CD86, which are important for antigen uptake.

Next to the LESC in the sinusoidal vascular space are Kupffer cells or hepatic macrophages. Kupffer cells account for approximately 20% of nonparenchymal cells in the liver and are the largest group of fixed macrophages in the body. They are localized in the periportal area but can migrate to different areas, including through the space of Disse to make direct contact with hepatocytes. Kupffer cells are very heterogeneous and can perform many specialized functions, including phagocytosis and antigen processing and presentation. Kupffer cells can also generate various products, including cytokines, prostanoids, nitric oxide, and reactive oxygen intermediates. These factors regulate not only the phenotypes of the Kupffer cells that produce them but also the phenotypes of other immune cells, such as natural killer cells and natural killer T cells.

The liver also has a very large population of T cells, including nonconventional T cells. In addition to the conventional CD8- and CD4-positive T cells, the liver also has many natural killer T cells and TCRγδ T cells. In fact, the liver has more natural killer T cells than any other organ. Natural killer T cells constitute up to 30% of all T cells in the liver, a situation very different from other parts of the body. The liver is also one the richest sources of γδδ T cells. The reason for this unique composition of immune cells is not known, but their presence likely plays an important role in both the first line of defense against microorganisms and in regulation of the immune response.

Prothrombin Formation

Several plasma proteins involved in the complex process of blood coagulation, such as factors I (fibrinogen), II (prothrombin), V, VII, IX, X, XII, and XIII, are manufactured by the liver. The capacity to make prothrombin as well as factors VII, IX, and X depends on the availability of vitamin K ₁ , a naphthoquinone derivative, ingested with food or formed by intestinal bacteria. This naturally occurring vitamin, existing in two chemically different forms (K ₁ and K ₂ ), is water-insoluble due to long carbon side chains and requires bile acids for its absorption. A synthetic water-soluble naphthoquinone without side chains (menadione) can substitute for the natural vitamin.

The prothrombin time, which measures the time it takes for prothrombin (factor II) to be converted to thrombin (activated factor II), is a very useful measure of the body's coagulation function and liver function. The liver produces, furthermore, a number of factors necessary for the conversion of prothrombin into thrombin (factors V, VII, and X). If these factors are deficient, the effects in liver disease parallel those of prothrombin lack.

Prothrombin formation is impaired in obstructive jaundice, because the absence of bile prevents vitamin K absorption, as well as in conditions with liver cell damage, because bile acid production is deficient and, more so, because the liver's ability to create prothrombin is fundamentally lost. Accordingly, parenteral administration of menadione restores prothrombin formation and therewith normalizes the prothrombin time; if the liver cells are damaged, however, parenteral administration does not serve these functions, or does so only temporarily. For this reason, parenteral administration of menadione can differentiate between vitamin K deficiency and liver dysfunction as the cause for a prolonged prothrombin time, and it will improve clotting in obstructive jaundice but not when there is liver dysfunction (liver cell damage).

Physical Diagnosis of Liver Disease

The clinical diagnosis of liver disease is not difficult in advanced hepatic decompensation. A history of deepening jaundice, dark urine, light stools, progressive increase in girth of the abdomen, and subjective symptoms of weakness, anorexia, and other digestive difficulties focus the attention of the clinician upon the liver.

Icterus (i.e., more or less deep staining of the skin, sclerae, and mucous membranes) may be present in extrahepatic obstructive jaundice, as well as in hepatocellular injury. The icterus present in prehepatic (hemolytic) jaundice, however, usually does not stain the tissues as deeply as in the other forms. In hepatic and posthepatic jaundice, the urine is dark and the feces are light, particularly if the jaundice is deep. In prehepatic jaundice, on the other hand, bilirubin does not appear in the urine, but the urine may be dark due to increased amounts of urobilin. For the same reason, the feces in prehepatic jaundice are also dark. It is important to remember that in certain advanced cases of liver disease little or no jaundice may be apparent.

The appearance of spider nevi or telangiectasias, gynecomastia, palmar erythema, testicular atrophy, fine skin, sparsity of body hair, and prostatic atrophy is generally believed to be due to hyperestrogenism. Despite the fact that these changes are secondary, their appearance frequently helps to establish the diagnosis.

The detection of an enlarged or a tender liver is seen in patients with biliary cirrhosis or alcoholic or nonalcoholic fatty liver disease. With a primary or secondary hepatic neoplasm, the liver may be massively enlarged and nodular. In congestive heart failure or constrictive pericarditis, the liver may also be enlarged and tender. In other types of cirrhosis, the organ may be very small and not palpable.

The presence of splenomegaly, ascites, and caput medusae raises the suspicion of portal hypertension, though the spleen may be enlarged in patients with parenchymal liver disease without portal hypertension (e.g., in congestive heart failure).

