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Test Category Serum Measurement

Chapter 18 - Liver and Biliary Tract

James M. Crawford MD, PhD

The Liver

Normal

The liver and biliary tree and the gallbladder occupy the right upper quadrant of the abdomen. The liver resides between the digestive tract and the rest of the body and functions as a way

station between the splanchnic and systemic circulation. As the headwater of the biliary tree, the liver sits astride the enterohepatic circulation. The liver has the critical job of maintaining

the body's metabolic homeostasis. This includes the processing of dietary amino acids, carbohydrates, lipids, and vitamins; removal of microbes and toxins in splanchnic blood en route to

the systemic circulation; synthesis of many plasma proteins; and detoxification and excretion into bile of endogenous waste products and pollutant xenobiotics. Hepatic disorders, therefore,

have far-reaching consequences.

The mature liver lies in the right hypochondrium under the rib cage and extends from the right fifth intercostal space at the midclavicular line to just below the costal margin. It projects

slightly below the costal margin at the right intercostal line and under the xyphoid process in the midline. The conventional division of the liver into the right, left, caudate, and quadrate

lobes is a topographic classification that does not correspond to the functional lobes or segments of the liver. The physiologic or functional right and left lobes are defined by the

distribution of the right and left portal vein systems. The watershed between these two vascular beds corresponds to a plane that passes superiorly through the left side of the sulcus of the

inferior vena cava to the middle of the gallbladder fossa inferiorly. The quadrate lobe and the greater part of the caudate lobe on the posterior aspect of the liver belong functionally to the

left hemiliver. Of greater significance to the surgeon is the functional organization of the liver into eight segments, numbered I to VIII, the caudate lobe being segment I and the remainder,

II to VIII, moving roughly from left to right across the liver. Each segment has its own independent vascular and biliary pedicle and venous drainage. This anatomic arrangement facilitates

limited segmental resections of the liver as is sometimes performed for partial hepatectomy.

The normal adult liver weighs 1400 to 1600 gm, representing 2.5% of body weight. Incoming blood—approximately 25% of total cardiac output—arrives via the portal vein (60% to 70%

of hepatic blood flow) and the hepatic artery (30% to 40%) through the hilum, the "gateway" of the liver (porta hepatis). The major bile ducts exit in this same region. The initial right and

left branches of the portal vein, hepatic artery, and bile duct lie just outside the liver. The remaining branches travel in parallel within the liver in portal tracts, ramifying variably through

17 to 20 orders of branches. The vast expanse of hepatic parenchyma is serviced via approximately 450,000 terminal branches of the portal tract system. Portal vein blood enters the



parenchyma via penetrating septal venules; hepatic arteriolar twigs supply the parenchyma, the major bile ducts, the vasa vasorum of the major portal veins and hepatic veins, and the

hepatic capsule. Blood from all sources is collected into ramifications of the hepatic vein, which exits by the "back door" of the liver into the closely apposed inferior vena cava.

Microarchitecture.

Classically, the liver has been divided into 1- to 2-mm diameter hexagonal lobules oriented around the terminal tributaries of the hepatic vein (terminal hepatic veins), with portal tracts at

the periphery of the lobule. Accordingly, the hepatocytes in the vicinity of the terminal hepatic vein are called "centrilobular" (or centrolobular); those near the portal tract are "periportal."

However, since hepatocytes near the terminal hepatic veins are most remote from the blood supply, it has been argued that they are at the distal apices of roughly triangular acini, with the

bases formed by penetrating septal venules from the portal vein extending out from the portal tracts ( Fig. 18-1 ). [1] In the "acinus," the parenchyma is divided into three zones, zone 1

being closest to the vascular supply, zone 3 abutting the terminal hepatic venule, and zone 2 being intermediate. This zonation is of considerable metabolic consequence, since a lobular

gradient of activity exists for many hepatic enzymes.[2] Moreover, many forms of hepatic injury exhibit a zonal distribution. While acinar architecture is of greater physiologic significance,

the anatomic terminology of the liver remains anchored in the older lobular terminology.

The hepatic parenchyma is organized into cribiform, anastomosing sheets or "plates" of hepatocytes, seen in microscopic sections as cords of cells ( Fig. 18-2 ). Hepatocytes immediately

abutting the portal tract are referred to as the limiting plate, forming a discontinuous rim around the mesenchyme of the portal tract. There is a radial orientation of the hepatocyte cords

around the terminal hepatic vein. Hepatocytes exhibit minimal variation in overall size, but nuclei may vary in size, number, and ploidy, particularly with advancing age. Uninucleate,

diploid cells tend to be the rule, but with increasing age, a significant fraction are binucleate, and the karyotype may range up to octaploidy.

