Liver transplantation in newborn liver failure: treatment for neonatal hemochromatosis. Living donor liver transplantation with reduced monosegments for neonates and small infants. Neonatal liver cirrhosis without iron overload caused by gestational alloimmune liver disease. Neonatal iron overload and tissue siderosis due to gestational alloimmune liver disease. Neonatal hemochromatosis and exchange transfusion: treating the disorder as an alloimmune disease. Cholestasis is a relatively common pediatric disorder, especially in neonates, affecting approximately 1 in every 2,500 live births. Patients with cholestasis frequently progress to end-stage liver disease, often despite initial palliative treatment. The outcome of pediatric patients with cholestasis has improved dramatically with progress in understanding the pathogenesis of cholestasis and the development of therapy targeted to the molecular defect. Biliary atresia is the most common cause of neonatal cholestasis, accounting for up to 25% of the cases; genetic forms of intrahepatic cholestasis account for 25%, 1-antitrypsin deficiency accounts for 10%, other metabolic diseases account for 20%, and viral infections account for 5% of neonatal cholestasis. The goal is prompt identification of treatable disorders such as sepsis, endocrinopathies (including panhypopituitarism and congenital hypothyroidism), and specific metabolic disorders (such as galactosemia, tyrosinemia type I, and inborn errors of bile acid metabolism) to allow initiation of appropriate treatment and to prevent progression of liver damage. Cholestasis associated with severe hepatic synthetic dysfunction points to life-threatening metabolic disorders, such as tyrosinemia type 1 or neonatal iron storage disease. In infants without evidence of infection and with normal synthetic function, early evaluation of the patency of the biliary system is a high priority to recognize biliary atresia. It does not contain discussions of biliary atresia or metabolic and genetic/chromosomal disorders, which are covered elsewhere in this book. These patients may be grouped into "paucity syndromes," which may have different underlying pathological mechanisms, including congenital absence, partial failure to form, atrophy secondary to diminished bile flow, or progressive injury (secondary to immune, viral, or ischemic cause) with secondary disappearance. However, the progressive nature (segmental destructive changes or a progressive decrease in the number of bile ducts per portal tract seen in serial sectioning of biopsy specimens), from the early features of bile duct inflammation to the later observation of paucity, suggests immunological injury to existing ducts (similar to other syndromes of disappearing intrahepatic bile ducts) rather than failure of ducts to develop. Viral hepatitis in the neonate and metabolic liver disease differ from idiopathic neonatal cholestasis by the presence of an identifiable offending agent. Idiopathic neonatal cholestasis implies the existence of an unidentified pathophysiological process associated with inflammatory changes in the liver without evidence of mechanical obstruction. The presence of histological changes of pronounced giant cell transformation of hepatocytes with variable levels of inflammation of unknown etiology in this group of patients resulted in the use of idiopathic neonatal hepatitis to describe this group of patients. Despite the common use, the term implies some type of viral etiology and is best used when a specific agent is identified. Here, we will use the term idiopathic neonatal cholestasis to refer to the relatively common group of neonates with persistent cholestasis; giant cell transformation and lobular or portal inflammation; as a nonspecific response of the neonatal liver to injury. In the absence of a specific cause, idiopathic neonatal cholestasis is the only diagnosis that can be made in up to 15% of infants with prolonged neonatal cholestasis. The familial form (which probably represents a heterogeneous collection of undiagnosed or unrecognized genetic or metabolic causes) is more likely to be progressive or recurrent, whereas the nonfamilial forms have a more favorable outcome. The idiopathic category will continue to shrink with the discovery of new metabolic or genetic causes of liver disease presenting in the neonatal period. In a large series of infants in whom no cause could be found, the cholestasis was found to be transient and recovery was observed with long-term follow-up. Transient neonatal cholestasis was defined as a form of spontaneously resolving cholestasis that results from the association of several factors, including immaturity of bile secretion and perinatal disease leading to hepatic ischemia or hypoxia. Defects in these transporters involved in bile formation are known to be responsible for different types of autosomal recessive forms of familial intrahepatic cholestasis, which may have a benign course or a more progressive form that leads to end-stage cirrhosis. Emphasis is given to optimizing nutrition to maintain growth and prevent the consequences of vitamin deficiency by supplementation with fat-soluble vitamins. In both sporadic and familial forms the severe, progressive course of liver disease has been altered by liver transplantation. Before liver transplantation, however, patients with idiopathic neonatal cholestasis must be thoroughly evaluated so that specific infectious and metabolic disorders, such as 1-antitrypsin deficiency and inborn errors of bile acid metabolism, are ruled out. A close follow-up individualized to each patient is needed to establish the pace of the disease. Liver transplantation is indicated for these patients when they develop growth failure or end-stage liver disease. The frequency of neonatal cholestasis as an indication for liver transplantation varies Table 25-3). Alagille Syndrome Alagille et al described syndromic paucity of interlobular bile duct (arteriohepatic dysplasia) associated with a constellation of features, including (1) peculiar facial features (broad forehead; deeply set eyes; long, straight nose; and underdeveloped mandible) (95%), (2) chronic cholestasis (91%), (3) posterior embryotoxon (88%), (4) butterflylike vertebral arch defects (87%), and (5) peripheral pulmonary artery hypoplasia or stenosis, either isolated or associated with complex cardiovascular abnormalities (85%). Other less frequent features observed include growth retardation (50%), renal abnormalities (68%), bone abnormalities (<10%), high-pitched voice (<10%), delayed puberty (<10%), along with long bone fractures19 and other vascular malformations. Cholestasis manifests in the neonatal period, and pruritus and xanthomas become prominent during early childhood. Paucity is defined as an absence or marked reduction in the number of bile ducts in the portal triads (<0. It has been reported in successive generations of single kindreds, strongly supporting an autosomal dominant mode of inheritance, with decreased penetrance and variable expressivity. Interrelationship between the infantile cholangiopathies and paucity of the intrahepatic bile ducts. Members of the Notch gene family encode evolutionarily conserved transmembrane receptors that are involved in cell fate specification during embryonic development. Young patients usually do not develop cirrhosis; of the 80 patients in the initial Alagille series, 4 died of liver complications (2 each with liver failure and portal hypertension). Cardiac disease, hepatic disease, and intracranial