In moderately severe and advanced cases of hepatic disease, particularly when hepatic coma has supervened, a foetor hepaticus is often discerned by the trained clinician. This odor is distinctive but difficult to describe. It is a musty, sweetish odor, not unpleasant, which at times is more easily detected by the physician upon entering the sickroom than when he or she is close to the patient. Although it may disappear following enemas or drastic bowel movements, and though it is sometimes observed in mild or chronic forms of liver disease, foetor hepaticus is mostly to be considered of grave prognostic significance.

Clubbing of the fingers and whitening of the nail beds are seen in some patients with cirrhosis of the liver when there is the development of hepatopulmonary syndrome. These signs are not specific for hepatic disease. Severe pruritus, with or without jaundice, may be the outstanding symptom in patients with the cholestatic type of liver disease and is frequently present in posthepatic jaundice. The pruritus is thought to be due to an increased concentration of bile salts in the bloodstream. Elevated alkaline phosphatase and serum cholesterol are frequently seen in association with the pruritus; they are the outstanding features of so-called primary biliary cirrhosis.

Presacral and ankle edema, often notable in patients with advanced liver disease, is primarily the result of lowered serum albumin and sodium; free water retention is considered a contributive factor.

Liver Function Tests

Liver function tests are a panel of serum biochemical tests used to diagnose and monitor liver disease. Although generally referred to as liver function tests, serum aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase tests should more appropriately be named liver injury tests because they may represent markers of liver injury. Albumin and bilirubin levels and prothrombin time are more appropriately known as markers of liver synthetic function. Patterns of liver injury test elevations are useful in the diagnosis of liver disease. Patients with hepatitis or acute hepatic necrosis will have a pattern of liver injury tests that show marked increases in the serum transaminases (AST and ALT), and those with cholestasis (either intrahepatic or extrahepatic) will have marked increases in alkaline phosphatase and bilirubin relative to the serum transaminases.

Serum transaminase elevations usually reflect damage to hepatic parenchymal cells which results in increased cell membrane permeability and leakage of these enzymes into the circulation. Although this finding is most likely due to liver injury, it is important to recognize that similar elevations may occur with damage to other tissues; production of AST and, to a lesser degree, ALT may occur in damage to the heart, muscle, intestine, pancreas, and other tissues.

Although alkaline phosphatase can be derived from injury to cholangiocytes, alkaline phosphatase is also found in appreciable amounts in the bone-forming cells, or osteoblasts, which can also release the enzyme into the blood. The serum alkaline phosphatase activity is elevated with increased osteoblastic activity. It is very high in such bone diseases as rickets, osteomalacia, and Paget disease. It is moderately elevated with most carcinoma metastases to bone, especially so if they are osteoblastic. In myeloma, the activity is not elevated. Alkaline phosphatase is also delivered to the blood from the intestinal wall.

In many hepatobiliary diseases, alkaline phosphatase is also elevated. Some alkaline phosphatase is normally excreted in the bile, and, therefore, interference with bile flow may lead to an increase in the serum activity of alkaline phosphatase. In addition, there may be release from damaged hepatocytes and induction of these enzymes by processes that damage the biliary epithelia, including biliary obstruction or cholestatic liver disease.

Bilirubin and Bile Acid Metabolism

From the quantity of bile pigment excreted, the rate of hemoglobin turnover has been calculated to be 16 to 24 g/day under normal conditions. Of the available pathways of hemoglobin breakdown, the one via the bile pigments is the most important. The site of bile pigment formation is the reticuloendothelial system, of which the Kupffer cells are a part. The excretion of bile pigment, however, is the task of the parenchymal liver cells. Any defect in this excretion process, either because of liver cell damage or because the liver is unable to cope with the quantity of bile pigment, leads to jaundice. The increase of bilirubin in the blood results in its appearance in the urine.

Most of the hemoglobin molecule (96%) for each species is globin, a specific protein to which the pigment radicle, heme, is attached. Heme consists of four pyrrole rings connected by methene (–CH) bridges, forming a ring, inside of which a bivalent iron atom is bound. Hemoglobin is released when red blood cells are destroyed. Its breakdown starts by an opening of the tetrapyrrole ring structure at one of the methene bridges. The resulting biliverdin-iron-globin (verdohemoglobin) loses its iron and globin and becomes biliverdin, which is subsequently reduced to free or unconjugated bilirubin. This pigment, soluble in lipids but only slightly soluble in water, gives the red diazo reaction (with sodium nitrite and sulfanilic acid) of van den Bergh; however, this is possible only after special treatment of the pigment to increase its water solubility (e.g., by the addition of alcohol, caffeine, or urea). For this reason, the pigment has also been called indirect-reacting, unconjugated bilirubin (or heme bilirubin, bilirubin B, or bilirubin globin). Unconjugated bilirubin is taken up by liver cells, which conjugate it. A water-soluble bilirubin diglucuronide forms, which shows the van den Bergh reaction without pretreatment. This form has been designated as prompt (direct)- reacting bilirubin (conjugated bilirubin).

