Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

CHAPTER 5 – Liver Diseases

Keith Nemergut, MD,
Edward C. Littlewood, MD



Normal Hepatic Anatomy



Functions of the Liver in Health 



Carbohydrate Metabolism



Lipid Metabolism and Transport



Protein Synthesis



Detoxification and Transformation



Bilirubin Metabolism



The Injured Liver 



Cellular Responses in Injury and Disease



Laboratory Manifestations of Hepatobiliary Dysfunction



Diseases and Dysfunction of the Liver 



Etiology of Liver Dysfunction



Systemic Effects of Liver Disease 



Cardiovascular Effects of Liver Disease



Portal Hypertension and Ascites



Renal Effects of Liver Disease



Pulmonary Effects of Liver Disease



Hepatic Encephalopathy



Assessment of Perioperative Risk in the Patient with Liver Disease



Anesthetic Management 



Anesthetic Management for Patients with Liver Dysfunction



Anesthetic Management for Procedures Involving the Hepatobiliary System



Special Considerations




The liver plays a crucial role in many of the homeostatic processes of the body and, as a result, is affected by countless disease processes and physiologic abnormalities. Conversely, the dysfunctional liver can profoundly affect the function and reserve of multiple organ systems in the surgical patient. With the added complexities of perioperative stressors, a rational approach to the anesthetic management of patients with liver disease may seem a daunting task.

Fortunately, an understanding of (1) normal hepatic structure and function, (2) the acute and chronic responses of the liver to various types of injury, and (3) the behavior of the healthy or diseased liver during perioperative events allows a fairly straightforward approach to management issues. With these commonalities in mind, in the following sections we first discuss pertinent normal hepatic anatomy and physiology. Within this framework, representative individual disease processes are then examined and, finally, anesthetic management is addressed.


A complete review of normal liver structure and function is beyond the scope of this discussion. The intricacies of current concepts in hepatic function and disease can be found in standard reference texts.[1] [2] The goal here is to concisely present aspects of hepatic anatomy and physiology with implications for perioperative care of the patient with liver disease. Points of emphasis are (1) the dual blood supply of systemic blood via the hepatic artery and portal venous blood from the splanchnic circulation; (2) histologic arrangement of hepatocytes, including the unique hepatic sinusoids and the resulting blood-hepatocyte interface; and (3) isolation of biliary and blood compartments with regulation of enterohepatic circulation.

The liver is the largest parenchymal organ in the human body, representing approximately 2% of total body weight in the adult. Blood flow to the liver is normally 100 mL/ 100 g of tissue per minute, or 25% to 30% of the resting cardiac output. The liver is well situated to many of its metabolic functions by its interposition between the splanchnic and systemic venous systems. A critical result of this arrangement, however, is that approximately 75% of the blood supply to the liver is delivered by the portal vein. This blood is partially deoxygenated as a result of oxygen extraction by the splanchnic organs. After coursing through capillary beds of the stomach, pancreas, spleen, and intestines, portal venous blood does contain high concentrations of nutrients, as well as secreted and ingested exogenous substances. Under normal circumstances this portal blood provides 35% to 50% of the oxygen delivered to the liver. The well-oxygenated blood of the hepatic artery delivers the remaining 50% to 65% of oxygen, despite representing only 25% of the liver's blood supply. Portal venous flow is dependent on the normal variations in splanchnic blood flow as regulated by the arterioles and capillary flow of the splanchnic bed. Hepatic artery blood flow demonstrates autoregulatory changes in response to blood pressure, as well as to portal blood flow and sinusoidal oxygen levels.

Understanding liver structure can be difficult because of different nomenclatures regarding both its gross and its microscopic anatomy. The liver may be thought of as comprising two major lobes, the right and left, as roughly divided by the falciform ligament. These lobes can be further subdivided into the eight segments of Couinaud ( Fig. 5-1 ). Based conceptually on separate vascular and biliary branches, this classification belies the common “crossover” of these structures, especially hepatic veins, between segments.


FIGURE 5-1  Anatomic relationships of hepatic segments and their vascular structures.



From a surgical perspective, segments may be resected for the purpose of excision of pathological lesions or, more recently, living-directed donation for transplantation. When draining hepatic veins or portions of the biliary tree for remaining segments are removed, the remaining segments will be subject to venous congestion and/or biliary leakage. In the case of resection for transplantation, if nonresected tissue contains significant arterial and portal vein supply for resected tissue the latter will demonstrate areas of ischemia after transplant owing to the loss of this blood supply.

The older classic concept of the basic hepatic histologic structure is that of the hepatic lobule ( Fig. 5-2 ). This model is that of a polygon, typically a hexagon, with branches of the portal triad (hepatic artery, portal vein, and bile duct) at the vertices. A central vein (technically a venule) marks the central axis of the lobule. Mixed arterial and portal blood flows from the vessels at each vertex, via the sinusoids, to the common central vein. The sinusoids are formed by one-cell thick plates of hepatocytes and lined with endothelial cells. These sinusoids differ from normal capillaries because of the mixture of portal venous and arterial blood by which they are supplied. They also lack a basement membrane, and their endothelium has fenestrations typically ranging in size from 50 to 200 nm. These fenestrations and the low sinusoidal pressure allow a multitude of solutes, including macromolecules, to enter the perisinusoidal space of Disse. Here, molecules are in direct contact with the microvilli of the hepatocyte's basolateral membrane. There is evidence that the fenestrations are modified by contractile components along their circumference, thus offering some regulation of the movement of large molecules between the sinusoidal blood and the space of Disse. The hepatocyte also has specialized canalicular membrane portions with distinct microvilli. In combination with the adjacent hepatocyte, this specialized area forms the wall of the bile canaliculi, its isolation completed by tight intercellular junctions. Intracellular actin and myosin filaments along the canalicular channel are presumed to promote drainage of bile into the canals of Hering and subsequently into the interlobar bile ducts.


FIGURE 5-2  Top, Organization of the liver. CV, central vein; PS, portal space containing branches of bile duct, portal vein, and hepatic artery. Bottom, Arrangement of plates of liver cells, sinusoids, and bile ducts in a liver lobule, showing centripetal flow of blood in sinusoids to central vein and centrifugal flow of bile in bile canaliculi to bile ducts.  (Reproduced with permission from Ganong WF: Review of Medical Physiology, 21st ed. New York, McGraw-Hill, 2003.)




The alternative histologic perspective is the acinus model. The venule, which was considered to be central in the lobule model, is now the peripheral structure. This places the portal triad structures centrally, with concentric zones radiating out to the draining venule. The zones are numbered from 1 to 3 with progression to the vein. Conceptually, these zones reflect decreasing oxygen content in the sinusoidal blood and decreasing concentrations of nutrients (and toxins) arriving from the gut. Although less easily visualized histologically, the zones of the acinar model correlate with differential enzyme concentrations, metabolic activities, and degree of cellular damage caused by a variety of agents and situations. Figure 5-3 diagrams the perspectives and nomenclature of the lobular and acinar models.


FIGURE 5-3  Microscopic liver architecture depicted schematically. The classic hexagonal lobule is centered around a central vein (terminal hepatic venule), with portal tracts at three of its apices. The triangular acinus has as its base the penetrating vessels, which extend from portal veins and hepatic arteries to penetrate the parenchyma. The apex is formed by the terminal hepatic vein. Zones 1, 2, and 3 represent metabolic regions increasingly distant from the blood supply.  (Reproduced, with permission from Crawford JM: The liver and the biliary tract. In Cotran RS, Kumar V, Collins T (eds): Robbins Pathologic Basis of Disease, 6th ed. Philadelphia, WB Saunders, 1999, p 846.)


Although hepatocytes make up about 80% of the liver, a host of other cells are found in the liver. Two of the many nonparenchymal cells of the liver deserve mention. Kupffer cells are members of the monocyte-phagocyte system (macrophage derived) and typically reside on the luminal aspect of sinusoidal endothelial cells. Their phagocytic and inflammatory responses are important in several of the disease processes to be discussed. Stellate cells (Ito cells) are found in the space of Disse and, in health, store lipids and vitamin A. In the fibrogenic response to injury, however, the stellate cells undergo transformation to fibroblasts and produce collagen, which is an early step in the “capillarization” of the sinusoids, with loss of fenestrations and creation of a pseudo–basement membrane. This is believed to be a fundamental step in the development of hepatic fibrosis and cirrhosis, to be discussed below.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier


Carbohydrate Metabolism

The liver routinely provides the body's widely varying energy requirements under the modulation of neural and endocrine regulators. Complex interacting systems of energy storage and utilization are required to compensate for asynchronous periods of nutritional ingestion and energy demand. Figure 5-4 presents a simplified diagram of carbohydrate and lipid metabolism in the hepatocyte.


FIGURE 5-4  Hepatic carbohydrate and lipid metabolism. Gluconeogenic pathways are identified by dashed lines. GK, glucokinase; Glu-6-Pase, glucose-6-phosphatase; 6-Fru Kinase/Pase, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; Fructose 6-P, fructose-6-phosphate; 6 PF-1-K, 6-phosphofructo-1-kinase; Fruc-1,6-P2 ase, fructose-1,6-biphosphatase; PK, pyruvate kinase; PEPCK, phosphoenol pyruvate carboxykinase; CPT, carnitine palmitoyltransferase; Glut 2, glucose transporter 2; T, carnitine:acylcarnitine transferase; PEP, phosphoenol pyruvate; FAD, flavine adenine dinucleotide; PYR, pyruvate; OAA, oxaloacetate; UDPG, uridine diphosphate glucose.  (Reproduced, with permission from Stolz A: Liver physiology and metabolic function. In Feldman M, Friedman LS, Sleisenger MH (eds): Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 7th ed. Philadelphia, WB Saunders, 2002, p 1204.)