Between the cords of hepatocytes are vascular sinusoids. Blood traverses the sinusoids and exits into the terminal hepatic vein through innumerable orifices in the vein wall. Hepatocytes

are thus bathed on two sides by well-mixed portal venous and hepatic arterial blood, placing hepatocytes among the most richly perfused cells in the body. The sinusoids are lined by

fenestrated and discontinuous endothelial cells, which demarcate an extrasinusoidal space of Disse, into which protrude abundant microvilli of hepatocytes. Scattered Kupffer cells of the

mononuclear phagocyte system are attached to the luminal face of endothelial cells, and scattered fat-containing perisinusoidal stellate cells are found in the space of Disse. These stellate

cells play a role in the storage and metabolism of vitamin A and are transformed into collagen-producing myofibroblasts when there is inflammation of the liver.

Between abutting hepatocytes are bile canaliculi, which are channels 1 to 2 μm in diameter, formed by grooves in the

Figure 18-1Microscopic anatomy of the liver. The portal tract carries branches of the portal vein, hepatic artery, and bile duct system. The portal vein gives rise to branching septal veins,

which penetrate the hepatocellular parenchyma at regular intervals. Blood from the septal veins enters directly into the parenchymal sinusoids between hepatocytes. The hepatic artery

gives off capillaries that supply the bile duct system; these capillaries usually dump into the portal vein but may deposit blood directly into sinusoids. Arterioles also occasionally convey

blood directly to the sinusoids. The bile duct system gives off bile ductules, which traverse the mesenchyme of the portal tract to penetrate the parenchyma; at that point, they become

hemicircular, abutting hepatocytes (not shown) to form the canals of Hering. Bile traveling through the bile canalicular system between hepatocytes enters into the biliary tree through these

canals of Hering. Blood from the portal vein and hepatic artery travels through the sinusoids of the parenchyma toward the terminal hepatic vein, leaving the liver by this route. On the

basis of blood flow, three zones can be defined, zone 1 being the closest to the blood supply and zone 3 being the farthest. Pathologists refer to the regions of the parenchyma as "periportal,

midzonal, and centrilobular," the last term owing to the historical concept that the terminal hepatic vein was at the center of a "lobule."

Figure 18-2Photomicrograph of liver (trichrome stain). Note the blood-filled sinusoids and cords of hepatocytes; the delicate network of reticulin fibers in the subendothelial space of

Disse stains light blue.

Necrosis frequently exhibits a zonal distribution. The most obvious is necrosis of hepatocytes immediately around the terminal hepatic vein (so-called centrilobular necrosis,using the

historical terminology), an injury that is characteristic of ischemic injury and a number of drug and toxic reactions. Pure midzonaland periportal necrosisare rare; the latter may be seen

in eclampsia. With most other causes of hepatic injury, a variable mixture of hepatocellular death through the parenchyma is encountered. The hepatocyte necrosis may be limited to

scattered cells within hepatic lobules (focalor spotty necrosis) or to the interface between the periportal parenchyma and inflamed portal tracts (interface hepatitis). With more severe

inflammatory injury, necrosis of contiguous hepatocytes may span adjacent lobules in a portal-to-portal, portal-to-central, or central-to-central fashion (bridging necrosis). Necrosis of

entire lobules (submassive necrosis) or of most of the liver (massive necrosis) is usually accompanied by hepatic failure. With disseminated candidal or bacterial infection, macroscopic

abscessesmay occur.

Inflammation.Injury to the liver associated with an influx of acute or chronic inflammatory cells is termed hepatitis. Direct toxic or ischemic hepatocyte necrosis incites an

inflammatory reaction. With toxic damage, inflammation may also precede the onset of inflammation. Destruction of antigen-expressing liver cells by cytotoxic lymphocytes is a common

mechanism of liver damage, especially during viral infection. In viral hepatitis, quiescent lymphocytes may collect in the portal tracts as a reflection of mild smoldering inflammation, spill

over into the periportal parenchyma as activated lymphocytes (interface hepatitis) causing a moderately active hepatitis, or suffuse the entire parenchyma in severe hepatitis. Once killed,

apoptotic hepatocytes do not incite an inflammatory reaction per se. However, scavenger macrophages (Kupffer cells and circulating monocytes recruited to the liver) engulf the apoptotic

cell fragments within a few hours, generating clumps of inflammatory cells. Hence, identification of apoptotic hepatocytes is a sign of very recent hepatocyte destruction. Foreign bodies,

organisms, and a variety of drugs may incite a granulomatous reaction.