bleeding account for the majority of the cases of mortality in Alagille syndrome. The prognosis of liver disease is worse in children who present with neonatal cholestatic jaundice. However, severe liver complications are possible even after late onset of liver disease. In cases of extreme, intractable pruritus, biliary diversion is a successful therapeutic option. Liver transplantation is indicated in patients with refractory debilitating pruritus and poor quality of life or when the patient develops end-stage liver disease or portal hypertension. In our experience severe osteopenia and recurrent long bone fractures was the indication for liver transplantation in a 6-year-old with Alagille syndrome. Ganschow et al reported 23 children with Alagille syndrome, 14 of whom underwent liver transplantation. Three of the 14 patients who underwent transplantation showed unexpected extrahepatic complications, such as severe bleeding (caused by intrathoracic arterial malformation) and hypoplastic aorta. Emerick et al have reported that liver transplantation for hepatic decompensation was necessary in 21% (19 of 92) of patients. The factors that contributed significantly to mortality were complex congenital heart disease (15%), intracranial bleeding (25%), and hepatic disease or hepatic transplantation (25%). The diagnosis must be established to avoid surgical procedures that will worsen the clinical course. The clinical and pathological features and natural progression vary, implying significant heterogeneity. A characteristic combination of clinical, biochemical, and histological features is often present. The evolution of molecular diagnostic testing for inherited cholestatic liver disease has provided confirmation of the diagnosis in patients with intrahepatic cholestasis, opportunity for counseling, and detection of asymptomatic siblings. At our institution the Jaundice Chip analysis is employed for the molecular diagnosis of the five most common genes associated with heritable liver disease in childhood. Some patients may have delayed clinical findings not noted until later in the first year of life. Disabling pruritus nonresponding to medical therapy is the dominant presentation in some of these patients. Patients develop progressive and persistent cholestasis with the development of cirrhosis and end-stage liver disease during the first decade of life. Although there is a marked elevation of serum bile acids and bilirubin levels, serum cholesterol levels are normal or only mildly elevated. The authors speculate that hypercholanemia and cholestasis develop because of enhanced ileal uptake of bile acids through the increased expression of the apical sodium-dependent bile acid transporter and diminished canalicular secretion of bile acids secondary to downregulation of the bile acids excretory pump. Later biopsy specimen findings demonstrate periportal fibrosis or progression to biliary cirrhosis. Proliferating ductules at the margins of portal tracts increased as fibrosis progressed and were especially prominent histologically in end-stage disease. Symptomatic treatment of pruritus is important because it is a frequent, debilitating symptom. Following diversion, the coarse granular bile changes to the normal amorphous state; this was associated with conversion of the bile salt pool to predominantly chenodeoxycholic acid and resolution of hepatic morphological and biochemical abnormalities. Steatosis was associated with diarrhea and attributed to altered bile acid enterohepatic circulation. Resin therapy was useful in controlling the diarrhea and delaying the progression of the graft steatosis. In hepatectomy and autopsy specimens, chronic hepatitis with lobular inflammation and portalportal bridging fibrosis has been found. Bile acids retained within hepatocytes cause progressive injury and, with efflux of bile salts back into the blood, a progressive increase in serum bile 25 TransplanTaTion for CholesTaTiC liver Disease in ChilDren 295 acid concentrations. Therapy is ineffective, and relatively rapid progression to cirrhosis is the rule. It is characterized by a mild and variable pruritus, moderately raised concentrations of serum bile acids, and normal concentrations of biliary primary bile acids. The absence of phospholipid would be expected to destabilize micelles and promote lithogenic bile and crystallized cholesterol-induced small bile duct obstruction. In neonates, bile duct proliferation and inflammatory infiltration dominates; portal and periportal fibrosis progressing to cirrhosis ensues at a later stage. It typically presents with transient jaundice in an infant who is otherwise healthy and progresses to biliary cirrhosis and portal hypertension. Early-onset portal hypertension and variceal hemorrhage necessitate portosystemic shunts in the majority of patients. Patients present with jaundice, pruritus, bleeding episodes, malnutrition, growth retardation, steatorrhea, thrombocytosis, osteodystrophy, and dwarfism, with death in childhood resulting from end-stage liver disease. Patients have several episodes of pronounced jaundice with intense pruritus and biochemical evidence of cholestasis, with increased serum bile acid levels and a mild increase in aminotransferase levels. Approximately 20% of patients experience their first attack by 1 year of age; other patients have the onset during adolescence or in their late 20s. A suggested care plan includes the following: · Effort to ascertain a precise diagnosis · Institution of nutritional support and vitamin supplementation · Treatment of the associated pruritus · Close follow-up Hereditary Cholestasis with Lymphedema (Aagenaes Syndrome) Hereditary cholestasis with lymphedema is a syndrome of intrahepatic cholestasis and lymphedema of the legs that was first described by Aagenaes et al91 in 1968 in 16 patients from the southwest of Norway. Jaundice is consistently present during the neonatal period through the first few years of life, with later recurrence in childhood; precipitating factors are infection, trauma, surgery, puberty, and pregnancy. Some of the patients progress to liver failure in early infancy, some experience prolonged cholestasis before the development of cirrhosis and liver failure, and some have a normal life span. Patients with chronic clinical or biochemical evidence of hepatobiliary injury later in life are at risk for developing cirrhosis. Lymphedema in the lower extremities begins in later childhood and has been attributed to lymphatic vessel hypoplasia. The relationship between the peripheral lymphatic obstruction and liver disease is uncertain. Aagenaes postulates a hepatic lymph hypoplasia or a functional defect in lymphatic flow leading to cholestasis. Cholestasis in patients with Aagenaes syndrome has not been shown to be caused by a primary defect of bile acids or other biliary constituents but might be a consequence of other factors, such as a primary defect in the lymphatic circulation. Diagnosis of a sporadic case of this syndrome has so far been impossible until lymphedema develops, which may be moderate and therefore overlooked in some cases. Lymphatic hypoplasia in the liver would probably not be observed in the histological examination, not even through electron microscopy. Lymphedema tends to become the dominant symptom of disease later in life and can be disabling in some patients. It may improve later in life and can be controlled in some patients by symptomatic treatment such as physiotherapy and wrapping of the lower extremities. Inborn errors of bile