Many cells of the body are glucose dependent (e.g., erythrocytes, renal medulla, and retina) or glucose preferential (e.g., brain). Maintenance of blood glucose levels is accomplished by glycogenolysis or gluconeogenesis, depending on nutritional circumstances. Glycogenolysis, promoted by epinephrine and glucagon, is the process by which glucose is eventually released from stored glycogen. The liver and skeletal muscle contain the vast majority of the body's glycogen. Glucose-6-phosphatase in the liver is capable of converting glucose-6-phospate (cleaved from glycogen by glycogen phosphorylase) to glucose for release into the blood. Muscle, however, lacks glucose-6-phosphatase, and thus its glycogen is destined for utilization in the myocyte. Glycogen stores in the adult liver during fasting are capable of providing adequate glucose levels for 24 to 48 hours, representing 250 to 500 mg of glucose. It is interesting to note that during this period of fasting, the brain will initiate transition from glucose dependency to ketone metabolism and thus sustain itself while markedly decreasing the body's daily glucose utilization. Gluconeogenesis is the creation of glucose from lactate, pyruvate, and amino acids, themselves the products of anaerobic and catabolic metabolism. It is stimulated with the depletion of glycogen stores.

The liver can rapidly switch from glycogen breakdown to formation, depending on the nutritional circumstances and energy requirements of the moment. This is because the enzyme systems involved in glycogen creation (glycogen synthase) and breakdown (glycogen phosphorylase) are activated and deactivated by their phosphorylation state as modulated by the presence of glucose, glucose-6-phosphate, and endocrine mediators. In this way, proglycogen and macroglycogen are immediately available as a glucose source when needed, or as a depository for storage of excess glucose.

Disruption of carbohydrate homeostasis can be a manifestation of liver dysfunction. Acute liver injury (e.g., viral hepatitis) is often associated with mild hypoglycemia despite normal or depressed insulin levels. Postulated mechanisms for this abnormality include partial depletion of glycogen reserves, decreased gluconeogenesis, ineffective glycogen repletion after dietary carbohydrate intake, and decreased glucagon promotion of glycogenolysis. Hypoglycemia can be pronounced in the alcoholic despite apparently minimal hepatic decompensation. This occurs because ethanol itself cannot be used in gluconeogenesis and, further, its metabolism can critically reduce the availability of pyruvate for gluconeogenesis. In fulminant hepatic failure of any cause, hypoglycemia can be life threatening.

Glucose intolerance, conversely, is often observed in chronic liver disease, especially cirrhosis. Although insulin levels may actually be elevated because of decreased hepatic clearance, peripheral receptors are decreased in number. Additionally, receptor binding characteristics and activity may be altered. Hepatocytes may also be isolated from the usual concentrated levels of portal pancreatic insulin release because of portosystemic shunting. Skeletal muscle in the cirrhotic patient demonstrates decreased glycogen stores and impaired uptake of glucose, thought to be an effect of increased serum free fatty acids. This decreased uptake by muscle amplifies hyperglycemia in the fed state.

The liver processes other carbohydrates, some of which will be discussed in the context of metabolic abnormalities. Fructose, which is mentioned here because of its seemingly universal presence in the modern western diet from fructose corn syrup derivatives, and the impact of fructose intolerance, is discussed later. Fructose is converted to fructose-1-phosphate (fru-1-P) in the liver, which in turn increases glucokinase activity. Fru-1-P cannot directly enter the gluconeogenic pathway, but its metabolites (glyceraldehyde-3-phosphate and dihydroxylacetone) can enter the glycolytic pathway, be converted to fructose-1,6-P2 for gluconeogenesis or glycolysis, or serve as glycerol building blocks for phospholipids and triglycerols. Finally, fructose is more readily incorporated into fatty acid synthesis than is glucose, having bypassed early steps and regulations of this process.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

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Lipid Metabolism and Transport

Fatty acids provide the most efficient energy source for both intrahepatic and extrahepatic storage and utilization. The liver's central role in lipid metabolism, beyond utilization, involves regulated conversion of excess carbohydrates to fatty acids, esterification of free fatty acids to form triglycerides for transport and storage, and synthesis of transport proteins. In normal circumstances, the liver takes up a relatively fixed amount of free (nonesterified) fatty acids regardless of dietary intake. This provides the major energy source for hepatocytes. The nutritional state determines the subsequent balance between synthesis and esterification of fatty acids in the fed state versus oxidation in the fasting state.

Hepatic steatosis (“fatty liver”) refers to abnormal accumulation of predominately triglycerides with fatty acids in hepatocytes. Steatosis occurs when triglyceride production exceeds secretion into the plasma (usually after incorporation into very low density lipoproteins). Abnormalities of either production and/or secretion can thus be responsible for fatty liver. Previously defined in terms of weight percentage (greater than 5%) or number of hepatocytes affected (greater than 30% in a lobule), the diagnosis is now also grossly correlated to findings of noninvasive imaging. Some conditions associated with steatosis that are considered later include obesity, alcohol ingestion, pregnancy, nonalcoholic steatohepatitis, and certain drug toxicities.

Cholesterol is not a direct energy source but serves as a structural unit of membranes and is a precursor for steroid production. Most cholesterol is synthesized in the liver and, in combination with dietary cholesterol, is either secreted in the bile, incorporated into lipoproteins for plasma transport, or converted to bile acids. Figure 5-5 provides an overview of lipoprotein metabolism and transport.


FIGURE 5-5  Lipoprotein metabolism. FFA, free fatty acids; ACAT, acylcholesterol acyltransferase; CETP, cholesteryl ester transfer protein; LCAT, lecithin-cholesterol acyltransferase; FA, fatty acids; LDL, low-density lipoproteins; HDL, high-density lipoproteins; VLDL, very-low-density lipoproteins.  (Reproduced, with permission from Stolz A: Liver physiology and metabolic function. In Feldman M, Friedman LS, Sleisenger MH (eds): Sleisenger &Fordtran's Gastrointestinal and Liver Disease, 7th ed. Philadelphia, WB Saunders, 2002, p 1211.)


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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Protein Synthesis

With the exception of immunoglobulins, the liver produces the vast majority of proteins found in plasma. These include most of the proteins of coagulation, plasma-binding proteins involved in transport (e.g., albumin, transferrin, lipoprotein, and haptoglobin), and acute phase reactants. This wide variety of proteins share many common synthetic pathways but have distinguishing characteristics of substrate, modulation, and kinetics that explain the clinically variable response to injury and disease. For example, those clotting factors dependent on vitamin K for post-translational modification can be affected by its nutritional intake or absorption, while inflammatory mediators stimulate acute-phase reactants. Serum albumin levels reflect not only production from available amino acids but also volume of distribution, abnormal losses (e.g., ascites, pleural effusion, or proteinuria), and regulators responding to parameters such as serum oncotic pressure. Those altered protein levels, which are actually reflections of liver disease, will develop after variable periods, dependent on the synthetic rates and plasma half-times of the particular proteins.

Thus, although it is generally true that serum protein levels will be decreased with liver dysfunction, the specific laboratory abnormality and time frame (i.e., hours or days in the case of coagulation factors versus weeks in the case of albumin) are important diagnostic clues in liver disease.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Detoxification and Transformation

The liver is the major site in which both xenobiotics and endogenous substances undergo detoxification and/or transformation. These changes usually generate less active and more hydrophilic compounds. There are notable exceptions in which transformation actually renders substances toxic. This is discussed in the section on hepatotoxins that follows. The pathways involved are categorized into three phases. Phase 1 metabolism alters the molecule by reactions (usually involving the cytochrome P450 enzyme system) such as oxidation, reduction, and hydrolysis. Phase 2 metabolism conjugates the parent molecule or its metabolite with a polar molecule such as acetate, amino acid, sulfate, or glutathione, and thus further enhances water solubility. The more recently defined phase 3 elimination is an energy-dependent excretion. A particular molecule may undergo any or all of these processes. Changes in the pathway(s) utilized may occur as dictated by substrate concentrations, enzyme induction, disease, and nutritional status.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

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Bilirubin Metabolism

Bilirubin is a tetrapyrrole produced from the breakdown of heme at the rate of about 250 mg/day in the normal adult. About two thirds comes from hemoglobin of senescent erythrocytes processed by the reticuloendothelial system, and the remainder mostly from non-hemoglobin hemoproteins such as cytochrome P450 enzymes. The turnover of myoglobin is slow enough that its substantial hemoprotein content does not contribute significantly to bilirubin production. Heme is first converted to biliverdin by heme oxygenase and then to bilirubin by biliverdin reductase. This unconjugated bilirubin, which is water insoluble and neurotoxic at sufficiently high levels, is bound to albumin and transported to the hepatocyte. Here it is conjugated with glucuronic acid by uridine diphosphatase-glucuronyl-transferase to form bilirubin monoglucuronide and diglucuronide. After secretion into canaliculi, bilirubin is incorporated into bile and remains unchanged through the gallbladder and most of the small intestine. In the terminal ileum and colon, hydrolysis by bacterial enzymes produces urobilinogen, which is reabsorbed, and re-excreted predominately in bile with a small fraction filtered by the kidney into the urine.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

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Cellular Responses in Injury and Disease

As mentioned earlier, the liver can suffer injury from a variety of processes, both primary to the organ (e.g., viral hepatitis) and secondary (e.g., right-sided heart failure or metastatic cancer). Regardless of the multitude of causes, however, a few general categories of cellular consequences are typically observed.

Hepatitis is simply liver injury associated with the incursion of inflammatory cells. Depending on the type of hepatitis, hepatocyte injury may stimulate the inflammatory response (e.g., toxic injury) or be secondary to it.

Degeneration is defined in terms of microscopic findings. Foamy degeneration occurs with ineffective biliary excretion, whereas ballooning degeneration is found in toxic and immunologically mediated injury. Steatosis specifically represents accumulation of fat droplets in the cell. Multiple small accumulations are seen in microvesicular steatosis (as seen in the acute fatty liver of pregnancy), whereas macrovesicular steatosis is defined as a large nucleus-displacing droplet (as seen in obese and diabetic patients).

Necrosis can occur after a variety of injuries. Necrosis demonstrates poorly stained cells with lysed nuclei, frequently exhibiting zonal distributions. Centrilobular necrosis is a common pattern in which the most severe damage immediately surrounds the central vein. This is characteristic of toxins and ischemic injury, the latter presumably reflecting the decreasing oxygen content of the sinusoidal blood as it flows to the terminal venule, whereas the toxic pattern may reflect not only relative hypoxia but also regions of high metabolic activity and biotransformation. Periportal necrosis, conversely, is exceedingly unusual but may be found in preeclamptic patients for unknown reasons. With most injuries, a variety of necrotic and inflammatory patterns are seen. Focal necrosis denotes scattered necrosis within lobules, whereas more severe bridging necrosis spans adjacent lobules. More severe still are submassive necrosis and massive necrosis in which entire lobules or most of the liver are affected, respectively.Apoptosis, the energy-dependent deconstruction of cells with an attenuated inflammatory response and salvage of cell components that can be reutilized, will not be discussed here. The conditions and regulators that influence apoptosis in the liver are being elucidated. [3] [4] Whether the balance between necrosis and apoptosis can be predicted or even manipulated clinically remains to be seen.