Regeneration.Hepatocytes have long life spans, and they proliferate in response to tissue resection or cell death (see Chapter 3 ). Regeneration occurs in all but the most

fulminant hepatic diseases. Hepatocellular proliferation is marked by mitoses, thickening of the hepatocyte cords, and some disorganization of the parenchymal structure. The canal of

Hering-bile ductule unit constitutes a reserve compartment for restitution of severe parenchymal injury; when it is activated, innumerable serpentine profiles resembling bile ductules appear

—so-called ductular reaction. This compartment also proliferates during large bile duct obstruction. When hepatocellular necrosis occurs and

leaves the connective tissue framework intact, almost perfect restitution of liver structure can occur, even when the necrosis is submassive or massive.

Fibrosis.Fibrous tissue is formed in response to inflammation or direct toxic insult to the liver. Unlike other responses, which are reversible, fibrosis points toward generally

irreversible hepatic damage. However, there is now considerable debate about the irreversibility of liver fibrosis and even cirrhosis (see below). Deposition of collagen has lasting

consequences on patterns of hepatic blood flow and perfusion of hepatocytes. In the initial stages, fibrosis may develop around portal tracts or the terminal hepatic vein or may be deposited

directly within the space of Disse. With continuing fibrosis, the liver is subdivided into nodules of proliferating hepatocytes surrounded by scar tissue, termed "cirrhosis."This

end-stage form of liver disease is discussed later in this section.

The ebb and flow of hepatic injury may be imperceptible to the patient and detectable only by abnormal laboratory tests ( Table 18-1 ). Alternatively, hepatic function may be so impaired

as to be life threatening. The major clinical consequences of liver disease are listed in Table 18-2 and are discussed next.

HEPATIC FAILURE

The most severe clinical consequence of liver disease is hepatic failure. This may be the result of sudden and massive hepatic destruction, with about 2500 new cases per year in the United

States. More often, it is the end point of progressive damage to the liver as part of chronic liver disease, either by insidious destruction of hepatocytes or by repetitive discrete

TABLE 18-1-- Laboratory Evaluation of Liver Disease

Test Category Serum Measurement

Hepatocyte integrity Cytosolic hepatocellular enzymes

••Serum aspartate aminotransferase (AST) *

••Serum alanine aminotransferase (ALT) *

••Serum lactate dehydrogenase (LDH) *

Biliary excretory function Substances normally secreted in bile

••Serum bilirubin

••••Total: unconjugated plus conjugated *

••••Direct: conjugated only *

••••Delta: covalently linked to albumin *

••Urine bilirubin *

••Serum bile acids *

Plasma membrane enzymes (from damage to bile canaliculus)

••Serum alkaline phosphatase *

••Serum g-glutamyl transpeptidase *

••Serum 5'-nucleotidase *

Hepatocyte function Proteins secreted into the blood

••Serum albumin

••Prothrombin time * (factors V, VII, X, prothrombin, fibrinogen)

Hepatocyte metabolism

••Serum ammonia *

••Aminopyrine breath test (hepatic demethylation) †

••Galactose elimination (intravenous injection) †

The most common tests are in italics.

*An elevation implicates liver disease.

†A decrease implicates liver disease.

TABLE 18-2-- Clinical Consequences of Liver Disease

Characteristic signs Hepatic dysfunction:

••Jaundice and cholestasis

••Hypoalbuminemia

••Hyperammonemia

••Hypoglycemia

••Fetor hepaticus

••Palmar erythema

••Spider angiomas

••Hypogonadism

••Gynecomastia

••Weight loss

••Muscle wasting

Portal hypertension from cirrhosis:

••Ascites

••Splenomegaly

••Hemorrhoids

••Caput medusae—abdominal skin

Life-threatening complications Hepatic failure

••Multiple organ failure

••Coagulopathy

••Hepatic encephalopathy

••Hepatorenal syndrome

Portal hypertension from cirrhosis

••Esophageal varices, risk of rupture

Malignancy with chronic disease

••Hepatocellular carcinoma

waves of parenchymal damage. Whatever the sequence, 80% to 90% of hepatic functional capacity must be eroded before hepatic failure ensues. In many cases, the balance is tipped

toward decompensation by intercurrent diseases that place demands on the liver. These include gastrointestinal bleeding, systemic infection, electrolyte disturbances, and severe stress such

as major surgery or heart failure. In most cases of severe hepatic dysfunction, liver transplantation is the only hope for survival. Overall, mortality from hepatic failure without liver

transplantation is 70% to 95%.