acid biosynthesis are responsible for approximately 2% of persistent cholestasis in infants. Secondary effects of impaired bile acid production are cholestasis and malabsorption of fat-soluble vitamins. Exogenous administration of bile acid can supply adequate luminal concentrations of bile acids and also inhibit the biogenesis of toxic intermediate metabolites. Early recognition allows the institution of targeted bile acid replacement, which reverses the hepatic injury. There are several known enzymatic defects in this pathway that result in a defective 25 TransplanTaTion for CholesTaTiC liver Disease in ChilDren 297 transformation of the steroid nucleus or the cholesterol side chain, with identified genes. Defects in specific enzymatic steps have been identified via testing the urine for normal and abnormal bile acids by fast atom bombardment ionization­mass spectrometry and gas chromatography­ mass spectrometry. The histological findings are variable, ranging from giant cell hepatitis to chronic hepatitis. Mass spectrometry analysis documents increased urinary bile acid excretion and the predominance of oxo-hydroxy and oxo-dihydroxy cholenoic acids. The liver biopsy specimen revealed progressive periportal hepatitis with bridging fibrosis, giant cell transformation, bile duct proliferation, and severe intralobular cholestasis. The patient subsequently died after orthotopic liver transplant at 4Ѕ months of age. Severe cholestatic jaundice caused by intrahepatic cholestasis (and not hemolysis) has also been observed in patients with acute Plasmodium falciparum infection.

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However, various techniques for monitoring end-organ perfusion are being explored and will likely be increasingly used in the years to come. Progressive Declines in Systemic Blood Pressure As blood flows through the systemic circulation, perfusion pressure decreases progressively to nearly 0 mm Hg Components of the Systemic Circulation the components of the systemic circulation are the arteries, arterioles, capillaries, venules, and veins. Resistance to blood flow in the aorta is minimal, and mean arterial pressure decreases only 3 to 5 mm Hg as blood travels into arteries as small as 3 mm in diameter. Resistance to blood flow begins to increase rapidly in small arteries, causing the mean arterial pressure to decrease to about 85 mm Hg at the beginning of the arterioles. It is in the arterioles that resistance to blood flow is the highest, accounting for about 50% of the resistance in the entire systemic circulation. At the venous end of the capillaries, the intravascular pressure has decreased to about 10 mm Hg. The decrease in systemic blood pressure from 10 m m Hg to nearly 0 mm Hg as blood traverses veins indicates that these vessels impart far more resistance to blood flow than would be expected for vessels of their large sizes. This resistance to blood flow is caused by compression of the veins by external forces that keep many of them, especially the vena cava, partially collapsed. Pulse Pressure in Arteries Pulse pressure reflects the intermittent ejection of blood into the aorta by the heart (see Table 14-3). The difference between systolic and diastolic blood pressure is the pulse pressure. Mean arterial pressure is equal to the area under the blood pressure curve divided by the duration of systole. Factors that Alter Pulse Pressure the principal factors that alter pulse pressure in the arteries are the left ventricular stroke volume, velocity of blood flow, and compliance of the arterial tree. The larger the stroke volume, the greater the volume of blood that must be accommodated in the arterial vessels with each contraction resulting in an increased pulse pressure. When systemic vascular resistance decreases, flow of blood from arteries to veins is accelerated. Pulse pressure is also increased in the presence of patent ductus arteriosus and aortic regurgitation, reflecting rapid runoff of blood into the pulmonary circulation or left ventricle, respectively. In this regard, attempts have been made to predict systemic vascular resistance by the position of the dicrotic notch relative to the diastolic pressure. A controlled study, however, failed to confirm a correlation between the position of the dicrotic notch and the calculated systemic vascular resistance. Pulse pressure is inversely proportional to the compliance (distensibility) of the arterial system. For example, with aging, the distensibility of the arterial walls often decreases (elastic and muscular tissues are replaced by fibrous tissue) and pulse pressure increases. Transmission of the Pulse Pressure There is often enhancement of the pulse pressure as the pressure wave is transmitted peripherally. Specifically, when a pulsatile pressure wave enters the peripheral arteries and distends them, the pressure on these peripheral arteries causes the pulse 200 140 120 100 80 60 0 0. If the returning pulse wave strikes an oncoming wave, the two summate, causing a much higher pressure than would otherwise occur. These changes in the contour of the pulse wave are most pronounced in young patients, whereas in elderly patients with less compliant arteries, the pulse wave may be transmitted virtually unchanged from the aorta to peripheral arteries. Augmentation of the peripheral pulse pressure must be identified whenever systemic blood pressure measurements are made in peripheral arteries. For example, systolic pressure in the radial artery is sometimes as much as 20% to 30% higher than that pressure present in the central aorta, and diastolic pressure is often decreased as much as 10% to 15%. Mean arterial pressures are similar regardless of the site of blood pressure measurement in a peripheral artery. Pulse pressure becomes progressively less as blood passes through small arteries and arterioles until it becomes almost absent in capillaries. Furthermore, resistance to blood flow in these small vessels is such that fl w of blood and, consequently, the transmission of pressure are greatly impeded. Systemic Blood Pressure Measurement during and after Cardiopulmonary Bypass Reversal of the usual relationship between aortic and radial artery blood pressures can occur during the late period of hypothermic cardiopulmonary bypass and in the early period after termination of cardiopulmonary bypass. Systemic blood pressure measured in the brachial artery is more accurate and reliable during the periods surrounding cardiopulmonary bypass, which are most likely to be associated with disparities between the aortic and radial artery blood pressures. During normal inspiration, the decrease in intrathoracic pressure increases the compliance of the pulmonary vasculature, which leads to a relative decrease in pulmonary venous return to the left ventricle. The resultant reduction in left ventricular preload decreases the stroke volume, which manifests as a mildly decreased systolic blood pressure during inspiration (,10 mm Hg). Cardiac tamponade causes an exaggeration of this change in blood pressure with respiration. Pulsus Alternans Pulsus alternans is alternating weak and strong cardiac contractions causing a similar alteration in the strength of the peripheral pulse. Digitalis toxicity, varying degrees of atrioventricular heart block, and left ventricular dysfunction are commonly associated with pulsus alternans. In the setting of left ventricular dysfunction, pulsus alternans is caused by cyclic alterations in the contractile state of the heart. A reduced stroke volume increases end