Regeneration and fibrosis represent two different outcomes in the liver's attempt to replace lost or extinct liver units. The liver, since at least the ancient Greek myth of Prometheus, has a deserved reputation for its unparalleled ability to regenerate. When its connective tissue framework is left intact the liver can, as demonstrated in living directed liver donors and recipients, actually re-form itself from less than half of its original size. Similarly, the liver that has suffered submassive and even massive necrosis may subsequently recover essentially normal structure, except for minor abnormalities of bile ductules and parenchymal arrangement. Stimulating factors thus far identified in the human include epidermal growth factor, transforming growth factor, and hepatocyte growth factor.

Fibrosis is a very different consequence of injury response. It is generally irreversible and will compromise function to at least some extent. Fibrosis results from the deposition of collagen within the space of Disse, around portal tracts, or around the central vein by transformed stellate cells (see previous description of anatomy). Previously healthy hepatocytes are eventually replaced with connective tissue.Cirrhosis is the term applied to nodules of regenerating hepatocytes within such scar tissue, reflecting the impact of disruption of the normal connective framework before or during regeneration. This architectural disruption results in increased resistance to hepatic blood flow with eventual portal hypertension and decreased functional mass with impairment of metabolic and excretory function. Box 5-1outlines causes of hepatic fibrosis and cirrhosis with representative causes. Obviously, cirrhosis and fibrosis represent the consequences of a wide range of diseases. In the western world, about 90% of cirrhosis of known etiology is related to alcoholic liver disease, viral hepatitis, or biliary disease. Approximately 10% of cases are of unknown etiology and termed cryptogenic cirrhosis.

BOX 5-1 

Etiologies of Hepatic Fibrosis and Cirrhosis





















Oral contraceptives



Sulfa antibiotics



Vitamin A












Carbon tetrachloride






Methylene diamine



Pyrrolizidine alkaloids












Chronic hepatitis (B, C, and D)












Syphilis (tertiary and congenital)



Metabolic and genetic disorders



α1-Antitrypsin deficiency






Alagille syndrome



Biliary atresia



Familial intrahepatic cholestasis (Byler's disease) types 1, 2, and 3



Fanconi's syndrome



Fructose intolerance






Gaucher's disease



Glycogen storage disease






Hereditary fructose intolerance



Hereditary tyrosinemia



Ornithine transcarbamylase









Wilson's disease



Wolman's disease



Autoimmune chronic hepatitis



Biliary obstruction (chronic)



Budd-Chiari syndrome (including Veno-occlusive subset)



Cystic fibrosis



Idiopathic portal hypertension



Jejunoileal bypass



Nonalcoholic steatohepatitis



Primary biliary cirrhosis



Primary sclerosing cholangitis



Right-sided heart failure and tricuspid regurgitation (chronic)




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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Laboratory Manifestations of Hepatobiliary Dysfunction

The multiple functions of the liver and its vulnerability to a variety of extrahepatic abnormalities have already been emphasized and are relevant to the discussion of laboratory evaluation. Most commonly used tests have significant limitations of sensitivity and specificity and are capable of assessing very narrow aspects of hepatic function. The concept of a single test or even a panel of tests that represent a measure of hepatic reserve or “liver function tests” is therefore flawed. Different patterns of abnormalities do, however, often correlate with the instigating clinical presentation and allow further targeted investigation. Tests commonly selected to evaluate liver disease are summarized in typical pathologic patterns in Table 5-1 . The tests can be broadly divided into two categories, those that reflect liver injury as opposed to those that actually depend on the function of the liver. The markers of direct injury include released hepatic enzymes. Synthetic function can be reflected in protein levels and clotting times, whereas dye clearance and drug transformation can be used to investigate blood flow and metabolic capacity.

TABLE 5-1   -- Characteristic Biochemical Markers in Liver Disease


Hepatocellular Necrosis

Biliary Obstruction


Etiologies and Laboratory Results[*]

Toxin or Ischemia





Chronic Infiltration





NL to 5×

NL to 5×


Alkaline phosphatase






NL to 20×







NL to 5×

Prothrombin time

Prolonged. Minimal or no improvement with vitamin K


Often prolonged. May improve with parenteral vitamin K



Decreased in chronic disease


Often normal; may be decreased

Usually normal

Illustrative disorders

Shock liver, acetaminophen toxicity

Hepatitis A or B


Pancreatic Cancer

Hilar tumor, sclerosing cholangitis

Sarcoid, metastatic carcinoma

Modified from Davern TJ, Scharschmidt B: Biochemical liver tests. In Feldman M, Friedman LS, Sleisenger MH (eds): Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 7th ed. Philadelphia, Elsevier, WB Saunders, p 1231.



×, times elevation from normal; NL, normal

Acute onset of complete biliary obstruction may result in massive elevations in aminotransferases that are transient and in the range of 20 to 50 times normal.


Tests That Reflect Hepatic Clearance


The liver normally clears ammonia from the blood and converts it to urea for renal excretion. With severe liver dysfunction and/or portosystemic shunting, ammonia levels may be elevated. Although commonly used in the evaluation of possible hepatic encephalopathy, ammonia levels correlate poorly with the severity of clinical presentation.


As discussed with normal metabolism, bilirubin is a product of heme breakdown. It exists in conjugated (water soluble) and unconjugated (lipid soluble) forms, which are reported imprecisely as the direct and indirect fractions, respectively. Serum bilirubin is usually less than 1 mg/dL and unconjugated. Elevated serum levels occur in most significant liver disease. With primary biliary cirrhosis, alcoholic hepatitis, and fulminant failure the degree of elevation correlates with prognosis. The appearance of conjugated bilirubin in the blood is thought to be from hepatocyte reflux but does not discriminate between obstructive and parenchymal causes. Other causes of elevated bilirubin include Gilbert's syndrome; increased production in situations such as hemolysis, ineffective erythropoiesis, or hematoma resorption; and inherited disorders of bilirubin transport.

Tests That Reflect Synthetic Function


Albumin is synthesized only in the liver, typically at a rate of 100 to 200 mg/kg/day in the adult, and under normal circumstances the plasma half-life is 3 weeks. Abnormalities are poorly specific for liver disease, however, because many factors affect its production and turnover. Nutritional state, plasma osmotic pressure, and thyroid levels, for example, all affect the rate of albumin production. Increased albumin losses as seen in nephrotic syndrome, burns, and protein-wasting enteropathies also affect the balance between production and loss of albumin. Hypoalbuminemia can be helpful in assessing chronic liver disease when nonhepatic causes are excluded. Its prolonged half-life means that measured changes are slow to develop and slow to revert to normal in relation to the causative process's onset and resolution.

Prothrombin Time.

Prothrombin time (PT) determinations depend on serum concentrations of fibrinogen, prothrombin, and factors V, VII, and IX, all of which are products of the liver. Furthermore, the half-life of these factors is short enough (less than 24 hours) that the PT changes rapidly. An abnormal PT can result from reduced factor synthesis (as seen in vitamin K deficiency, liver failure, and warfarin therapy) or increased factor loss (as seen in disseminated intravascular coagulation).

Vitamin K deserves special mention in the context of the PT. Prothrombin and factors VII, IX, and X undergo post-translational carboxylation of glutamic acid residues that is necessary for activity and requires vitamin K as a cofactor. Deficiency of vitamin K or antagonism of this process by warfarin is thus understood to alter the PT. Additionally, in the jaundiced patient, a favorable response to parenteral vitamin K implies that intake or absorption of vitamin K is abnormal, as opposed to a nonresponse, which implies that parenchymal disease is at least in part the basis for abnormality (see Table 5-1 ).

Serum Enzyme Tests

Alkaline Phosphatase.

Hepatic alkaline phosphatase (AP) is concentrated in the canalicular hepatocyte membrane and bile duct epithelial cells, and increased production and release appear to cause the elevated AP levels seen in cholestasis. However, AP exists in normal tissues throughout the body as well as in extrahepatic neoplasms. A further diagnostic issue arises from the fact that states of increased metabolic activity are associated with increased AP activity in the affected tissue. For these reasons, young adults with rapid bone growth and gravid patients with placental production routinely have elevated AP levels.

AP levels as high as three times normal occur in many liver diseases and are often diagnostic. More pronounced elevations suggest infiltrative processes or biliary obstruction, the latter of which can be either intrahepatic (e.g., tumor) or extrahepatic. Diagnostically, if the entire biliary tree is not obstructed then the unaffected portion of the liver can often maintain bilirubin within normal ranges, but AP will be markedly elevated.

γ-Glutamyl Transpeptidase.

γ-Glutamyl transpeptidase (GGTP) has a tissue distribution similar to alkaline phosphatase except that it has low concentrations in bone. Thus, GGTP may be helpful in discriminating the source of AP elevations. GGTP can also be quite sensitive to the ingestion of alcohol and drugs, including several anticonvulsants. The variability of this phenomenon, however, makes GGTP a suggestive but unreliable indicator of alcohol ingestion.


Aspartate aminotransferase (AST, also known as SGOT [serum glutamic oxaloacetic transaminase) and alanine aminotransferase (ALT, also known as SGPT [serum glutamic pyruvic transaminase) are participants in gluconeogenesis. Both enzymes are plentiful in the cytosol of the hepatocyte, while an AST isozyme is present in the mitochondria as well. AST is also found in a variety of tissues including heart, brain, and skeletal muscle; ALT is more specific to the liver. These enzymes are elevated in many forms of liver disease, presumably as a result of leakage from damaged cells. Substantial hepatic necrosis as found in chemical and ischemic injury appears to be particularly associated with elevation of these enzymes. Nonspecific AST elevations can be seen with injury to skeletal or cardiac muscle, so ALT levels should be evaluated as well. Notably, advanced cirrhosis can exist without significant elevations if active cell injury is absent or minimal at the time of evaluation.