The morphologic alterations that cause liver failure fall into three categories:

Massive hepatic necrosis. This is most often drug- or toxin-induced, as from acetaminophen (38% of massive hepatic necrosis cases in the United States), halothane,

antituberculosis drugs (rifampin, isoniazid), antidepressant monoamine oxidase inhibitors, industrial chemicals such as carbon tetrachloride, and mushroom poisoning (Amanita

phalloides), collectively accounting for an additional 14% of cases. The mechanism may be direct toxic damage to hepatocytes (e.g., acetaminophen, carbon tetrachloride,

mushroom toxins) but more often is a variable combination of toxicity and inflammation with immune-mediated hepatocyte destruction. Hepatitis A infection accounts for 4% of

cases, hepatitis B infection accounts for 8%, and other causes (including unknown) account for 37%. Hepatitis C infection does not cause massive hepatic necrosis.

Chronic liver disease. This is the most common route to hepatic failure and is the endpoint of relentless chronic hepatitis ending in cirrhosis. The many causes of cirrhosis will be

discussed shortly.

Hepatic dysfunction without overt necrosis. Hepatocytes may be viable but unable to perform normal metabolic function, as with Reye syndrome, tetracycline toxicity, and acute

fatty liver of pregnancy.

Clinical Features.

Regardless of cause, the clinical signs of hepatic failure are much the same. Jaundice is an almost invariable finding. Hypoalbuminemia, which predisposes to peripheral edema, and

hyperammonemia, which may play a role in cerebral dysfunction, are extremely worrisome developments. Fetor hepaticus is a characteristic body odor that is variously described as

"musty" or "sweet and sour" and occurs occasionally. It is related to the formation of mercaptans by the action of gastrointestinal bacteria on the sulfur-containing amino acid methionine

and shunting of splanchnic blood from the portal into the systemic circulation (portosystemic shunting). Impaired estrogen metabolism and consequent hyperestrogenemia are the putative

causes of palmar erythema (a reflection of local vasodilatation) and spider angiomas of the skin. Each angioma is a central, pulsating, dilated arteriole from which small vessels radiate. In

the male, hyperestrogenemia also leads to hypogonadism and gynecomastia.

Hepatic failure is life-threatening because with severely impaired liver function, patients are highly susceptible to failure of multiple organ systems. Thus, respiratory failure with

pneumonia and sepsis combine with renal failure to claim the lives of many patients with hepatic failure. A coagulopathy develops, attributable to impaired hepatic synthesis of blood

clotting factors II, VII, IX, and X. The resultant bleeding tendency can lead to massive gastrointestinal bleeding as well as petechial bleeding elsewhere. Intestinal absorption of blood

places a metabolic load on the liver, which worsens the extent of hepatic failure. The outlook of full-blown hepatic failure is grave: A rapid downhill course is usual, death occurring within

weeks to a few months in about 80% of cases. A fortunate few can endure an acute episode until hepatocellular regeneration restores adequate hepatic function. Alternatively, liver

transplantation might save the patient.

Two particular complications merit separate consideration, as they herald the most grave stages of hepatic failure.

Hepatic encephalopathy is manifested by a spectrum of disturbances in consciousness, ranging from subtle behavioral abnormalities to marked confusion and stupor to deep coma and

death. These changes may progress over hours or days in fulminant hepatic failure or more insidiously in a patient with marginal hepatic function from chronic liver disease. Associated

fluctuating neurologic signs include rigidity, hyperreflexia, and particularly asterixis: nonrhythmic, rapid extension-flexion movements of the head and extremities, best seen when the

arms are held in extension with dorsiflexed wrists. Hepatic encephalopathy is regarded as a disorder of neurotransmission in the central nervous system and neuromuscular system[5] and

appears to be associated with elevated blood ammonia levels, which impair neuronal function and promote generalized brain edema. In the great majority of instances, there are only minor

morphologic changes in the brain, such as edema and an astrocytic reaction, and the encephalopathy is reversible if the underlying hepatic condition can be corrected.