diastolic volume, which results in increased myocardial contraction and therefore increased ventricular emptying and blood pressure (per the Frank-Starling law). During the subsequent cardiac cycle, the lower filling pressures in the left ventricle result in a decreased stroke volume and therefore decreased ventricular emptying and blood pressure. This electrocardiographic fi ding is seen in cardiac tamponade and pericardial effusion, where the heart essentially moves within the fluid-filled pericardial sac during contraction. Pulse Deficit In the presence of atrial fibrillation or ectopic ventricular beats, two beats of the heart may occur so close together that the ventricle does not fill adequately and the second cardiac contraction ejects an insufficient volume of blood to create a peripheral pulse. Conversely, others describe the appearance of this gradient with initiation of cardiopulmonary bypass, suggesting that the etiology is associated with events such as cross-clamping of the aorta occurring during initiation of cardiopulmonary bypass rather than rewarming or discontinuing cardiopulmonary bypass. Differences between aortic and radial artery pressure associated with cardiopulmonary bypass. These tapping sounds occur because flow velocity through the constricted portion of the blood vessel is increased, resulting in turbulence and vibrations that are heard through the stethoscope. Right Atrial Pressure Right atrial pressure is regulated by a balance between venous return and the ability of the right ventricle to eject blood. Normal right atrial pressure is about 5 mm Hg, with a lower limit of about 25 mm Hg, which corresponds to the pressure in the pericardial and intrapleural spaces that surround the heart. Right atrial pressure approaches these low values when right ventricular contractility is increased or venous return to the heart is decreased by hemorrhage. Poor right ventricular contractility or any event that increases venous return (hypervolemia, venoconstriction) tends to increase right atrial pressure. Veins coursing through the abdomen are compressed by intraabdominal pressure, which may increase 15 to 20 mm Hg as a result of pregnancy or ascites. It is important to recognize that veins inside the thorax are not collapsed because of the distending effect of negative intrathoracic pressure. Varicose Veins Valves of the venous system can be destroyed when the veins are chronically distended by increased venous pressure as occurs during pregnancy or in an individual who stands most of the day. The end result is varicose veins characterized by bulbous protrusions of the veins beneath the skin of the legs. Reference Level for Measuring Venous Pressure Hydrostatic pressure does not alter venous or arterial pressures that are measured at the level of the tricuspid valve. As a result, the reference point for pressure measurement is considered to be the level of the tricuspid valve. An appropriate external reference point for the level of the tricuspid valve in a supine individual is 5 cm posterior to the sternum at the level of the 4th intercostal space. A precise hydrostatic point to which pressures are referenced is essential for accurate interpretation of venous pressure measurements. The potential error introduced by measuring pressures above or below the tricuspid valve is greatest with venous pressures that are normally low. The reason for lack of hydrostatic effects at the tricuspid valve is the ability of the right ventricle to act as a regulator of pressure at this site. For example, if the pressure at the tricuspid valve increases, the right ventricle fills to a greater extent, thereby decreasing the pressure at the tricuspid valve toward normal. Conversely, if the pressure decreases at the tricuspid valve, the right ventricle does not fill optimally and blood pools in the veins until pressure at the tricuspid valve again increases to a normal value. For example, in a standing human, pressure in the veins of the feet is 90 mm Hg because of the distance from the heart to the feet. Conversely, veins above the heart tend to collapse, with the exception being veins inside the skull, where they are held open by surrounding bone. Hydrostatic pressure affects peripheral pressure in arteries and capillaries as well as veins. Venous Valves and the Pump Mechanism Valves in veins are arranged so that the direction of blood flow can be only toward the heart. In a standing human, movement of the legs compresses skeletal muscles and veins so blood is directed toward the heart. This venous pump or skeletal muscle pump is usually sufficient to maintain venous pressure below 25 mm Hg in a walking human. As a result, pressures in the veins and capillaries of the legs can increase rapidly, resulting in leakage of fluid from the intravascular space. Indeed, as much as 15% of the blood volume can be lost from the intravascular space in the first 15 minutes of quiet standing. The percentage of blood comprising erythrocytes is the hematocrit, which to a large extent determines the viscosity of blood. Viscosity exerts fewer effects on blood flow in capillaries than in larger vessels. This most likely reflects alignment of erythrocytes as they pass through small blood vessels rather than the random arrangement characteristic of fl w through larger vessels. The net effect may be that viscous effects in small blood vessels are similar to those that occur in large blood vessels. Plasma is considered extracellular fluid that is identical to interstitial fluid except for the greater concentrations of proteins (albumin, globulin, fibrinogen) in plasma. These greater concentrations reflect the inability of plasma proteins to pass easily through capillaries into the interstitial spaces. Rearrangement of this formula emphasizes that pressure is directly proportional to flow times resistance. Likewise, resistance is directly proportional to pressure and inversely proportional to flow. It is important to understand that resistance to blood flow cannot be measured but rather is a calculated value based on measurement of driving pressures and the cardiac output. For example, systemic vascular resistance is calculated as the difference between mean arterial pressure and right atrial pressure divided by cardiac output. Pulmonary vascular resistance is calculated as the difference between mean pulmonary artery pressure and left atrial pressure divided by the cardiac output. Conductance is the reciprocal of resistance and is a measure of the amount of blood flow that can pass through a blood vessel in a given time for a given pressure gradient. Vascular Distensibility Blood vessels are distensible such that increases in systemic blood pressure cause the vascular diameter to increase, which in turn decreases resistance to blood flow. The ability of blood vessels to distend as intravascular pressure increases varies greatly in different parts of the circulation. Systemic blood pressure can eventually decrease to a level where intravascular pressure is no longer capable of keeping the vessel open. Vascular Compliance Vascular compliance is defi ed as the increase in volume (capacitance) of a vessel produced by an increase in intra- Determinants of Tissue Blood Flow Tissue blood flow is directly proportional to the pressure difference between two points (not absolute pressure) and inversely proportional to resistance to flow through the vessel. The compliance of the entire circulatory system is estimated to be 100 mL f or each 1 mm Hg increase in intravascular pressure. For