Conjugated bilirubin passes from the liver cells into the bile canaliculi and flows from there into the biliary passages. If it is retained there for protracted periods, it can be oxidized to biliverdin. Under normal conditions, conjugated bilirubin eventually reaches the intestines, where it is reduced by intestinal bacteria into several compounds, mainly the colorless mesobilirubinogen and stercobilinogen, both being designated collectively as urobilinogen. Only with the suppression of bacterial flora by antibiotics or with increased peristalsis in diarrhea does bilirubin appear in the feces. The main fecal pigment is urobilin, the intestinal oxidation product of a part of the urobilinogen compounds. Approximately one third of the urobilinogen formed from bilirubin is reabsorbed and returned by the portal bloodstream to the liver. The bulk of the reabsorbed portion is transformed back into bilirubin, completing an enterohepatic circulation.

A very small amount of urobilinogen escapes the liver and appears in the urine. Oxidizing bacteria may transform urobilinogen into urobilin either in the bladder or, more frequently, in urine that has been left standing too long before examination. One should be mindful that this type of urobilin formation may lead to erroneous diagnostic interpretations.

Although bilirubin accounts for the color of bile and serves an important function in hemoglobin metabolism and elimination, the biliary pathway also serves many other important functions. The predominant components of bile are bile acids, which are synthesized by hepatocytes and excreted via specialized receptors into the bile canaliculi to the gastrointestinal tract, where they facilitate the formation of the micelles needed for absorption of dietary fat and fat-soluble vitamins. Bile acids also have many other functions related to interactions with the intestinal epithelium. In addition, the biliary pathway is important for the transport of cholesterol to the gastrointestinal tract and elimination of lipid-soluble toxins, drugs, metals, and other substances. Many organic anions and cations are excreted in the bile, such as drugs and toxins. Other components of bile include hormones, vitamins, cytokines (such as tumor necrosis factor and leukotrienes), and divalent cations such as copper. In fact, as an important component of body copper regulation, chronic cholestasis leads to excess copper accumulation in the liver. Thus it is not surprising that Wilson disease (a copper storage disorder) is caused by the loss of function mutations in the ATPB7 gene, which regulates copper excretion from the biliary tract. In addition, bile contains albumin, lysosomal enzymes, haptoglobin, and secretory immunoglobulin A, all of which likely serve important immune functions in the gastrointestinal tract.

Primary bile acids are synthesized by bile, and secondary bile acids are the result of bacterial action by gastrointestinal bacteria. Both primary and secondary bile acids are resorbed and recycled through the liver, and only small amounts are lost in the feces. Extrahepatic obstruction or intrahepatic disorders result in cholestasis, which leads to loss of bile acids in the stool and elevates systemic bile acid levels. With cholestasis, there are decreased serum proteins and clotting factors, which can lead to weight loss and easy bruising.

Liver Biopsy

The microscopic examination of liver tissue, obtained by biopsy, is an important tool in the diagnosis of liver disease. It provides important basic information on potential causes of liver disease, as well as prognostic information based on the degree of damage and fibrosis.

Liver biopsy can be performed in several ways. Wedge specimens, obtained from the free edge of the liver during surgery (either laparoscopic or open), may be useful but may also be unsatisfactory because subcapsular fibrosis is accentuated on the free edge to the extent that an almost normal liver may appear to be cirrhotic. Specimens should be excised from the anterior aspect of the liver, or a needle biopsy of the more central parts may be obtained. The procedure is best performed at the beginning of the operation, in order to minimize the observation of misleading, nonspecific tissue alterations, particularly focal necrosis with leukocytes, which may result from the operation per se.

Liver biopsy can be performed percutaneously either blindly or with ultrasound guidance. The patient is placed in a supine position with arms above the head and legs positioned to increase the intercostal space. The liver is localized with percussion, and a suitable area in the intercostal space is identified in the midaxillary line. Localization can also be made and confirmed by ultrasound.

Multiple different needles are available but can be categorized as two types: an aspiration/suction needle, such as the Jamshidi, Menghini, or Klatskin needle, or a cutting needle, such as the Tru-Cut, Vim-Silverman, or spring-loaded automatic device. With the aspiration needles, a syringe usually containing saline is attached. After local anesthesia is placed, the needle is inserted into the subcutaneous tissue. A small amount of fluid is injected to remove tissue fragments from the needle lumen. The plunger is retracted, creating suction in the syringe, and the needle is advanced into the liver at the end of an expiration or while the breath is held in expiration. The instrument is withdrawn quickly, aspiration being maintained. The diameter of the specimen is relatively small, but not distorted, and is sufficient in diffuse hepatic diseases such as hepatitis. The technique is readily applied in small children and in other uncooperative persons. Larger specimens, thus obtained, are particularly advantageous in detecting focal lesions such as granulomas or carcinomas.

With the cutting needles, a split needle is passed through a cannula and advanced into the liver, where the beveled halves punch out a small core. The cannula is advanced over the needle, so that both halves are brought together, trapping some tissue. The entire instrument is then quickly withdrawn.