Hepatorenal syndrome refers to the appearance of renal failure in patients with severe chronic liver disease, in whom there are no intrinsic morphologic or functional causes for the renal

failure. Sodium retention, impaired free-water excretion, and decreased renal perfusion and glomerular filtration rate are the main renal functional abnormalities.[6] Several factors are

involved in its development, including a decreased renal perfusion pressure due to systemic vasodilation, activation of the renal sympathetic nervous system with vasoconstriction of the

afferent renal arteriolae, and increased synthesis of renal vasoactive mediators, which further decrease glomerular filtration. Onset of this syndrome is typically heralded by a drop in urine

output, associated with rising blood urea nitrogen and creatinine. The ability to concentrate urine is retained, producing a hyperosmolar urine devoid of proteins and abnormal sediment,

and surprisingly low in sodium (unlike renal tubular necrosis). Rapid development of renal failure is usually associated with a precipitating stress factor such as infection, gastrointestinal

hemorrhage, or a major surgical procedure. Insidious development of renal failure is the result of progressive destabilization of circulatory physiology, frequently in the setting of severe

refractory ascites. The prognosis is poor, with a median survival of only 2 weeks in the rapid-onset form and 6 months with the insidious-onset form.

CIRRHOSIS

Cirrhosis is among the top 10 causes of death in the Western world. The chief worldwide contributors are alcohol abuse and viral hepatitis. Other causes include biliary disease, and iron

overload. An example of the progression to cirrhosis is given under the subsequent discussion on alcohol. Cirrhosis as the end-stage of chronic liver disease is defined by three

characteristics:

• Bridging fibrous septae in the form of delicate bands or broad scars linking portal tracts with one another and portal tracts with terminal hepatic veins

Parenchymal nodules containing proliferating hepatocytes encircled by fibrosis, with diameters varying from very small (<3 mm, micronodules) to large (several centimeters,

macronodules)

Disruption of the architecture of the entire liver

Several features of cirrhosis should be underscored:

The parenchymal injury and consequent fibrosis are diffuse, extending throughout the liver. Focal injury with scarring does not constitute cirrhosis, nor does diffuse nodular

transformation without fibrosis.

Nodularity is part of the diagnosis and reflects the balance between regenerative activity and constrictive scarring. It should be noted that rapid development of fibrosis, as in

alcoholic hepatitis, may leave little time for the development of spherical nodules.

Vascular architecture is reorganized by the parenchymal damage and scarring, with the formation of abnormal interconnections between vascular inflow and hepatic vein

outflow channels. As a result, portal vein and arterial blood partially bypasses the functional hepatocyte mass through these abnormal channels.

Fibrosis is the key feature of progressive damage to the liver. With cessation of the causal injury, slow regression of fibrosis may occur. Once cirrhosis has developed, reversal is

thought to be rare. However, the liver contains abundant metalloproteinases and collagenases that are capable of degrading extracellular matrix. Collagen degradation is a slow

process, since collagen I sustains extensive crosslinking after its deposition and hence becomes more resistant to collagenases over time. Nevertheless, there are a sufficient number

of clinical reports of patients whose full-blown cirrhosis has subsided to a form of incomplete septation of the liver or apparent absence of fibrosis, to raise

hopes that even patients with cirrhosis may improve without resorting to liver transplantation.

The only satisfactory classification of cirrhosis is based on the presumed underlying etiology. The descriptive terms "micronodular" and "macronodular" should not be used as primary

classifications. Many forms of cirrhosis (particularly alcoholic cirrhosis) are initially micronodular, but there is a tendency for nodules to increase in size with time, counterbalanced by the

constraints imposed by fibrous scarring.

The etiology of cirrhosis varies both geographically and socially. The following is the approximate frequency of etiologic categories in the Western world, most of which are discussed in

detail later:

Alcoholic liver disease 60% to 70%

Viral hepatitis 10%

Biliary diseases 5% to 10%

Primary hemochromatosis 5%

Wilson disease Rare

a1 -Antitrypsin deficiency Rare

Cryptogenic cirrhosis 10% to 15%

Infrequent types of cirrhosis also include the cirrhosis developing in infants and children with galactosemia and tyrosinosis ( Chapter 10 ), and drug-induced cirrhosis, as with a-

methyldopa. Severe fibrosis can occur in the setting of cardiac disease (sometimes called "cardiac cirrhosis," discussed later). After all the categories of cirrhosis of known causation have

been excluded, a substantial number of cases remain. Referred to as cryptogenic cirrhosis, the magnitude of this "wastebasket" category speaks eloquently to the difficulties in discerning

the many origins of cirrhosis. A growing concern is that many of these cases are due to undiagnosed nonalcoholic fatty liver disease, to be discussed. Once cirrhosis is established, it is

usually impossible to establish an etiologic diagnosis on morphologic grounds alone.