The relative increases in AST and ALT (the AST/ALT ratio) can be useful in supporting a diagnosis of alcohol injury (AST/ALT > 2) versus most other acute liver injuries (AST/ALT ≤1), although cirrhosis is also associated with AST/ALT > 1. Absolute levels can be diagnostic when extreme, and helpful when moderately elevated, as depicted in Table 5-1 .

Lactate Dehydrogenase.

Because of its presence in tissues throughout the body, lactate dehydrogenase (LDH) usually offers little diagnostic discrimination beyond that of aminotransaminases. LDH does, however, demonstrate a short-lived but exceptionally high elevation in ischemic injury, and a moderate but sustained elevation in some malignancies.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier


Liver dysfunction has been categorized in a variety of ways. Clinical presentation (e.g., jaundice), etiology (e.g., viral hepatitis), circumstances (e.g., postoperative liver dysfunction), time frame, and/or severity (e.g., subfulminant liver failure) are commonly used descriptors. None of these approaches is complete. For example, acute liver failure may have an infectious or toxic etiology, whereas viral hepatitis may result in abrupt severe liver dysfunction or proceed along a chronic subclinical course. The discussion to follow will first address representative individual causes of liver dysfunction and then relevant situations that can be the common outcome of several disease processes (e.g., cirrhosis and acute liver failure).

Etiology of Liver Dysfunction

Viral Hepatitis

Although there are a vast number of viruses that have the capacity to produce hepatitis ( Table 5-2 ), there are only five viruses that produce liver disease as their primary clinical manifestation.[5] Each of the five hepatitis viruses has been designated with a letter (e.g., hepatitis A virus, hepatitis B virus) according to their clinical manifestations ( Table 5-3 ). It is important to remember that although each virus infects the liver, the viruses have different biochemical, biologic, and clinical characteristics. Indeed, the viruses do not form a formal phylogenetic family and are not related to one another per se. Although infection with each virus can be associated with significant morbidity and mortality, infection with any virus may result in an anicteric illness and may not be diagnosed as hepatitis.[6]

TABLE 5-2   -- Uncommon Causes of Viral Hepatitis


Vaccine Available

Epstein-Barr virus (EBV)


Cytomegalovirus (CMV)


Herpesvirus, type 1

In development

Herpesvirus, type 2

In development

Coxsackievirus, type B





Yes—for certain subtypes, limited to military use

Yellow fever virus


Varicella zoster virus






TABLE 5-3   -- Characteristics of Human Hepatitis Viruses


Hepatitis A

Hepatitis B

Hepatitis C

Hepatitis D

Hepatitis E

Virus Family








Partially dsDNA




























Incubation Period

15–50 days

4–26 wk

2–26 wk

3–7 wk

15–60 days


IgG anti-HAV




IgG anti-HEV

Chronic Hepatitis






Fulminant Failure





1% (30% in pregnancy)







Adapted from Ryder SD, Beckingham IJ: ABC of diseases of liver, pancreas, and biliary system: Acute hepatitis: BMJ 2001;322:151–153; and Berenguer M, Wright T: Viral hepatitis. In Feldman M, Friedman L, Sleisenger M (eds): Sleisenger & Fordtran's Gastrointestinal and Liver Diseases, 7th ed. Philadelphia, WB Saunders, 2002.



Hepatitis A.

The hepatitis A virus (HAV) is a 27- to 32-nm nonenveloped virus with a 7.5-kb genome of single-stranded RNA. HAV is the only member of the genus Hepatovirus in the viral family Picornaviridae. HAV is almost always transmitted via the fecal-oral route through the ingestion of contaminated food or drink. After ingestion, the virus is absorbed through the small bowel and transported via the portal blood flow to the liver.[7] The virus replicates in the liver and is then shed into the blood or, more commonly, through the bile and into the stool. Viral shedding begins as early as the second week of infection and consequently may occur before the patient experiences any clinical signs or symptoms of hepatitis (see later). Viral shedding may continue until 2 weeks after the onset of jaundice. Although the virus is shed into the stool in high titers, titers of virus in the blood remain low during the short (1-2 week) viremic phase.[8] As such, transmission of HAV by blood transfusion is extremely rare, although transmission from a single donor has been reported. [9] [10] The virus has also been transmitted to hemophiliacs with contaminated factor VIII concentrates.[11]

After an incubation of 15 to 50 days, patients may experience the acute onset of systemic complaints, including fever, malaise, nausea, vomiting, and abdominal pain. Patients may also note the appearance of dark urine and jaundice. Mild hepatic enlargement and tenderness is noted in approximately 85% of patients, with splenomegaly noted in 15% of patients or less.[12] Coagulopathy, encephalopathy, and renal failure are rare in the setting of acute HAV infection. [12] [13] HAV is normally a self-limited illness with complete recovery noted in most patients in less than 2 months; however, serious complications can occur.[14] Underlying liver disease is associated with increases in the risk of fulminant hepatic failure with HAV superinfection. [15] [16] Chronic hepatitis does not occur, but an atypical relapsing course has been described in both children and adults.[17]

Diagnosis is normally confirmed by serologic testing. Anti-HAV IgM is detectable in the serum approximately 3 weeks after exposure. Early diagnosis is also possible with the detection of HAV in stool using electron microscopy or the detection of viral RNA; however, both of these methods are impractical. Although 75% of adult patients with HAV have obvious clinical manifestations, up to 70% of infections in children younger than age 6 years are totally asymptomatic.[18] When one considers the combination of the developing bowel habits of young children with their capacity to act as asymptomatic carriers, it should come as no surprise that young children are considered the principal reservoir for the virus.

HAV infections occur throughout the world but are clearly more common in developing countries with poor sanitation. In the United States, the incidence of HAV infection is 9 to 10 per 100,000, with an overall seroprevalence of 30%. Two highly effective vaccines has been available in the United States since 1996.[18] The vaccines have been recommended for children[19] and adults[18] with chronic liver disease. Anesthesiologists and all health care providers should consider immunization. In the event of possible transmission of HAV to a health care provider, a single dose of 0.02 mL/kg immune globulin is highly effective in preventing infection if given within 14 days of exposure.[18]

Hepatitis B.

The hepatitis B virus (HBV) is a 42-nm enveloped virus with 3.2-kb genome of partially double-stranded DNA. HBV is a member of the viral family Hepadnaviridae. Worldwide, more than 400 million people are chronically infected by HBV. [20] [21] Unlike HAV, HBV is primarily transmitted by blood, blood products, and sexual contact. Perinatal infection can occur and there is evidence that infection can occur across mucous membranes by semen, saliva, and breast milk.[22] Intravenous drug abuse (IVDA) remains a major mode of HBV transmission[23] and outbreaks among intravenous drug abusers are frequently reported.[24] Nosocomial transmission has been reported through the use of multidose vials of local anesthetics.[25] Acupuncture has been linked to occasional outbreaks of HBV.[26]Fortunately, transfusion-related HBV infection is a rare event, as HBV screening of donated blood and appropriate screening of donors has been routine for almost 2 decades.[21] Nevertheless, it is estimated that 1:50,000 to 1:63,000 transfused units transmits HBV.[27]

In the United States, Canada, Europe, and Australia sexual transmission is the most important mode of HBV infection. [28] [29] Both heterosexual and homosexual activities can transmit HBV, but heterosexual activity accounts for the majority of HBV infections. Prostitutes, their clients, and individuals with many sexual partners are at an increased risk of HBV infection. The risk of heterosexual transmission is greater when the infected person is female than when the infected person is male.[5] In endemic regions like China and sub-Saharan Africa, most infections occur neonatally or in early childhood,[21] and sexual transmission is less important.

After parenteral exposure, there is a long asymptomatic incubation period with a range of 4 to 26 weeks (average, 6 to 8). During this incubation period, infected hepatocytes synthesize and secrete large quantities of noninfective hepatitis B surface antigen (HBsAg). Consequently, HBsAg is detectable before the onset of signs and symptoms of hepatitis. Hepatitis B DNA (HBV-DNA) is detectable in the serum by polymerase chain reaction (PCR) shortly after HBsAg and indicates active viral replication. HBeAg, another important indicator of active viral replication, is also detectable at this time. Continued expression of HBeAg is an important biochemical predictor of progression to chronic hepatitis (see later). IgM to hepatitis core antigen (HBc), a viral protein not detected in the serum, can be detected in the serum shortly before the onset of acute illness. IgM anti-HBc is gradually replaced by IgG anti-HBc over several months. IgG anti-HBs does not appear until after the resolution of jaundice and clinical symptoms and after the disappearance of HBsAg. During this “core window” after the disappearance of HBsAg and before the appearance of anti-HBs, IgM anti-HBc (and IgM anti-HBe, if available) are the only laboratory markers of HBV infection.

Of the approximately 325,000 new infections in the United States each year, approximately 60% of patients will develop subclinical disease without jaundice and completely recover. Twenty-five percent of infected patients will develop acute hepatitis characterized by fever, nausea, vomiting, anorexia, abdominal pain, and jaundice. Almost all patients who develop acute hepatitis will completely recover; however, approximately 1% of patients will develop fulminant hepatic failure and will die without liver transplantation. Five to 10 percent of patients will become “healthy carriers” of the disease. These individuals do not normally manifest signs or symptoms of hepatitis but are able to transmit the disease to others. Less than 5% of patients infected with HBV will develop a persistent infection characterized by mild but persistent elevation of serum transaminases for months to years. Most patients with persistent infection will ultimately recover; however, 20% to 30% will go on to develop chronic hepatitis and cirrhosis. There is evidence that patients who develop chronic hepatitis may have a defective immune response. [30] [31] [32] HBV cirrhosis is a significant risk factor for hepatocellular carcinoma, and approximately 10% of patients with HBV cirrhosis will go on to develop hepatocellular carcinoma.