With any technique, the specimen can be extruded from the needle into a glass tube in which it can be inspected with transillumination, frequently permitting a macroscopic diagnosis. In cirrhosis, nodules can be seen, and the specimen readily breaks into small pieces. In severe cholestasis, the specimen appears green, in hemochromatosis it is brown, and granulomas or tumor metastases may be recognized as white nodules.

In addition to the percutaneous approach, liver biopsy can also be performed via a transjugular approach. This is indicated in patients with a bleeding tendency such as coagulopathy, ascites, or other disorders precluding a percutaneous approach. The theoretical advantage of a transjugular approach is that if bleeding were to occur, it would occur into the vascular space. Contraindications to liver biopsy are significant hemorrhagic tendencies, infections, and a dilated, aberrant bile duct on the surface of the liver. Further risks of lacerating the liver occur with intraperitoneal hemorrhage, bleeding from tumor tissue, and fracture of a liver containing amyloid. Additional hazards include laceration of an intercostal artery, perforation of the gallbladder or bile ducts, and pneumothorax. The most common risks are pain and bleeding, with the risk of a fatal complication at around 1 in 10,000 patients. Careful consideration of the indications for biopsy and vigilant observation of the patient following the procedure will sharply reduce the chance of dangerous complications.

Noninvasive Assessments for Hepatic Fibrosis

Accurate staging of hepatic fibrosis is important for the prediction of patient prognosis and response to treatment in liver disease. Liver biopsy is considered the gold standard for the diagnosis of pathologic conditions of the liver and the staging of fibrosis, but it has several drawbacks. It is invasive and expensive and associated with a mortality rate of approximately 0.2% for all causes. It can be inaccurate owing to sampling error from the irregular distribution of pathologic changes. Several noninvasive tests have been developed, most commonly for patients with chronic hepatitis C and nonalcoholic fatty liver disease (NAFLD); they can be divided into serum markers and imaging modalities. Testing aims to differentiate between minimal fibrosis (stage 0 to 1 out of 4) and significant fibrosis (higher than stage 2 out of 4), but up to 50% of tests will fall in the indeterminate range. A combination of serologic testing and imaging can improve accuracy. Practice guidelines have now incorporated a few noninvasive tests into the recommendations for determining the presence of advanced fibrosis, but biopsy is still typically recommended for prognosis and treatment decisions.

Imaging Studies of Liver

Over the past few decades, there have been tremendous advances in medical imaging technology which have made radiologic imaging a standard for the care of patients with liver disease. Ultrasound, CT scanning, and MRI now produce images with high resolution and are routinely used in clinical practice.

Liver Disease in Pregnancy

Normal physiologic changes occurring in pregnancy may result in altered liver function tests but are not evidence for intrinsic liver disease. With progression of pregnancy, serum albumin levels drop owing to expansion of the total body volume. Serum alkaline phosphatase levels increase because of a rise in placental alkaline phosphatase. Serum transaminases, however, are not anticipated to change with pregnancy.

Diseases of the liver that occur during pregnancy can be divided into three types: (1) liver disease that occurs only in pregnancy, (2) liver disease that can occur at any time, including during pregnancy, and (3) chronic underlying liver disease that is detected during pregnancy. Liver diseases that occur only in pregnancy are hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, liver diseases associated with preeclampsia/eclampsia (e.g., the syndrome of h emolytic anemia, e levated l iver enzymes, and l ow p latelets [HELLP syndrome]), and acute fatty liver of pregnancy.

Hyperemesis gravidarum is a condition of excessive nausea and vomiting that develops during pregnancy. This condition is not an intrinsic liver disease but can result in abnormalities of liver function. During the first trimester, liver function tests can be abnormal in some patients. Abnormalities are generally mild, but transaminase levels may occasionally be 20 to 30 times the abnormal range. Liver biopsy is usually not necessary but can show mild fatty change or no abnormality. The liver abnormalities of hyperemesis gravidarum usually resolve rapidly when dehydration and nutritional deficits are controlled.

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic liver disease that usually appears in the third trimester. It disappears abruptly after delivery but may recur with subsequent pregnancies or with use of oral contraceptives. It is characterized by the presence of pruritus (the sine qua non of this condition) and increased bile acids. Pruritus usually occurs at 28 weeks but can occur earlier. Mild liver enzyme elevations (particularly, of serum transaminases) are also noted, with mild elevations in alkaline phosphatase. Visible jaundice is unusual but can occasionally occur. Elevated bile acid levels are very diagnostic; they can vary widely, from mildly elevated levels up to levels that are 100-fold the upper limit of normal. In patients with severe pruritus accompanied by jaundice, fat malabsorption may occur with vitamin K deficiency. In a few patients, this will result an abnormal prothrombin time.