Pathogenesis.

The central pathogenetic processes in cirrhosis are progressive fibrosis and reorganization of the vascular microarchitecture of the liver.[7] In the normal liver, interstitial collagens (types I

and III) are concentrated in portal tracts and around central veins, with occasional bundles in the space of Disse. The collagen (reticulin) coursing alongside hepatocytes is composed of

delicate strands of type IV collagen in the space of Disse. In cirrhosis, types I and III collagen are deposited in the lobule, creating delicate or broad septal tracts. New vascular channels in

the septae connect the vascular structures in the portal region (hepatic arteries and portal veins) and terminal hepatic veins, shunting blood around the parenchyma. Continued deposition of

collagen in the space of Disse within preserved parenchyma is accompanied by the loss of fenestrations in the sinusoidal endothelial cells. In the process, the sinusoidal space comes to

resemble a capillary rather than a channel for exchange of solutes between hepatocytes and plasma. In particular, hepatocellular secretion of proteins (e.g., albumin, clotting factors,

lipoproteins) is greatly impaired.

The major source of excess collagen in cirrhosis is the perisinusoidal stellate cells, which lie in the space of Disse. Although normally functioning as vitamin A fat-storing cells, during the

development of cirrhosis they become activated, a process that includes (1) robust mitotic activity in areas developing new parenchymal fibrosis, (2) a shift from the resting-state lipocyte

phenotype to a transitional myofibroblast phenotype, and (3) increased capacity for synthesis and secretion of extracellular matrix. It is predominantly the cytokines secreted by activated

Kupffer cells and other inflammatory cells that stimulate perisinusoidal stellate cells to divide and to produce large amounts of extracellular matrix. Moreover, the greatest activation of

stellate cells is in areas of severe hepatocellular necrosis and inflammation. As depicted in Figure 18-3 , the stimuli for stellate cell activation may come from several sources:

• Chronic inflammation, with production of inflammatory cytokines such as tumor necrosis factor (TNF), lymphotoxin, and interleukin-1 (IL-1).

• Cytokine production by activated endogenous cells (Kupffer cells, endothelial cells, hepatocytes, and bile duct epithelial cells), including transforming growth factor-b (TGF-b),

platelet-derived growth factor (PDGF), and lipid peroxidation products.

• Disruption of the extracellular matrix, as stellate cells are extraordinarily responsive to the status of their substrate.

• Direct stimulation of stellate cells by toxins.

Acquisition of myofibers by perisinusoidal stellate cells also increases vascular resistance within the liver parenchyma, since tonic contraction of these "myofibroblasts" constricts the

sinusoidal vascular channels.

Throughout the process of liver damage and fibrosis, remaining hepatocytes are stimulated to regenerate and proliferate as spherical nodules within the confines of the fibrous septae. The

net outcome is a fibrotic, nodular liver in which delivery of blood to hepatocytes is severely compromised, as is the ability of hepatocytes to secrete substances into plasma. Disruption of

the interface between the parenchyma and portal tracts obliterates biliary channels as well. Thus, the cirrhotic patient may develop jaundice and even hepatic failure, despite having a liver

of normal mass.

Clinical Features.

All forms of cirrhosis may be clinically silent. When symptomatic they lead to nonspecific clinical manifestations: anorexia, weight loss, weakness, osteoporosis, and, in advanced disease,

frank debilitation. Incipient or overt hepatic failure may develop, usually precipitated by a superimposed metabolic load on the liver, as from systemic infection or a gastrointestinal

hemorrhage. Imbalances of pulmonary blood flow, which are poorly understood, may lead to severely impaired oxygenation (hepatopulmonary syndrome), further stressing the patient. The

ultimate mechanism of most cirrhotic deaths is (1) progressive liver failure (discussed earlier), (2) a complication related to portal hypertension, or (3) the development of hepatocellular

carcinoma.


Date: 2016-04-22; view: 727


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