Unlike HAV, HBV infection tends to be more severe in younger patients. In neonates and children younger than 1 year of age, the risk of an infection becoming chronic is 90%. For children aged 1 to 5 years, the risk of chronic infection is 30%. For children older than the age 5, the risk of chronic infection approaches that of adults. [21] [33] It has been postulated that transplacental passage of HBeAg from an infected mother to the fetus induces immune tolerance in the neonate.[34]

Highly effective HBV vaccines have been available for almost 20 years. In 1991, the CDC recommended universal childhood vaccination against HBV in the United States. Broad-based vaccination initiatives have been effective in reducing the incidence of HBV infection in Alaska[35] and reducing the incidence of hepatocellular carcinoma in Taiwan.[36] Before HBV vaccination was widespread, the incidence of anti-HBs among anesthesiologists was greater than fourfold higher than that of the general population.[37] As such, the practice of anesthesiology is an independent risk factor for the development of HBV. [38] [39] All anesthesiologists should be vaccinated against HBV.

In the event of possible transmission of HBV to a nonimmunized individual (such as from an accidental needle stick), passive immunization with hepatitis B immune globulin (HBIG) is available. Current recommendations are to administer HBIG in a dose of 0.05 to 0.07 mL/kg immediately after exposure. A second dose 30 days after exposure may further reduce the risk of HBV infection. If HBIG is not given within 7 days of infection, antiviral treatment should be considered.

Most antiviral therapy in HBV is directed toward the treatment of chronically infected patients.[40] Therapy with interferon alfa has proven effective in the elimination HBeAg in patients chronically infected with HBV. [41] [42] Therapy normally consists of a 16-week course of either 5 mU daily or 10 mU three times a week. Lamivudine, a nucleoside analog, is available orally for HBV.[43] Long-term treatment with lamivudine has been shown to reduce fibrosis and necrosis in patients with chronic HBV infections.[44]

Despite these impressive results, there is evidence of emerging lamivudine-resistant mutants.[45] Adefovir dipivoxil, another nucleoside analog, is also effective.[46] Adefovir seems to have efficacy against lamivudine-resistant mutants.[47]

Hepatitis D (Delta Agent).

Hepatitis D virus (HDV) is a 35-nm viroid with a 1.7-kb genome of single-stranded RNA. The viroid is enveloped with HBsAg and requires co-infection with HBV for HDV infection and replication. Delta agent was first noted in 1977,[48] and its unique structure was described in 1986.[49] Like HBV, HDV is transmitted parenterally. Intravenous drug abuse remains the most common mode of transmission in North America, Europe, and Australia. [50] [51] [52] Sexual transmission of HDV can occur[53] but may be less efficient than HBV. Perinatal infection of HDV is rare.

HDV infection can occur in two settings.[54] In acute co-infection, HDV infection occurs at the same time as acute HBV infection. This normally happens when a patient has been exposed to blood or serum from a patient harboring both infections. Superinfection can occur when a patient with a persistent HBV infection or chronic hepatitis becomes infected with HDV. Co-infection with HBV and HDV results in a more severe course of acute hepatitis and increased risk (3% to 4%) of fulminant hepatic failure. Nevertheless, approximately 90% of co-infected patients go on to complete recovery and develop immunity.

Secondary to defective immunity (see earlier), patients with chronic HBV infection provide the ideal host for HDV superinfection. Approximately 10% of patients superinfected with HDV will go on to fulminant hepatic failure that rapidly progresses to death. Most of the remaining 90% of patients will go on to develop an accelerated cirrhotic picture.[55] A small percentage of patients will recover and develop consequent immunity.

The diagnosis of HDV infection is normally made by the detection of IgM anti-HDV. IgM anti-HDV is not normally detectable in patient serum until the onset of acute hepatitis and jaundice. It is possible to detect HDV antigen (HDVAg) in patient serum before the onset of hepatitis during the late incubation period; however, HDVAg is present only transiently and hence testing may be unreliable. HDV-RNA is the earliest marker of infection and can be detected by PCR, but this is rarely used establish HDV infection.

There is no specific treatment for HDV. Because HDV infection is only possible in the case of HBV infection, and vaccination reliably prevents HBV infection, vaccination against HBV remains the best method to prevent HDV infection.

Hepatitis C.

The hepatitis C virus (HCV) is a 55-nm enveloped virus with 9.4-kb genome of single-stranded RNA. HCV is the only member of the genus Hepacivirus in the viral family Flaviviridae. Worldwide, more than 170 million people are chronically infected with HCV.[56] HCV was not identified until 1989.[57] Like HBV, HCV is primarily transmitted by blood, blood products, and sexual contact. The two biggest risk factors for HCV infection are intravenous drug abuse (IVDA) and blood transfusion prior to 1990. [58] [59] Indeed, HCV has been identified as the etiologic agent in over 85% of all cases of post-transfusion non-A, non-B hepatitis before 1991.[5] Since routine screening for anti-HCV and blood donor risk factor assessment by most blood donor centers in 1991, transfusion-related infection of HCV is a rare event. [58] [59] It is estimated that 1 in 103,000 transfused units transmits HCV.[27]

Consequently, IVDA has emerged as the principal risk factor in the North America, Europe, and Australia.[60] Perinatal transmission is rare and occurs exclusively from mothers who are HCV RNA positive at the time of delivery. [61] [62] Perinatal transmission may be more common if co-infection with the human immunodeficiency virus (HIV) exists.[63] It is unclear whether birth by Cesarean-section increases or decreases the risk of perinatal transmission. [61] [64] [65] [66] Breast feeding appears to pose little risk to the infant. [67] [68] As noted earlier, sexual transmission of HCV is possible; however, transmission is significantly less efficient than for HBV. Nevertheless, prostitutes and their clients, men who have sex with other men, and individuals with multiple sexual partners are at increased risk for HCV infection. There is some suggestion that co-infection with HIV[69] or herpes simplex virus type 2[58] may increase the likelihood of HCV infection. Although the virus is present in saliva of chronically infected persons,[70] transmission through casual contact seems an unusual means of transmission.[71] Patient-to-patient transmission has occurred during colonoscopy,[72] and patients have been infected during surgery.[73] In one hospital, an anesthesia assistant became infected from a patient and subsequently spread the infection to five other patients.[74]

In contrast to HBV, HCV has a high rate of progression to chronic disease and eventual cirrhosis. After infection, HCV has a long incubation period that ranges from 2 to 26 weeks (average, 7 to 8 weeks).[56] Of the approximately 175,000 persons infected in the United States each year, 75% will develop subclinical disease. The remaining 25% develop a symptomatic disease characterized by fever, nausea, vomiting, abdominal pain, anorexia, and jaundice. Approximately 1% of patients with symptomatic disease will develop fulminant hepatic failure that rapidly progresses to death without transplantation. Almost 80% of all patients infected with HCV will go on to develop chronic hepatitis characterized by mild, episodic elevations in transaminases and occasional jaundice.[56] More than 25% of patients with chronic hepatitis will go on to develop cirrhosis. HCV cirrhosis is a significant risk factor for hepatocellular carcinoma, with an estimated risk of 1% to 4% per year. [56] [75]

The detection of antibodies against HCV is both sensitive and specific for HCV infection. Newer, third-generation enzyme immunoassays can detect antibodies within 4 to 10 weeks of infection.[75] Unlike HBV, PCR to detect HCV-RNA is commonly utilized in clinical practice to determine viral load. Viral load has been determined to be a significant predictor of the efficacy of antiviral therapy.[76] In addition, the detection of HCV-RNA is the most sensitive and specific test of HCV infection.[77] There is significant controversy regarding the use of liver biopsy in HCV infection. [78] [79] [80] [81]

There are a variety of treatment regimens available for HCV. Standard interferon three times a week for 24 to 48 weeks was approved for use in 1990 and has been successful in the treatment of HCV infection.[75] Interferon alfa (alfa-2a or 2b), 3 MU three times a week for 24 to 48 weeks, has shown response rates as high as 40%[76] and seems to be more effective than standard interferon. Pegylated interferons have been used to treat HCV since the late 1990s and have shown superior results when compared with interferon alfa.[82] When pegylated interferons are combined with ribavirin, studies have shown response rates as high as 88% in certain patient groups. [83] [84]

There is no vaccine available for HCV. Hence, avoiding exposure best prevents infection. For anesthesiologists and other health care professionals, the observation of universal precautions is critical. Prophylaxis after an accidental exposure is not currently recommended. There are no randomized, controlled studies examining the efficacy of therapy in acute HCV infection; however, one study showed that after treatment with interferon alfa-2b for 24 weeks, 43 of 44 patients did not have detectable HCV-RNA.[85]

Hepatitis E.

The hepatitis E virus (HEV) is a 32-nm nonenveloped virus with 7.5-kb genome of single-stranded RNA. HEV was discovered in 1983 and is part of the alpha-super group of viruses. Some virologists place HEV in the Caliciviridae family of viruses. HEV is responsible for the majority of cases of what was previously called enterically transmitted non-A, non-B hepatitis (ET-NANBH).[86] Like HAV, HEV is almost always transmitted via the fecal-oral route through the ingestion of contaminated food or drink. During epidemics, the most common mode of transmission is the ingestion of fecally contaminated water.[87] Compared with HAV, there is a low rate of person-to-person transmission of household contacts. Nosocomial infection has been reported.[88]

After ingestion, the virus is absorbed through the small bowel and transported via the portal blood flow to the liver. After an incubation period of 15 to 60 days (average, 35 to 42) a preicteric phase characterized by fever and malaise is reported by 95% to 100% of patients. An icteric phase characterized by abdominal pain, nausea, vomiting, anorexia, and jaundice follows shortly after. Symptoms normally resolve in less than 6 weeks, although the fulminant hepatic failure is a rare but reported complication. A characteristic feature of HEV is the high incidence of progression to fulminant hepatic failure in pregnant women. If contracted in the third trimester, HEV mortality may exceed 20%.

The diagnosis of HEV is normally made by exclusion after travel to an endemic area (South and Central America, Southeast Asia including China, India, and Africa). Nevertheless, assays to detect both IgM anti-HEV and IgG anti-HEV are commercially available. PCR can be utilized to detect HEV-RNA; however, this is almost always done only for research purposes.

Currently, there is no vaccine available for HEV. The administration of immune globulin from endemic areas has not decreased infection rates during epidemics.[89] As such, it seems unlikely that the use of immune globulin would be of no particular use in the event of an exposure in a nonendemic area such as North America or Europe. Health care providers should utilize universal precautions when dealing with patients with suspected HEV infections. Obviously, pregnant women should avoid any kind of exposure to HEV.

Hepatitis G.