example, the volume of blood normally present in all veins is about 2,500 mL, whereas the arterial system contains only about 750 mL of blood when the mean arterial pressure is 100 mm Hg. Sympathetic nervous system activity can greatly alter the distribution of blood volume. Enhancement of sympathetic nervous outflow to the blood vessels, especially the veins, decreases the dimensions to the circulatory system, and the circulation continues to function almost normally even when as much as 25% of the total blood volume has been lost. Vasoconstriction or vasodilation refers to resistance changes in arterioles, whereas changes in the caliber of veins are described as venoconstriction or venodilation. Autoregulation of Blood Flow Autoregulation is a local mechanism that controls blood flow in which a specific tissue is able to maintain a relatively constant blood flow over a wide range of mean arterial pressures. When the mean arterial pressure increases, the associated increase in tissue blood flow causes the blood vessels to constrict, thereby limiting any increase in blood flow. Conversely, decreases in mean arterial pressure result in vasodilation, which maintains tissue blood fl w. Autoregulatory responses to sudden changes in mean arterial pressure occur within 60 to 120 seconds. The ability of autoregulation to return local tissue blood flow to normal is incomplete. For example, sustained increases in mean arterial pressure to specific tissues, as occurs above a coarctation of the aorta, is accompanied by a decrease in the size and number of blood vessels. Likewise, if metabolism in a tissue becomes chronically increased, vascularity increases, or, if metabolism is decreased, vascularity decreases. There may be so much overgrowth that the new vessels cause blindness (retrolental fibroplasia). Autonomic Nervous System Control of Blood Flow Autonomic nervous system control of blood flow is characterized by a rapid response time (within 1 second) and an ability to regulate blood flow to certain tissues at the expense of other tissues. The sympathetic nervous system is the most important component of the autonomic nervous system in the regulation of blood flow; sympathetic stimulation causes release of norepinephrine, which stimulates a-adrenergic receptors to produce vasoconstriction. Constriction of small arteries influences resistance to blood fl w through tissues, whereas venoconstriction alters vascular capacitance and distribution of blood in the peripheral circulation. Sympathetic nervous system innervation is prominent in the kidneys and skin and minimal in the cerebral circulation. Vasomotor Center the vasomotor center, which is located in the pons and medulla, transmits sympathetic nervous system impulses through the spinal cord to all blood vessels.

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After a combined renal/liver transplant the patient was weaned off protein C concentrate by 2 weeks after transplant, when plasma protein C activity was maintained at greater than 70%. Follow-up 1 year after transplantation demonstrated normal protein C activity and graft function. Normal protein C activity and antigen and excellent graft function continued 8 years after transplantation. Worsening hepatic injury may further decrease ferrochelatase activity, creating a vicious cycle that promotes progressive hepatic failure. Phototoxic burns on the abdomen and viscera resulting from intense light exposure during surgery are caused by exposure of protoporphyrin to ultraviolet light and can result in biliary fistula, intestinal perforation, and even death. It is not uncommon for porphyrins to accumulate in the liver allograft, sometimes leading to fulminant allograft failure. The effect that hematin has on hepatic disease is still unclear, but a decrease in postadministration plasma protoporphyrin levels has been correlated with increased excretion in feces and urine. Reduction in the size of hemangiomas has been observed with antiangiogenic agents interferon alpha2115,123 and bevacizumab,124 corticosteroids, and cyclophosphamide,125 but no randomized, controlled trials have been conducted. Intraoperative blood loss is high, mean 12 L, and the large size of the hemangioma and the native liver present additional technical challenges. Arterial ligation before mobilization of the liver can be helpful in reducing the hemangioma size. Giant hepatic hemangiomas can cause compressive symptoms and consumptive coagulopathy because of platelet sequestration, clotting, and fibrinolysis within the hemangioma. Underlying Defect Almost completely corrected Probably not corrected Correction of factor deficiency to variable degree Completely corrected Not corrected Partial correction (liver but not other tissues) Completely corrected if hemangiomas primarily in liver Transplantation of defective liver Clinical Result Stabilization or improvement in organ function if further amyloid deposition prevented Immediate correction of hepatic failure Hepatic failure corrected Prevention of spontaneous bleeding Thrombophilia cured, no need for anticoagulation Hepatic failure corrected Resolution of hepatic failure Resolution of compressive hepatic symptoms, coagulopathy Induction of thrombophilia or hemophilia Potential Problems Cardiac and other organ function may not improve (deposition of wild-type transthyretin) Reaccumulation of tissue iron May still require factor for surgical procedures Recurrent viral hepatitis Risk for vascular complications Likely will require ongoing antithrombotic therapy Possible phototoxic injury (neuropathy) during surgery Recurrent disease Perioperative bleeding and coagulopathy Rare occurrence hepatic vessel thrombosis is low. Acquired protein S deficiency138 and combined protein C deficiency and dysfibrinogenemia139 resulting in thrombosis have also been reported. This treatment is appropriate for hereditary hemochromatosis with advanced liver disease, but it may not alleviate iron-related damage in other organs or the underlying genetic defect. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Changes in renal function in patients with familial amyloid polyneuropathy treated with orthotopic liver transplantation. Peripheral nerves regenerated in familial amyloid polyneuropathy after liver transplantation. Deposition and passage of transthyretin through the blood-nerve barrier in recipients of familial amyloid polyneuropathy livers. Systemic but asymptomatic transthyretin amyloidosis 8 years after domino liver transplantation. Iatrogenic amyloid neuropathy in a Japanese patient after sequential liver transplantation. Clinical symptomatic de novo systemic transthyretin amyloidosis 9 years after domino liver transplantation. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Identification of amyloid prealbumin variant in familial amyloidotic polyneuropathy (Japanese type). Presence of an abnormal transthyretin (prealbumin) in Portuguese patients with familial amyloidotic polyneuropathy. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation: a prospective cohort study in men in eastern Finland. An analysis of liver transplant experience from 37 transplant centers as reported to Medicare. Liver transplantation in patients with hepatic iron overload: favorable or unfavorable outcome? Liver allograft iron accumulation in patients with and without pretransplantation hepatic hemosiderosis. Increased hepatic iron and cirrhosis: no evidence for an adverse effect on patient outcome following liver transplantation. A 58-year-old man with hemophilia, hepatocellular carcinoma, and intractable bleeding. Successful treatment of homozygous protein C deficiency by hepatic transplantation. En bloc heterotopic auxiliary liver and bilateral renal transplant in a patient with homozygous protein C deficiency. Long-term survival of a child with homozygous protein C deficiency successfully treated with living donor liver transplantation. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Successful liver transplantation in a patient with Budd-Chiari syndrome caused by homozygous factor V Leiden. Liver transplantation for acute Budd-Chiari syndrome in identical twin sisters with Factor V Leiden mutation. Liver transplantation in a patient with Budd-Chiari syndrome secondary to factor V Leiden mutation. Acute Budd-Chiari syndrome treated by liver transplantation in a woman homozygous for factor V Leiden. Acute Budd-Chiari syndrome with fulminant hepatic failure in a pregnant woman with factor V Leiden mutation. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management. Liver transplantation for Budd-Chiari syndrome: A European study on 248 patients from 51 centres. Eighteen years of liver transplantation experience in patients with advanced Budd-Chiari syndrome. Vascular liver disorders (I): diagnosis, treatment and prognosis of Budd-Chiari syndrome. Multiple-electrode radiofrequency ablation of symptomatic hepatic cavernous hemangioma. Symptomatic-enlarging hepatic hemangiomas are effectively treated by percutaneous ultrasonography-guided radiofrequency ablation. Successful treatment of skeletal hemangioma and Kasabach-Merritt syndrome with aminocaproic acid. Treatment of severe coagulopathy in the Kasabach-Merritt syndrome with aminocaproic acid and cryoprecipitate. Living donor liver transplantation in a patient with giant hepatic hemangioma complicated by Kasabach-Merritt syndrome: report of a case. Treatment of a giant haemangioma of the liver with Kasabach-Merritt syndrome by orthotopic liver transplant a case report. Living donor liver transplantation for giant hepatic hemangioma with KasabachMerritt syndrome with a posterior segment graft. Orthotopic liver transplantation in a patient with a giant cavernous hemangioma of the liver and Kasabach-Merritt syndrome. Giant hepatic hemangioma with Kasabach-Merritt syndrome: is the appropriate treatment enucleation or liver transplantation? New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care. Autosomal recessive erythropoietic protoporphyria: a syndrome of severe photosensitivity and liver failure. Erythropoietic protoporphyria: evidence for multiple sites of excess protoporphyrin formation. Hemolytic anemia in protoporphyria: possible precipitating role of liver failure and photic stress. Evidence that hepatic crystalline deposits in a patient with protoporphyria are composed of protoporphyrin. Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation. The effect of liver transplantation in a 13-year-old boy with erythropoietic protoporphyria. Erythropoietic protoporphyria: unusual skin and neurological problems after liver transplantation. Photosensitivity and perioperative polyneuropathy complicating orthotopic liver transplantation in a patient with erythropoietic protoporphyria. Effect of hematin administration to patients with protoporphyria and liver disease. The value of intravenous heme-albumin and plasmapheresis in reducing postoperative complications of orthotopic liver transplantation for erythropoietic protoporphyria. Repression by hematin of porphyrin biosynthesis in erythrocyte precursors in congenital erythropoietic porphyria. Benefits of chronic plasmapheresis and intravenous heme-albumin in erythropoietic protoporphyria after orthotopic liver transplantation. Long-term cure of the photosensitivity of murine erythropoietic protoporphyria by preselective gene therapy. Gene therapy of a mouse model of protoporphyria with a self-inactivating erythroid-specific lentiviral vector without preselection. Acquired protein S deficiency with multiple thrombotic complications after orthotopic liver transplant. Heterozygous protein C deficiency and dysfibrinogenemia acquired by liver transplantation. The venous occlusion is usually thrombotic and occurs at the level of the major hepatic veins or the inferior vena cava at any point proximal to the right atrium. Histologically there is centrolobular congestion, sinusoidal dilatation, hepatocyte necrosis, and varying degrees of fibrosis. The clinical presentation depends on the tempo and extent of hepatic vein occlusion. As recently as 1996 it was stated that "as many as 70% of patients with occlusion of the hepatic veins may not have a primary detectable cause. Because these mechanisms have important bearing on long-term patient management and outcome, it is important to identify the specific cause responsible for hepatic vein occlusion in individual patients. In India and other parts of Asia, many cases are idiopathic or caused by vena cava webs. Hepatic vein obstruction because of hepatocellular carcinoma is common in South Africa. In Asian countries the common finding is a membranous web in the inferior vena cava, specifically at the suprahepatic region, resulting in progressive thrombosis of the inferior vena cava and the liver ostia. The weight of the clinical evidence now indicates that the primary process is thrombotic rather than inflammatory. Centrilobular extravasation of red cells and necrosis can extend to the periphery of the lobules; however, the portal areas are preserved. The principal cause of this disease is continuous exposure to hepatotoxic pyrrolizidine alkaloids. B, Sagittal gray-scale ultrasonographic image demonstrates coarse echotexture of the hepatic parenchyma with no visualization of the intrahepatic inferior vena cava. C, Sagittal gray-scale ultrasonographic image demonstrates the presence of the transjugular intrahepatic portosystemic shunt in a patient with Budd-Chiari syndrome. Splenomegaly and an enlarged caudate lobe (palpable epigastric mass) are frequent additional findings. Patients with occlusion of the inferior vena cava have lower extremity edema, distended abdominal flank and back veins, and albuminuria. Sudden-onset upper abdominal pain with vomiting and rapid accumulation of ascites with an enlarged, tender liver are less common and are associated with acute onset of disease. Only rarely will these patients experience fulminant liver failure, which is characterized by massive liver necrosis and consequent liver coma, severe coagulopathy, and hypoglycemia. Fatigue and poor nutritional status are common; however, spider angiomas and palmar erythema are unusual, and jaundice is usually mild. A common physical finding is lower extremity edema resulting from partial or complete occlusion of the retrohepatic vena cava by the hypertrophied caudate lobe. Caval obstruction may decrease kidney perfusion pressure, thereby contributing to the development of kidney failure. Despite severe portal hypertension in this patient population, variceal bleeding is uncommon. Serum transaminase, bilirubin, and alkaline phosphatase levels are normal or mildly elevated. Serum albumin level may be decreased, and albumin levels correlate well with the severity of liver injury and the magnitude of protein loss into ascitic fluid. Liver biopsy typically demonstrates intense centrilobular congestion and pressure necrosis of the liver parenchyma. Often ultrasonography is the initial imaging modality in patients being evaluated for hepatic venoocclusive disease. Notice the splenomegaly, ascites, and altered hepatic morphologic structures typical of Budd-Chiari syndrome. In the preoperative evaluation, specific flow-sensitive sequences are often employed to evaluate splenoportal morphological features and hepatovenous morphological characteristics. Although not routinely necessary, magnetic resonance cholangiopancreatography may be added to preoperative protocols in those patients who are suspected of harboring biliary pathological conditions. Hepatic venography also allows measurement of the hepatic wedge pressure, and inferior venacavography can be performed during the same catheterization in the rare occasion shunt surgery is contemplated.