The mechanism by which ICP occurs is likely a combination of hormonal and genetic factors. Impairment of bile formation owing to the cholestatic effects of estrogen and, possibly, progesterone during pregnancy is superimposed on genetic variances in one or more hepatocyte bile transporters. Mutations of the ABCB4 (adenosine triphosphate–binding cassette, subfamily b, member 4) gene, which encodes the hepatic phospholipid transporter MDR3 (multidrug resistance 3), have been found in some patients with the disease. Mutations in other genes that regulate bile acid transport have also been noted, including ATP8B1, ABCB11 (ATP-dependent canalicular transporter for bile acids), and NRH1HA encoding the familial intrahepatic cholestasis 1 protein, and in the bile salt export pump or farnesoid X. The pathologic finding in ICP is golden yellow–brown bile pigment retained in hepatocytes and small dilated canaliculi located between pairs of hepatocytes. Inflammation and hepatocyte necrosis are generally absent, and the intrahepatic bile ducts in the portal tracks appear normal. This finding is pathognomonic of intrahepatic cholestasis of any origin and differs markedly from the pathologic findings in other unique liver disorders of pregnancy.

Pruritus can cause significant distress and morbidity in the mother. ICP is not associated with an increased rate of maternal death, but the disorder is associated with significant rates of perinatal morbidity and mortality, which appear to be correlated with levels of serum bile acids. The fetal complication rate is increased in parallel with maternal serum bile acid levels; most of the complications occur in women with bile acid levels greater than 40 µmol. The treatment of choice for IHCP is delivery of the infant; once the infant has been born, pruritus usually resolves. If the fetus is too immature to be delivered, symptomatic therapy is recommended. Ursodeoxycholic acid has been shown to improve liver function and relieve pruritus in the mother and may also benefit the fetal outcome. The bile acid binder cholestyramine has been tried but does not appear as effective as ursodeoxycholic acid. Because fetal hemorrhage has been reported in women with severe disease and vitamin K deficiency, vitamin K supplementation should be given near term to all women with jaundice or prolonged cholestasis.

Unlike hyperemesis gravidarum and ICP, HELLP syndrome and acute fatty liver of pregnancy are associated with preeclampsia. In fact, HELLP syndrome was first described as a distinct entity in a subset of women who had severe preeclampsia/eclampsia and liver disease. A rare but devastating disease, HELLP syndrome is diagnosed by a constellation of symptoms, including microangiopathic hemolytic anemia, thrombocytopenia, and elevated liver tests occurring in the third trimester. Although the pathogenesis is unknown, the relationship with preeclampsia/eclampsia suggests that this is a disease of abnormal hepatic endothelial reactivity or disruption. The initial event may be abnormal trophoblastic implantation leading to reduced tissue perfusion and endothelial dysfunction. This endothelial dysfunction is accompanied by platelet activation and aggregation. The characteristic liver lesion seen on biopsy is fibrin thrombi in the periportal sinusoids, hepatocyte necrosis, and periportal hemorrhage.

Acute fatty liver of pregnancy also has some association with preeclampsia, but it is not as strong as in HELLP syndrome. There is a strong association of acute fatty liver of pregnancy with mitochondrial long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) in the fetus. LCHAD deficiency in the fetus can cause accumulation of long-chain 3-hydroxy-fatty acyl metabolites, which are toxic to the liver. It is thought that some interaction of the accumulation in long-chain 3-hydroxy-fatty acyl metabolite with environmental stresses to the mother in the third trimester may result in sudden onset of liver failure from acute fatty liver of pregnancy. Patients often present with nonspecific symptoms, such as nausea, vomiting, and right upper quadrant or epigastric pain, associated with malaise, headache, and anorexia. Patients typically develop progressive jaundice, but pruritus is rare. Acute liver failure may ensue, with the onset of severe coagulopathy and hypoglycemia. The serum aminotransferases can be elevated 10-fold to 15-fold but are relatively unimpressive in view of other laboratory evidence of fulminant hepatic failure. Liver biopsy shows the diagnostic finding of centrilobular microvesicular fatty infiltration with little or no inflammation.

During pregnancy, acute liver disease may occur coincidentally or chronic disease may be found that predated the pregnancy. Common diseases such as viral hepatitis may occur more commonly given the risk factors present in a young female population. Some liver diseases such as gallbladder disease, herpes hepatitis, and Budd-Chiari syndrome occur more commonly in the setting of pregnancy because of the pathophysiologic changes that take place during pregnancy. Some patients may exhibit signs of liver disease during pregnancy owing to preexisting chronic liver disease. In this latter group, the ability to become pregnant depends on the severity of the liver disease; patients with more active or progressive liver disease may not be able to conceive.

In patients with preexisting liver diseases, several issues need to be addressed. First, the risk of pregnancy depends on the level of portal hypertension. Portal pressure increases with each stage of pregnancy; in patients with preexisting portal hypertension, the risk of variceal bleeding is a major cause of morbidity and mortality. Pregnancy has not been shown to aggravate quiescent autoimmune hepatitis or Wilson disease; however, it is best to have the disease under control before a woman becomes pregnant and not to stop therapy prior to or during pregnancy. In patients with viral hepatitis B, certain precautions need to be taken to decrease the risk of transmission to the fetus.