Hepatitis G virus (HGV) was first described in the serum of a patient with non-A, non-B, non-C hepatitis.[90] HGV and so-called GB viruses have been described.[91] HGV/GB are detectable in a substantial proportion of blood donors.[92] HGV and GB have a genomic sequence similar to HCV. Despite its genetic similarity to HCV, it does not appear that HGV/GB causes liver disease.[93] Indeed, the initial patient was later found to have HCV. Probably the most interesting aspect of HGV/GB study is that patients co-infected with HIV and HGV/GB seem to enjoy prolonged survival.[94]

Hydatid Cyst Disease

Hydatid cyst disease is caused by an infection of the animal tapeworm Echinococcus. Like all tapeworms, Echinococcus lives in the small bowel of definitive hosts. Definitive hosts include carnivorous animals such as dogs, wolves, and other canines. Tapeworm-infected canines pass eggs in their feces, which contaminate the environment. Sheep, cattle, and humans become intermediate hosts when they ingest the eggs by eating contaminated foodstuffs. Infected domestic dogs remain the most important vector for transmission of hydatid disease. [95] [96]

Once the eggs are ingested, gastric acid and digestive pancreatic enzymes dissolve the egg's external shell. The larvae then penetrate the bowel wall, enter the portal circulation, and are carried to the liver. Approximately 70% of the larvae remain in the liver, with 20% infecting the lungs, although other organs, including the brain,[97] spinal cord, [98] [99] kidney,[100] and heart[101] can be infected. In the liver,Echinococcus has virtually no symptoms until the cysts become very large. Although pain is the most common complaint, a large cyst may cause obstructive jaundice, cholangitis, pancreatitis, or portal hypertension. [95] [96] Blunt trauma may cause cyst rupture.[102] Diagnosis is normally made by serologic testing after abdominal imaging reveals hepatic cysts. An eosinophilia may also be present.

The treatment of large hydatid cysts is surgical, and the anesthesiologist is likely to encounter patients scheduled for cyst drainage. The surgical approach may be attempted by laparoscopy,[103] laparotomy, or thoracotomy if a subdiaphragmatic cyst is present. There are multiple case reports of an anaphylactic reaction to hydatid fluid during surgical excision. [104] [105] [106] Preoperative steroids and antihistamines[107] should be considered.

Genetic Causes of Liver Disease

Alagille Syndrome (Arteriohepatic Dysplasia).

Alagille syndrome (AGS) is a rare inherited disorder characterized by the progressive loss of the intralobular bile ducts and narrowing of extrahepatic bile ducts.[108] It is the most common form of familial intrahepatic cholestasis, and over 90% of patients experience chronic cholestasis. [108] [109] The disease has an autosomal dominant pattern of inheritance, and over 70% of patients have a mutation in the jagged 1 (JAG1) gene on the short arm of chromosome 20.[109] AGS has an incidence of approximately 1:100,000 live births.

Most patients present with jaundice, clay-colored stools and other symptoms of mild cholestasis during the neonatal period. Patients might also present with rapidly progressive, fulminant hepatic failure. The disease is slowly progressive, and treatment is generally supportive. Approximately 15% of patients will require transplantation.[110] A Kasai procedure may provide patients with some relief; however, a previous Kasai increases perioperative mortality if the patient should require hepatic transplantation.[110]

Although the primary manifestation of AGS is cholestasis, AGS is of particular interest to anesthesiologists secondary to the high morbidity of its associated conditions. Over 90% of patients with AGS have congenital heart disease. Approximately 67% of patients have uncomplicated peripheral pulmonic stenosis; however, the remaining 33% have more serious defects, including tetralogy of Fallot (16%), patent ductus arteriosus (5%), ventricular septal defect (4%), and atrial septal defect (4%). The presence of significant cardiovascular disease is associated with increased perioperative mortality during liver transplantation.[110] So-called “butterfly vertebrae” resulting from clefting abnormalities are present in as many as 85% of patients. [108] [111] Patients are described as having a characteristic facies, and as many as 90% of patients have ophthalmologic abnormalities, commonly anterior chamber defects such as posterior embryotoxon. [108] [111] Patients have a characteristic short stature, and resistance to growth hormone has been described.[112]

A meticulous preoperative evaluation of patients with AGS is critical for perioperative planning and optimization of care. Careful attention must be given to associated conditions, with particular attention to each patient's cardiac,[113] hepatic, renal, and orthopedic disease.[114] In some patients, a vitamin K deficiency develops secondary to malabsorption. If blood loss is possible, preoperative clotting studies may be indicated. Severe postoperative cholestasis has been reported in patients with AGS.[115]

α1-Antitrypsin Deficiency.

α1-Antitrypsin deficiency is the most common metabolic disease affecting the liver. The disease is most common among white Europeans, in whom the incidence of disease may be as high as 1:1500 persons.[116] The disease is somewhat less common among North American and Australian whites, in whom the incidence approaches 1:2000 persons. The incidence among African, Asian, and Hispanic individuals is very low. The precise geographic distribution of the disease is critically dependent on the specific genotype.

α1-Antitrypsin is a potent serine protease inhibitor synthesized in the liver and secreted into the blood. As it circulates, it binds to and promotes the degradation of serine proteases produced throughout the body. One of the most important proteases inhibited by α1-antitrypsin is elastase. Indeed, α1-antitrypsin is responsible for more than 90% of all the serum antielastase activity and is principally involved in the degradation of alveolar elastase. Once bound to its protease target, the α1-antitrypsin:protease complex binds to a receptor on hepatocytes and is removed from the circulation.[117]

The α1-antitrypsin gene has been localized to chromosome 14 and is part of the SERPIN (Serine Protease Inhibitor) supergene. This gene cluster also encodes for corticosteroid binding globulin, C1 inhibitor, and antithrombin III.[116] At least 17 different mutant alleles of α1-antitrypsin have been described; however, two mutations account for the majority of disease. Individuals homozygous for the more common S mutation (Glu264Val) have a 40% decrease in serum α1-antitrypsin concentration.[118] The S mutation is more common among Southern Europeans, with peak incidences recorded in the Iberian peninsula.[116] Individuals homozygous for the more serious Z mutation (Glu342Lys) have an 85% decrease in serum α1-antitrypsin concentration.[118] Unlike the S mutation, the Z mutation is more common among Northern and Western Europeans, with peak incidences in northern France, the United Kingdom, and Scandanavia.[116] In general, the S mutation only produces clinically significant disease when it is combined with the Z mutation (SZ genotype).

The low serum protein concentrations observed in individuals with α1-antitrypsin deficiency do not occur secondary to defective protein synthesis but rather to ineffective processing and secretion. [119] [120]These ineffective processes leave the hepatocyte with large quantities of defective protein that accumulate in the cell. Defective processing is particularly severe in the Z mutation, where processing errors lead to the formation of long polymers of Z - α1-antitrypsin.[119] In both mutations, the excess of defective α1-antitrypsin is visible under light microscopy as large cytoplasmic inclusions. Stores of excessive defective protein ultimately can interfere with normal hepatic function.[121]

The abnormal accumulation of defective protein leads to hepatocyte death and eventual cirrhosis. In general, the severity of hepatic disease is closely associated with the amount of accumulated protein. Liver disease does not occur in individuals with unusual mutations of α1-antitrypsin that do not result in the accumulation of defective protein the hepatocyte. There is significant variation in clinical presentation and age at onset among patients with α1-antitrypsin deficiency, even among individuals with the same genotype. It has been suggested that the variation in the age at onset of liver disease is due to variations in the rate of synthesis between individuals.[122] Indeed, the appearance of jaundice in infants with ZZ α1-antitrypsin deficiency may reflect a chronic infection resulting in increased synthesis of defective protein.[123] Regardless, the appearance of jaundice during the neonatal period is a poor prognostic sign. Although α1-antitrypsin deficiency has a number of other manifestations, it is well accepted that liver disease has the greatest effect on survival.

The other primary clinical manifestations of individuals with α1-antitrypsin deficiency occur secondary to the absence of normal protease inhibition. The most obvious manifestation of disease secondary to the lack of normal protease inhibition occurs in the lung, as patients with α1-antitrypsin deficiency suffer from the early onset of panlobular emphysema. All individuals experience an age-related decline in the forced expiratory volume in 1 second (FEV1) after age 30; however, this decline is accelerated by α1-antitrypsin deficiency. This acceleration is further exacerbated by tobacco smoke, which can double the rate of decline.[124]

The diagnosis of α1-antitrypsin deficiency is made by the measurement of serum α1-antitrypsin concentration. The genotype is confirmed by protein electrophoresis. There is no specific therapy for α1-antitrypsin deficiency, and liver transplantation may be required.

Cystic Fibrosis.

Cystic fibrosis (CF) is the single most common lethal inherited disease among white populations, with an incidence of approximately 1:3300 persons in the United States. CF was one of the first genetic diseases to be characterized. The gene for CF, the cystic fibrosis transmembrane conductance regulator (CFTR), resides on chromosome 7. Presence of the gene results in defective cellular chloride conductance. Although the principal manifestation of CF is pulmonary with associated viscid secretions, atelectasis, emphysema, and chronic infections with mucoid chronic infection with Pseudomonas aeruginosa, hepatic abnormalities may complicate 20% of cases. Portal hypertension and eventual hepatic cirrhosis may complicate up to 10% of all CF cases and represent the second most common cause of death after respiratory failure. As the median age of CF increases secondary to a reduction in mortality, there has been concern that the incidence of liver disease would increase.

Although pathologic elevation of liver enzymes is frequently observed in infants, most patients do not progress to childhood or adult cirrhosis.[125] Nevertheless, it is clear that certain genotypes are clearly associated with liver dysfunction and an increased incidence of cirrhosis.[126] There is also an increased incidence of liver disease in patients with certain major histocompatibility complex genotypes,[127]male gender, coexisting liver disease, and poor nutrition (especially fatty acid deficiency). Major liver disease is rarely noted in the absence of pancreatic insufficiency.