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These cascades converge with the activation of apoptotic proteins (Bax, Bim, Bad, Bid) and inhibition of antiapoptotic proteins (Bcl-2, Bcl-xL), which results in mitochondrial permeabilization. The intracellular portion contains "death domains" that recruit adaptor proteins leading to the activation of caspase 8 and cleavage of Bid, which then translocates to mitochondria and leads to mitochondrial permeabilization. In addition to lymphocytes, hepatocytes also appear to be capable of expressing FasL in certain situations. A physiological role for Fas in liver homeostasis is suggested by the observation that mice genetically deficient in Fas develop, among other abnormalities, significant liver hyperplasia. Also, mice deficient in the proapoptotic protein Bid (Bid-/-) treated with agonistic Fas antibody are resistant to apoptosis and fulminant liver failure. Fas expression has been demonstrated on murine endothelial cells, stellate cells, and cholangiocytes. Knocking down expression of Fas in this fashion largely protected mice against an otherwise lethal challenge with either an apoptosis-inducing anti-Fas antibody, or concanavalin A, which causes immune-mediated liver damage. The intrinsic pathway of liver cell death is mediated through intracellular stress on organelles. These proteins (Bax and Bak), either in isolation or together, insert into the outer mitochondrial membrane, forming pores. Interestingly, in mice with conditional deletion of either Bcl-xL or Mcl-1 in the liver produces a phenotype characterized by chronic liver damage and liver fibrosis. These mice show widespread activation of caspases, hepatocyte apoptosis, and elevated serum aminotransferase levels. The lysosomal/ endosomal compartment comprises single membranebound, cytosolic organelles responsible for degradation and recycling of cellular components. Under physiological stress, lysosomes undergo selective permeabilization and release of the contents. The lysosomal enzymes known as cathepsins play a major role in the execution of the apoptotic cell death these proteases can activate apoptosis either by cooperating with caspases or via caspase-independent mechanisms. The apoptotic pathway for lysosomes acts upstream of the mitochondria, and several lines of evidence show the involvement of Bax, Bim, Mcl-1, and Bid in lysosomal permeabilization in different models of liver injury. Bid is cleaved and activated by a number of cathepsins; cysteine cathepsins also cleave the antiapoptotic Bcl-2, Bcl-xL, and Mcl-1, and Bax is a substrate for cathepsin D. This stress is emerging as a potential cause of damage in hypoxia and ischemia-reperfusion injury. Interferon-, a proinflammatory cytokine involved in macrophage and T-lymphocyte activation, mediates liver cell injury in a mouse model of hepatitis B. It is only in the rare situations, when these mechanisms are critically impaired or have been overwhelmed, that clinically overt liver failure becomes manifest. The majority of individuals have compensated cirrhosis, in which liver biopsy results demonstrate cirrhosis, but patients exhibit no symptoms or signs of liver disease, and their test results show that liver synthetic function is intact. Diagnosis of asymptomatic cirrhosis is usually made when incidental screening tests such as determination of liver transaminase levels or radiological findings suggest liver disease. Compensated cirrhosis, however, can progress, eventually compromising hepatocyte function and hepatic circulation. If cirrhosis becomes sufficiently severe, liver failure and portal hypertension can occur. The first signs of advanced cirrhosis are commonly laboratory test result abnormalities, which can include thrombocytopenia, prolonged prothrombin time, hyperbilirubinemia, or hypoalbuminemia. When cirrhosis causes hepatic decompensation, any or all of a number of clinical manifestations can occur (see Table 3-1). Advances have been made in prevention and treatment of the common complications of cirrhosis such as variceal bleeding, ascites, spontaneous bacterial peritonitis, and encephalopathy. Alcoholism is reported to contribute to 40% to 90% of cases of cirrhosis in North America and Europe. One hundred million persons around the world are chronically infected with hepatitis C, with approximately 4 million cases in the United States. Of those with hepatitis C, 15% to 20% of livers are believed to progress to cirrhosis. Currently approximately 60% of those receiving liver transplants are chronically infected with hepatitis C. Because space constraints permit us to provide only an overview, the reader is directed to a number of excellent reviews for a deeper examination of the pathogenesis of cirrhosis. In the discussion to follow, primary references are provided for data that are not already found in these comprehensive review articles. Ultimately, hepatic fibrosis leads to cirrhosis, associated with nodule formation and organ contraction. Cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury. The resultant vascular distortion leads to shunting of the portal and arterial blood supply, compromising exchange between hepatic sinusoids and the adjacent hepatocytes. If sufficiently severe, fibrosis can result in compromised hepatocyte function and is responsible for nearly all the complications of end-stage liver disease, including portal hypertension, ascites, encephalopathy, synthetic dysfunction, and impaired metabolic capacity. Despite the source of injury, the alterations in hepatic structure and function associated with cirrhosis are similar, which indicates that the general mechanisms underlying fibrosis of the liver are shared. Hepatic myofibroblasts are not present in the normal liver but transdifferentiate from heterogeneous cell populations in response to a variety of fibrogenic stimuli. Currently the origin of hepatic myofibroblasts remains under debate; however, Etiology Nearly all causes of chronic liver injury can produce fibrosis and lead to the development of cirrhosis (see Table 3-2). Alcoholic liver disease and hepatitis C are the most common causes in developed countries, whereas hepatitis B is the prevailing cause worldwide. Cirrhosis will develop in 25% to 33% of the estimated 400 million individuals chronically infected with hepatitis B throughout the world. These different cellular pools reflect differing contributions to fibrosis, disease progression, and likely different causes. A key attribute of this cell type is that it displays prominent cytosolic vesicles in which retinoids, primarily vitamin A, are stored. In addition, stellate cells release soluble growth factors, cytokines, and peptides that contribute to liver cell development, differentiation, and survival. Thus, under normal conditions, stellate cells store vitamin A, support the homeostasis of hepatocytes