Trauma

Because of its size, location, and fixation, the liver is frequently subjected to trauma, which may be either penetrating or blunt. Next to the brain, the liver is the organ most commonly hit by blunt violence. Bullet or stab wounds penetrate to various depths and produce an intrahepatic canal with a ragged wall and a lumen filled with blood. In more than a fourth of penetrating thoracoabdominal wounds, the liver is injured. The blunt injuries lead to ruptures or lacerations varying in size and sometimes in number. They are most commonly the result of automobile accidents or of falls. The lacerations may be inflicted by broken ribs, or the organ may be crushed by the impact of the thoracic cage and the resisting spine. Internal stress or contrecoup effects during a blunt injury may lead to subcapsular or central lacerations; if the impact is slight, only a subcapsular hematoma may develop.

Rupture, as the consequence of blunt injury, is facilitated if the liver has become more friable or when the capsular tension has increased owing to abscesses, cysts, infectious diseases such as malaria or hepatitis, and fatty liver. Unlike in the spleen, so-called spontaneous rupture of a mildly damaged liver is rare. It has been claimed that postprandial hyperemia may predispose to rupture of the liver, and rupture during pregnancy has also been reported.

Except for temporary slight peritoneal irritations from blood oozing into the peritoneal cavity, subcapsular hematomas and small lacerations or ruptures usually heal with few clinical manifestations and leave a pigmented or white subcapsular scar. If the hematoma becomes infected, intrahepatic or subphrenic or subhepatic abscesses may complicate the clinical course. Hepatic cysts also may develop, as may biliary fistulae after laceration of a small bile duct. Rarer complications are portal vein thrombosis or arterial aneurysms. From a forensic point of view, it is interesting that acute hepatitis, including the fulminant variety, and even cirrhosis have been connected causally with a preceding trauma. Centrilobular necrosis may be a consequence of shock. A definite association of trauma with other diffuse hepatic diseases is, however, rather difficult to prove.

Severe laceration or rupture of the liver has a high mortality rate, more so in military than in civilian practice. Death early after the trauma is caused by hepatic hemorrhage, which is severe and does not stop readily for several reasons: the walls of the valveless hepatic veins are thin, the liver is extremely vascular, the bile admixed with the blood interferes with clotting, and the diaphragm massages the liver. During the past decade, angiographic embolization has supplanted surgery as the preferred treatment of hepatic hemorrhage in hemodynamically stable patients. Later, the effects of biliary peritonitis, following laceration of bile ducts or shock or infection, become important causes of death. Previously, the term hepatorenal syndrome was coined to describe the complication of renal failure after trauma that was thought to be a result of the toxic effect from tissue breakdown products from the liver. However, traumatized, necrotic, and even completely separated hepatic tissue has not been convincingly proved to exert a toxic effect different from that of other organs, although it must be admitted that interruption of blood flow to parts of the liver leads to rapid ischemic necrosis; if the patient survives, the area may be surrounded by a demarcation zone with fibroplasia. Completely detached liver tissue pieces are well tolerated within the peritoneal cavity and may even be organically attached in the lateral gutter.

The laboratory manifestations of hepatic trauma are surprisingly insignificant. Jaundice is rare and occurs mainly if the gallbladder and bile ducts are ruptured. In later stages, it may be the result of liver abscesses or traumatic cholangitis. Foreign bodies, such as bullets, in the liver may eventually migrate into the biliary ducts and produce obstructive jaundice.

The liver is relatively insensitive to external ionizing radiation; even the effects of internal radiation from radioactive substances accumulating in the liver (e.g., phosphorus-32) are not severe.

Jaundice in Neonatal Period

Jaundice in the first days of life is a common phenomenon. In general, the yellowish discoloration of the skin and sclera results from accumulation of unconjugated hyperbilirubinemia and is a normal physiologic event that resolves on its own. This physiologic jaundice has multiple causes, including a higher hematocrit, shorter life span of fetal blood cells, and relatively low level of conversion of bilirubin to urobilinogen by intestinal flora, resulting in higher absorption of bilirubin back into the circulation. In addition, there is low activity of the enzyme uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1), which normally converts unconjugated bilirubin to conjugated bilirubin. UGT1A1 activity in term infants at 7 days of age is approximately 1% of adults and levels do not reach adult levels until 14 weeks of age. Before birth, this enzyme is actively down-regulated because bilirubin needs to be unconjugated to cross the placenta. After birth, the enzyme gains function over time. These are slowed in preterm infants, and thus prematurity aggravates and prolongs the physiologic process of the decline of bilirubin. Severe bile stasis has been observed in the livers of such prematurely born children, as have many hematopoietic foci, but no hepatocellular degeneration has been seen, except, occasionally, in the left hepatic lobe, which quite suddenly loses its supply of oxygenated blood after interruption of the placental circulation.