When hepatic disease advances to cirrhosis, it normally presents during the first decade of life. Portal hypertension is usually manifested by splenomegaly, hypersplenism with thrombocytopenia, and ascites.[128] Bleeding of esophageal varices is also noted in some patients. Transjugular intrahepatic portosystemic shunting (TIPS) has been used with success in children and adolescents with refractory esophageal bleeding. [129] [130] In severe cases, liver transplantation has been performed. [131] [132] The anesthesiologist should be aware that the metabolism of certain drugs[133] may be increased in CF secondary to increased hepatic drug clearance.[134]


Galactosemia is an inherited deficiency of the enzyme galactose-1-phosphate uridyltransferase. Galactose-1-phosphate uridyltransferase catalyzes the conversion of galactose-1-phosphate to UDP-galactose, and deficiency leads to the abnormal accumulation of galactose-1-phosphate in cells. The enzyme is normally present in liver and erythrocytes. Galactosemia is an extremely rare disorder with an incidence of approximately 1:60,000 births. Galactose-1-phosphate is directly toxic to cells, and accumulation is most notable in the kidney, liver, and brain.

Breast milk contains lactose, a disaccharide consisting of glucose and galactose. As newborn infants receive up to 20% of their caloric intake in the form of lactose, infants with galactosemia rapidly accumulate galactose-1-phosphate. Routine newborn screening normally makes the diagnosis of galactosemia. If the diagnosis is not made, the accumulation of galactose-1-phosphate can ultimately lead to cataracts, severe mental retardation, and cirrhosis. Treatment involves the avoidance of lactose in the diet; however, patients treated appropriately still develop long-term complications, including cognitive impairment, cataracts, speech abnormalities, and primary ovarian failure. [135] [136] Infants born with galactosemia have an increased incidence of Escherichia coli neonatal sepsis that normally precedes the diagnosis of galactosemia.[137] Without treatment, the disease is generally fatal, although case reports of adult patients presenting decompensated cirrhosis exist.[138] Galactokinase deficiency, another inherited disorder of galactose metabolism, is less common than galactosemia and generally has a milder course.[139]

Galactosemia may present the anesthesiologist with several unique challenges. Newly diagnosed newborns who have been treated for a short time may have elevated clotting times and be prone to bleeding. Some patients may have hemolysis, and preoperative evaluation of hemoglobin may be valuable in any jaundiced patient. Finally, albuminuria may cause an osmotic diuresis, and, consequently, urine volume may be a poor indicator of intravascular volume.

Glycogen Storage Diseases.

Glycogen is the principal storage form for glucose in the human body. It is composed of long chains of glucose joined together by α-1,4 linkages. The chains intermittently branch by α-1,6 linkages to form long, tree-like strands of stored glucose. Glycogen stands as a ready reserve for glucose in times of metabolic need. Glycogen metabolism principally occurs in skeletal muscle and liver. Skeletal muscle glycogen provides exercising muscles with a ready source of fuel while hepatic glycogen serves to maintain plasma glucose during fast. The glycogen storage disorders compromise a family of 10 different diseases. Each disease is characterized by an enzyme deficiency in glycogen metabolism. Only glycogen storage disorders type I, III, and IV are associated with severe hepatic disease. The characteristics of the glycogen storage disorders are summarized in Table 5-4 .

TABLE 5-4   -- Glycogen Storage Disorders


Enzyme Deficiency

Main Clinical Features

Liver Disease



Type Ia (von Gierke's disease)


Profound hypoglycemia

Hepatomegaly (normal spleen)

Portal diversion shunting

Type Ib (10% of type I disease) also associated with neutropenia and neutrophil dysfunction



Growth failure

Hepatic adenomas (by second decade of life)

Glucose supplementation (cornstarch, nocturnal glucose infusion)




Metabolic acidosis

Occasional hepatocellular carcinoma

Liver transplantation










Renal failure (by second decade of life)






Diagnosis in infancy




Type IIIa (Cori-Forbe's disease)

Liver and muscle debranching enzyme

Profound hypoglycemia

Hepatomegaly (normal spleen)

High-protein, low-carbohydrate diet

Type IIIb (15% of type III) has normal muscle debranching enzyme and no muscular symptoms



Growth failure

Hepatic adenomas (less common than type I)

Glucose supplementation (cornstarch, nocturnal glucose infusion) rarely necessary

Generally improves with age



Progressive muscle weakness with activity

Rare hepatocellular carcinoma





Muscle atrophy






More tolerant to fasting than type I






Diagnosis in infancy




Type IV (Andersen's disease)

Branching enzyme

Failure to thrive


Death without liver transplantation




Abdominal distention

Progressive macronodular cirrhosis





Miscellaneous gastrointestinal complaints

Hepatic failure











Hypoglycemia rare






Diagnosis in infancy






The perioperative management of any patient with a glycogen storage disorder requires meticulous care and planning. Obviously, the blood glucose level should be carefully monitored in any patient with a type I or III glycogen storage disorder. NPO guidelines should be followed, and patients may require preadmission for the intravenous administration of glucose-containing fluids. Case reports of successful anesthetic management of patients with a type I glycogen storage disease have been reported. [140] [141] [142] Patient-controlled sedation with propofol during spinal anesthesia has also been successfully employed.[143] Patients with a type III glycogen storage disease may pose a special challenge to anesthesiologists secondary to muscle disease.[144] Liver transplantation has been used to treat type I, III, and IV glycogen storage diseases,[145] but cardiomyopathy may persist in type IV secondary to cardiac amylopectin deposition.[146]

Hereditary Fructose Intolerance.

Hereditary fructose intolerance (HFI) is an inherited deficiency of the enzyme fructose-1,6-bisphosphate aldolase (aldolase B). Aldolase B catalyzes the conversion of fructose-1,6-bisphosphate to two triose phosphates, dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. Deficiency leads to the abnormal accumulation of fructose-1-phosphate and initiates severe symptoms when patients are exposed to fructose. The enzyme is normally present in liver, kidney, and small bowel. HFI is an extremely rare disorder, with an incidence of approximately 1:23,000 births, almost three times that of galactosemia.

When patients consume fructose or sucrose (a disaccharide consisting of glucose and fructose), the acute presentation of abdominal pain, malaise, hypoglycemia, nausea, and vomiting is often noted. Continued ingestion of fructose yields jaundice, hepatomegaly, and renal dysfunction.[147] Persistent fructose consumption results in fulminant hepatic failure. Treatment consists of the avoidance of fructose and sucrose in the diet. Unlike galactosemia, patients are normally without symptoms if fructose is avoided, and intellectual development is unimpaired. Some investigators believe that HFI is underdiagnosed, and formal testing yields the diagnosis among patients with unexplained, chronic abdominal pain.[148] Secondary to an almost complete absence of dietary sucrose, patients with HFI have an excellent dentition.[149] Obviously, oral medications containing sucrose or fructose should be avoided in patients with HFI.

Hereditary Hemochromatosis.

Hereditary hemochromatosis is an autosomal recessive disease characterized by an inappropriately high degree of iron absorption. In the past, it had been theorized that the disorder occurred due to alcohol abuse and was merely a secondary nutritional disorder; however, the gene was later found to reside on the short arm of chromosome 6, closely linked to the genes encoding for human leukocyte antigen (HLA). [150] [151] It was not until 1996 that the gene responsible for hemochromatosis (HFE) was discovered, allowing for formal genetic testing and diagnosis.[152] There are a variety of conditions, both acquired and idiopathic, that can be characterized by excessive total body iron ( Table 5-5 ). In many cases, these diseases mimic hereditary hemochromatosis and may be superficially indistinguishable in their clinical manifestations. Nevertheless, it is universally accepted that hereditary hemochromatosis refers specifically to increased iron absorption secondary to HFE-related genetic mutations.

TABLE 5-5   -- Iron Overload Conditions



Primary Iron Overload



Hereditary hemochromatosis






Juvenile hemochromatosis



Transferrin receptor-2 mutations



Ferroportin-1 mutations



African iron overload



Secondary Iron Overload



Red blood cell transfusions



Iron loading anemias



Thalassemia major



Sideroblastic anemia



Chronic hemolytic anemia



Aplastic anemia



Pyruvate kinase deficiency



Long-term dialysis



Chronic liver disease



Hepatitis B



Hepatitis C



Alcoholic liver disease



Nonalcoholic steatohepatitis



Portocaval shunting

Adapted from Harrison SA, Bacon BR: Hereditary hemochromatosis: Update for 2003. J Hepatol 2003;38:S14–S23.




As specific HFE mutations are identified and investigated, it has become increasingly clear that hereditary hemochromatosis represents a spectrum of clinical disease. Indeed, some homozygotes may manifest disease without a substantial increase in iron stores[153] whereas others do not manifest clinical symptoms in any appreciable way. In addition, although HFE is equally distributed between the sexes, clinical disease is two to eight times more common in men than women. It has become increasingly popular to classify patients with hereditary hemochromatosis into four groups: (1) genetic predisposition without abnormalities, (2) iron overload without symptoms, (3) iron overload with early symptoms, and (4) iron overload with end organ damage.[154] It is clear that other factors, genetic and environmental,[155] influence the development of clinical disease. Indeed, the early observation of the link between hereditary hemochromatosis, cirrhosis, and alcohol abuse may be explained by the fact that alcohol further increases the absorption of iron.[156]

The normal adult has a total body iron content of 3 to 5 g. Most iron is recycled through the phagocytosis of senescent erythrocytes and only 1 to 2 mg of iron is normally lost each day.[157] Obviously, losses may be greater among menstruating women and in the case of acute or chronic blood loss. Consequently, dietary iron absorption is tightly regulated with the amount absorbed paralleling the body's needs. In hereditary hemochromatosis, regulatory processes fail. [155] [158] This results in an abnormal increase in dietary iron absorption with iron deposition in the skin, heart, pancreas, joints, and liver.

Hereditary hemochromatosis is surprisingly common. In some white European populations, 10% to 12% of people are heterozygous carriers of the disease.[159] The incidence of homozygous hereditary hemochromatosis ranges between 1:100 to 1:400 in white persons of European descent. [160] [161]

Primary presentation of symptomatic hereditary hemochromatosis is becoming rare. Most patients are asymptomatic and report for evaluation and genetic testing after a family member develops the disease. Nevertheless, most symptomatic patients present in the fifth or sixth decade of life. The liver is the first organ to be affected in hemochromatosis, and hepatomegaly is noted in nearly 100% patients. The most common presenting symptoms include generalized weakness, malaise, arthralgias, abdominal pain, and impotence (in men).[162] Physical examination may reveal hepatomegaly and, in advanced cases, signs and symptoms of cirrhosis including ascites and jaundice. Diabetes mellitus, secondary to pancreatic iron deposition, may also occur, although it is rare in the absence of cirrhosis. Iron deposition in skin may give patients a bronze coloration. Indeed, hemochromatosis has been referred to as “bronze diabetes.” Iron deposition in the heart can lead to fibrotic changes and most commonly to a restrictive cardiomyopathy. An increase in fatal and nonfatal arrhythmias is also noted. An arthropathy, especially of the hands, is noted in about 50% of patients but does not commonly present before age 50.