and the endothelium, and may contribute to regulation of the microcirculation. The stellate cell occupies the perisinusoidal space between the hepatocytes and sinusoidal endothelial cells. Portal fibroblasts appear to be especially important in cholestatic liver diseases and ischemia. Myofibroblasts derived from portal cells have a distinct phenotypic expression pattern, and the markers have been used experimentally to differentiate this population of cells. Immunohistochemical studies using these specific markers demonstrate that portal fibroblasts contribute to myofibroblasts in cholestatic liver injury. They differ from hematopoietic stem cells in that they do not express hematopoietic markers. The stellate cell responses facilitate parenchymal restitution after an acute hepatic insult. In this way the wound-repair response is terminated once injury has resolved and tissue healing has been accomplished. However, if liver injury persists, hepatic myofibroblasts are also recruited to affected sites. Whether normal healing or fibrosis occurs depends on the location, duration, and intensity of the injury response. Understanding the mechanism of hepatic fibrosis and potential therapeutic approaches. During the initiation phase, early changes in gene expression and phenotype allow the cells to become responsive to cytokines and other stimuli. Initiation is primarily the result of paracrine stimulation, due to changes in the surrounding milieu. Once the cell is primed for activation, perpetuation ensues as a continuous and dynamic process. During this phase autocrine and paracrine stimulation enhance growth factor expression and amplify the activated phenotype and generate fibrosis. Several phenotypic changes occur during this phase, including proliferation, contractility, fibrogenesis, matrix degradation, retinoid loss, chemotaxis, and inflammatory cell infiltration. With time, this sustained wound-healing response results in the development of fibrosis and subsequently cirrhosis. In other words, fibrosis occurs when the net balance of injury-induced signaling is tipped toward the woundhealing response for too long. Fibrosis Results From a Complex Cascade in Interconnected Signaling Events Current knowledge is insufficient to provide a complete picture of the pathogenesis of fibrosis. However, a plethora of studies over the past 2 decades provides a glimpse into the intricate signaling pathways that govern the wound-healing response. Much of this research has depended on well-characterized stellate cell and hepatic myofibroblast culture models. The relevance of this work is not entirely certain, but key elements have been validated by animal and human studies of liver injury. During injury the behavior of stellate cells is regulated by paracrine interactions with damaged hepatocytes and endothelial cells; activated platelets, Kupffer cells, and infiltrating leukocytes; and other stellate cells and hepatic myofibroblasts. The effects of these injury-associated extracellular mediators are primarily transduced by plasma membrane receptors. These receptors in turn act through intracellular signaling pathways that control protein expression or directly regulate the physical behavior of stellate cells and hepatic myofibroblasts. It has become clear that no single mediator or signaling pathway is sufficient to trigger hepatic fibrosis. Moreover, the functional consequence of any given mediator or signaling pathway is not stereotypical, but depends on the timing and subcellular localization of the signal, as well as crosstalk from other pathways. The emerging model for wound healing in the liver is one in which diverse stimuli orchestrate the activation and inhibition of multiple interconnected signal transduction pathways that regulate distinct cellular responses. During liver injury, expression of this growth factor and its cognate receptor are highest in areas of greatest damage. This cytokine, which is produced by Kupffer cells, platelets, and sinusoidal endothelial cells in response to injury, is derived from both paracrine and autocrine sources. These findings suggest that stellate cells contain most, if not all, of the molecules necessary to either activate or inhibit metalloproteinases. It is uncertain whether this phenomenon has physiological importance or is simply a technical artifact. Sinusoidal endothelial cells and fibrogenic cells secrete this peptide in response to hepatic injury. Evidence also suggests that alterations in the tension generated by stellate cells, which encircle the sinusoids, modulates hepatic blood flow. The role that this peptide plays in the regulation of proliferation is more complex. All of these other injury mediators also have pleiotropic effects that are mediated by signal transduction pathways that work in a coordinated manner. Thus the molecular and cellular mechanisms underlying the development of cirrhosis are incredibly complex. Despite this complexity, there have been advances to develop preventive and therapeutic strategies for the management of cirrhosis. Indeed, pharmacological antagonists of each of the three injury mediators discussed here prevent or reduce fibrosis in animal models of chronic liver injury. It is the location, duration, and intensity of liver injury that dictate clinical outcome. For example, in most forms of chronic liver injury, including hepatitis C and autoimmune hepatitis, fibrosis is initially most prominent in the portal region, the location most affected by these diseases. Conversely, liver fibrosis occurs only months to decades after onset of chronic hepatic injury. The clinical observation that only a portion of patients suffering from chronic liver diseases-such as hepatitis B and C, alcoholic and nonalcoholic steatohepatitis, and hereditary hemochromatosis-develop cirrhosis suggests that there may be an intensity threshold for a given individual that must be crossed in order for fibrosis to ensue. Finally, it has become generally recognized that if the source of chronic liver injury is removed, fibrosis can be reversed. The pathogenesis of cirrhosis is complex and is mediated by the dynamic and multifaceted response of the fibrogenic cells of the liver to chronic injury. In the case of cirrhosis, efforts will be directed toward the prevention or reversal of fibrosis. Thus safe and effective therapies for cirrhosis must blunt the injury response that causes fibrosis without compromising the normal wound-healing response. Second, the large majority of patients with chronic liver disease do not develop cirrhosis, and even those who do often live many years before developing clinical disease. Therefore improved strategies for determining which patients have the greatest disposition to progressing to decompensated cirrhosis are critical. Otherwise, any successful therapy for prevention must be very safe, because a large number of patients need to be treated for one to benefit. It is likely that a greatly increased understanding of the molecular and cellular mechanisms underlying fibrosis will be required to overcome the hurdles necessary to create effective and safe therapies for cirrhosis. Activation of mouse natural killer T cells accelerates liver regeneration after partial hepatectomy. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. The same questions can be applied to cirrhosis; a large majority of patients with chronic liver disease never develop cirrhosis. Indeed, the host response to injury is likely as important or even more important than the inciting agent or disease.