The physiologic jaundice seen in infants is generally benign; if serum bilirubin levels rise excessively, however, bilirubin may accumulate in the brain and portions of the brain may have a yellowish color. This brain affliction was named kernicterus by German pathologists in the latter part of the nineteenth century. Unconjugated bilirubin is toxic to the brain and can cause brain damage if the condition is left untreated. The nuclei (Kerne) in the basal ganglia are extremely pigmented and degenerated. In some cases, the cells of the Ammon horn and, rarely, some parts of the cortex are similarly colored and in the process of disintegration. The mechanism of these cellular changes in the central nervous system and the reason for the predilection for the basal ganglion cannot be explained. Abnormal permeability of the barrier between blood and spinal fluid in early postnatal life and damage produced by anoxia, predisposing to the deposition of bile pigment, have been cited as instrumental factors. The relationship between the degree of bilirubinemia and the postmortem finding of kernicterus has been studied, with the result that the level of the indirect-reacting or nonconjugated, and therefore lipid-soluble, bilirubin seems to have a bearing on the cerebral changes, but other factors, such as immaturity, anoxia, anemia, and the duration of jaundice, also have an influence. Kernicterus develops rarely when the level of the indirect-reacting bilirubin is kept below 20 mg/dL. If untreated, the brain complications of neonatal jaundice may become clinically recognizable within the first week of life. The infant becomes drowsy, vomits, and refuses to take food. Irregularities in respiration, instability of circulation, muscular twitchings, spasticity, and opisthotonus may be observed. A certain shrillness of the baby's cry has been considered a characteristic sign, as has the appearance of an abnormal Moro reflex. The majority of children who develop kernicterus die within a short time, usually in 1 to 10 days after showing the first signs. A minority, perhaps 25% to 30%, survive, with permanent brain damage. Their mental development may be retarded, and their ability to walk is delayed or is never acquired. Speech difficulties or inadequate muscle coordination occur, and the children remain physically helpless. Untreated kernicterus is a cause of cerebral palsy. Because of this, the general recommendation is to initiate phototherapy at a certain threshold bilirubin level determined by an assessment of the risk for severe hyperbilirubinemia based on level and age. The body temperature and fluid status must be monitored, and eye patches are required. In cases of severe unconjugated hyperbilirubinemia, exchange transfusion may prevent possible kernicterus.

Unconjugated hyperbilirubinemia may occur in isoimmune-mediated hemolysis caused by ABO or Rh incompatibility. The most significant type of neonatal jaundice is associated with hemolytic disease of the newborn, also known as erythroblastosis fetali s . The cause of this condition is the presence of maternal immunoglobulin G (IgG), which crosses the placenta to react with red blood cells in the fetal circulation, resulting in hemolysis. This may occur when a mother who is Rh-negative is exposed to the erythrocytes of an Rh-positive fetus who inherited this factor from the paternal side. Fetal erythrocytes passing through the placenta elicit the formation of maternal antibodies, which, in turn, enter the fetus and destroy the red blood cells carrying the Rh blood group. Rh-negative mothers who have been pregnant before and now are pregnant with an Rh-positive infant should be given Rh immunoglobulin during pregnancy and within 48 hours after delivery to prevent sensitization. This agent works by binding any fetal red blood cells with the offending antigen before the mother is able to produce an immune response and form antibodies.

Cholestasis may be a cause of neonatal jaundice. Cholestasis in the neonatal period can result from obstruction, metabolic/genetic abnormalities, infection, and toxic insults. Obstruction can have multiple causes, including extrahepatic biliary atresia, Alagille syndrome, inspissated bile/mucous plugs, and choledochal cysts. Biliary atresia or extensive hypoplasia of the extrahepatic bile ducts is an idiopathic disease that affects the extrahepatic bile ducts, resulting in progressive jaundice within 8 weeks of birth. This results from persistence of the early temporary stage of solid-duct anlagen prior to the development of hollow channels. The fibrous cord, which may be found in place of the bile duct or parts thereof, contains no epithelium and may be so fine as to suggest complete aplasia. Obliteration occurs mostly in the lower parts of what should have developed into the common bile duct. Early recognition and surgical intervention improve the outcome in biliary atresia. Even with optimal management, the sequelae of biliary cirrhosis can occur with time, and many patients require liver transplantation for long-term treatment. In addition to extrahepatic biliary atresia, abnormalities of intrahepatic ducts can occur in Alagille syndrome. In this disease, there is a paucity of interlobular ducts associated with systemic features, such as cardiac abnormalities, butterfly vertebrae, and dysmorphic facies (the classic features in the syndrome are a broad nasal bridge, triangular facies, and deep-set eyes). Most cases of the syndrome have been associated with a JAG-1 gene mutation.

Other causes of obstruction include cystic changes of the bile ducts (choledochal cysts), gallstones, sludge, and tumors. Bile inspissation has been described in infants with cystic fibrosis.

Other causes of chronic cholestasis in infants are infections, including bacterial, protozoal, and viral infections. Commonly acquired pathogens include the TORCH group of agents, Toxoplasma gondii, rubella virus, cytomegalovirus, herpesvirus, and Treponema pallidum. Bacterial infections can also result in jaundice.

Metabolic causes include alpha-1 antitrypsin deficiency, which can present as neonatal hepatitis. Galactosemia occasionally produces jaundice in the neonatal period. Parenteral nutrition is another important cause of neonatal cholestasis that can lead to jaundice.

Congenital Malpositions of Liver

Though encountered only on very rare occasions, congenital malpositions of the liver may create diagnostic problems. Transposition of the liver, in which the large lobe and gallbladder are lying on the left side and, correspondingly, the small lobe is on the right side, is usually accompanied by transposition of other intraperitoneal organs, at least. In such instances, the pylorus lies to the left of the midline; the fundus of the stomach, descending colon and sigmoid colon, and spleen are found on the right side, and the appendix and cecum, of course, are on the left. This situation, in which the positional anomaly is restricted to the intraabdominal organs, is called partial situs inversus; in complete situs inversus, which is more common, the chest organs are transposed in the same mirror-image fashion. In such cases, the pulsation of the apex of the heart may be felt on the right side. The aortic arch and the aorta descend on the right side; the right lung has two lobes and the left three. In some cases, only the chest organs are transposed, and the abdominal organs, including the liver, are in the normal position. Absence of the normal hepatic dullness on auscultatory percussion may lead to a wrong diagnosis, particularly in gallbladder diseases, but these and other diagnostic difficulties arising from complete or partial situs inversus are readily resolved by roentgenologic examination.

The causes of situs inversus have not been established, and the explanations offered are all hypothetical. In complete situs inversus, the reversal of right to left and left to right must have been determined during the very first phases of structural organization in the embryo. Alteration of the normal rotation of the intestine has been offered as an explanation for partial situs inversus, with differences in the width of the vitelline and umbilical veins playing a determining role. Rotation of the stomach from the primitive median position to the right rather than to the left has been considered a causative factor for transposition of the liver.

Other congenital malpositions (not illustrated) include ectopia of the liver, resulting from an inherited defect of the muscles of the abdominal wall, and hepatic hernias at the umbilicus, which produce a peculiar mass near the navel. Bulging of the thin membranous part of the diaphragm into the cavity of the thorax permits herniation of part of the liver; this has characteristic radiologic findings but, nevertheless, may pose problems of differential diagnosis of intrathoracic or subdiaphragmatic masses.

Pathologic Features of Liver Injury

Liver cell injury may be brought about by nutritional deficiencies, chemical agents, lack of oxygen, viral and bacterial infections, and metabolic disturbances. Whatever the etiologic factors may be, certain similar histologic features of liver injury may be present. One of the first signs of injury that can be recognized in a morphologic sense occurs most frequently in the centrilobular zone, where cells lose their basophilism and become acidophilic or eosinophilic. A more severe degree of degeneration is characterized by variations in size and staining qualities of nuclei and cytoplasm of the neighboring liver cells. This diffuse change results in a polymorphous irregularity of the liver cell plates (disarray or unrest).

Progression of eosinophilic cytoplasmic degeneration leads to formation of acidophilic clumps around the nuclei. They are found in various types of hepatic injuries, though Mallory, describing these bodies, first considered them originally characteristic of alcoholic cirrhosis. Mallory bodies are accumulations of cytokeratin intermediate filaments inside liver cells; they are often caused by Wilson disease or cholestasis. Diffuse clumping of the cytoplasm may induce a homogeneous appearance; the nucleus becomes pyknotic and eventually disappears. The cell remnants are expelled from the liver plate and lie in the tissue spaces as acidophilic masses, or so-called Councilman bodies (named for the person who discovered similar formations in patients with yellow fever; these dead cells are also known as acidophil bodies or apoptotic bodies). The cells are present in the body for only a few hours, before they are cleaned up by Kupffer cells; their presence, therefore, suggests that liver injury is ongoing.

Another histologic expression of cell injury is hydropic swelling or balloon degeneration. The cells appear ballooned, with central but relatively small nuclei, rarefied cytoplasm, and sharp borders, an appearance that reminds one of plant cells. This is probably the result of defects in membrane and/or mitochondrial function and is common to many hepatic injuries, including alcoholic liver injury and nonalcoholic fatty liver disease.

Another manifestation of liver injury is fat accumulation in the hepatocytes or steatosis. The presence of fat, which can be microvesicular or macrovesicular, indicates some defect in lipid metabolism or lipoprotein synthesis or an increased quantity of adipose or dietary lipid brought to the liver. The most common causes of macrovesicular fat are alcohol consumption or nonalcoholic fatty liver disease. Another form of liver cell degeneration is feathery degeneration, a form of liver cell death associated with cholestasis. Cells undergoing this form of death have cytoplasm that appears flocculant, and they are larger than normal hepatocytes.