As iron accumulates in the liver, significant hepatocyte damage occurs. The fundamental disease mechanism results from direct iron toxicity and the consequent increase in iron-generated free radical production. [163] [164] [165] [166] The increased oxidative stress results in lipid peroxidation, [165] [166] mitochondrial injury,[154] and impaired calcium homeostasis. [164] [165] This results in an inflammatory response, fibrin deposition, and ultimately hepatic cirrhosis. Further oxidative stress may result in DNA damage and an increased risk of hepatocellular carcinoma.[164] Hepatocellular carcinoma is the most common cause of death in hereditary hemochromatosis and the risk is 200 times greater than the general population.[167] Complications arising from cirrhosis and congestive heart failure are other common causes of death.

Once the diagnosis of hereditary hemochromatosis is made, treatment with phlebotomy and reduction of alcohol and dietary iron intake should be initiated. The goal of therapy is to not make the patient iron deficient or anemic.[154] Thus, careful monitoring of hemoglobin, iron levels, ferritin, and transferrin saturation should guide therapy. Although phlebotomy and careful monitoring of dietary intake effectively reduce iron stores, therapy does not reverse cirrhosis nor totally eliminate the risk of hepatocellular carcinoma. This is especially true among patients first diagnosed at a more advanced age. As such, early diagnosis and treatment, ideally before the onset of symptoms, is critical. Liver transplantation may represent the only treatment in advanced disease or in cases of hepatocellular carcinoma; however, many studies reveal decreased survival in transplanted patients with hereditary hemochromatosis compared with other indications.[168]

Hereditary Tyrosinemia Type 1 (HT1).

There are four known deficiencies in the catabolism of tyrosine: alkaptonuria and tyrosinemia types 1, 2, and 3. Only tyrosinemia type 1 is associated with liver disease. HT1 is an inherited deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). The enzyme catalyzes the final step in phenylalanine and tyrosine catabolism, the conversion of fumarylacetoacetate to acetoacetate and fumarate. FAH deficiency leads to the abnormal accumulation of “upstream” tyrosine metabolites fumarylacetoacetate (FAA) and maleylacetoacetate (MAA). Both FAA and MAA are converted to two toxic products, succinyl acetoacetate (SAA) and succinylacetone (SA). SAA and SA have been shown to interfere with DNA ligase activity,[169] reduce blood and liver stores of glutathione,[170] and interfere with heme metabolism. These effects combine to decrease the body's ability to deal with oxidative stress and directly result in mutagenic damage and chromosomal breakage.[171] Initially, liver biopsy reveals steatohepatitis; however, this advances to fibrosis and cirrhosis.

HT1 is an extremely rare disorder with an incidence of approximately 1:100,000 births; however, the incidence may be higher in northern Europe (1:8000) and in Quebec, Canada (1:1846). [172] [173]Essentially two forms of the disease exist, an acute form and a chronic form. In the acute form, patients present with symptoms of severe hepatic dysfunction during the first 6 months of life. Liver biopsy reveals steatohepatitis that advances to fibrosis and micronodular cirrhosis with bile duct proliferation. In general, the acute form is rapidly fatal within the first year of life without hepatic transplantation.

The chronic form of HT1 presents more slowly than the acute form, with patients rarely seeking medical care before the age of 1 year. The progress of hepatic dysfunction tends to occur more slowly, and patients develop other symptoms, including nephropathy, rickets, and serious neurologic problems.[174] Secondary to continued DNA damage, a substantial risk of hepatocellular carcinoma exists. Liver biopsy reveals less cholestasis than the acute form; however, macro- and micronodular cirrhosis are eventually noted. Liver transplantation is normally indicated within the first decade of life; however, recent advances in the understanding and treatment[175] of HT1 offer some hope.[176] Patients may develop hypertrophic cardiomyopathy. Anemia and thrombocytosis may be observed. Clotting studies may be prolonged.

There is no specific information regarding anesthetic care in patients with HT1; however, preoperative assessment of cardiac, hepatic, metabolic, and hematologic function should be considered if possible.

Lysosomal Storage Diseases.

Lysosomal storage diseases are a heterogenous group of diseases resulting from different defects in lysosomal function. Each disease normally reflects a lysosomal enzyme deficiency and a consequent inability to metabolize various biomolecules. Most diseases follow an autosomal recessive pattern of inheritance. Of the more than 30 well-classified diseases, only a small number result in hepatic disease and impairment.


Each mucopolysaccharidosis (MPS) results from the deficiency of an enzyme responsible for glycosaminoglycan (GAG) metabolism. GAGs are complex, long-chain carbohydrates that are normally linked to proteins to form proteoglycans. Proteoglycans are common constituents of connective tissue.

MPS I results from the deficiency of α-l-iduronidase. At least three phenotypes exist: (1) MPS IH (Hurler's disease) has an acute course characterized by hepatosplenomegaly, mental retardation, and death normally occurring in the first decade; (2) MPS IS (Scheie's disease) has a less severe course characterized by hepatosplenomegaly after the age of 5 and normal life span without mental retardation; and (3) MPS IH/S follows an intermediate course. In all diseases, hepatosplenomegaly can be massive and the diseases can cause profound skeletal dysplasia.[177] Myocardial, coronary, and valvular heart disease are commonly observed.[177] Corneal “clouding” is an expected complication, and patients may present for corneal transplant. Patients frequently require surgical interventionfor orthopedic abnormalities. A stiff neck, large tongue, and tonsillar hypertrophy may make intubation difficult. [178] [179] Copious airway secretions may be treated with anticholinergics. Fiberoptic intubation through a laryngeal mask airway (LMA) has been reported and may represent a useful technique, especially in children.[180] Patients should be considered at risk for airway obstruction and postobstructive pulmonary edema.[181]Failure of epidural anesthesia has been reported and may be related to the accumulation of GAGs in the epidural space.[182] Perioperative antibiotics may be indicated in patients with valvular disease.

MPS II (Hunter's disease) results from the deficiency of iduronate sulfatase and has an X-linked recessive pattern of inheritance. Both a severe infantile and mild juvenile form of the disease exist. In addition to massive hepatosplenomegaly, GAGs accumulate in the head and neck and patients have a short neck and large tongue. Unlike MPS I, corneal disease is rare. Nevertheless, endotracheal intubation can be difficult [178] [179] and acute airway obstruction has been reported.[183] Failure of the LMA to secure the airway in a patient with MPS II has been reported[184]; however, fiberoptic intubation through an LMA has also been reported and may represent a useful technique in children.[180] Sleep apnea and postobstructive pulmonary edema have been reported.[181]

MPS VII (Sly syndrome) results from the deficiency of β-glucuronidase and has an autosomal recessive pattern of inheritance. At least four phenotypes exist.[185] The neonatal form of the disease presents as hydrops fetalis and is uniformly fatal.[186] An infantile form presents as hepatosplenomegaly, jaundice, and inguinal and umbilical hernias. It is rapidly progressive and has a poor prognosis. A second infantile form also presents as hepatosplenomegaly but seems to have a milder course.[187] The adult form of MPS VII presents in adolescence and is not normally complicated by hepatic involvement. Patients may have cardiac involvement with mitral and/or aortic insufficiency. Acute aortic dissection has been reported. Secondary to the accumulation of GAGs in the head and neck, patients with MPS VII may also be difficult to intubate; however, this has not been specifically reported with MPS VII. Intraoperative complete heart block has been observed.[188] Patients with aortic or mitral insufficiency may require perioperative antibiotic prophylaxis.

Lipid Storage Disorders.

Each of the lipid storage disorders results from the deficiency of an enzyme responsible for lipid metabolism. The lipid storage disorders include Fabry's disease (FD), Gaucher's disease (GD), and Niemann-Pick disease (NPD). Only GD and NPD have hepatic manifestations and are discussed here.

Gaucher's disease results from the deficiency of acid β-glucosidase and has an autosomal recessive pattern of inheritance. GD is the most common lysosomal storage disease. Three phenotypes have been described. [189] [190] The adult type (GD type 1) represents 99% of cases and has a variable onset. It is characterized by thrombocytopenia,[191] anemia, and hepatosplenomegaly. Bone pain is a common complaint, and pathologic fractures can occur. Although hepatosplenomegaly may be the most prominent feature, most morbidity occurs secondary to bone pain. Intelligence is normal, and neurologic symptoms are rare. The availability of placental and now recombinant glucocerebrosidase has improved morbidity in many patients and can result in a decrease in liver volume. [191] [192] Improvement in blood coagulation abnormalities has also been described.[193] Adult GD has a carrier rate of approximately 1:18 among Ashkenazi Jews and an annual incidence of approximately 1:1000 live births in the United States.[189]

The accumulation of glycosphingolipids in the head and neck may make endotracheal intubation difficult, and patients may require a smaller than predicted endotracheal tube. Patients should be considered at risk for upper airway obstruction. [194] [195] A small mouth may make LMA insertion difficult.[194] Preoperative evaluation should include a baseline hemoglobin and platelet count, because patients are at risk for anemia and thrombocytopenia. Spinal anesthesia has been used with success.[196]

Infantile GD (GD type 2) is characterized by hepatosplenomegaly and severe developmental delay. Stridor and laryngospasm are frequent complications. The disease progresses rapidly, and death occurs before age 2. Juvenile GD (GD type 3) is characterized by ataxia, hepatosplenomegaly, and mental retardation. The typical onset occurs during childhood and patients normally die before age 15. Juvenile GD has a peak incidence in the Swedish Norrbotten population, with an incidence of 1:50,000 persons. Gastroesophageal reflux and chronic aspiration can complicate both types 2 and 3 GD. As in type 1 GD, the airway management of patients with types 2 and 3 may be difficult and patients are at risk for postoperative respiratory compromise.[197] Regional anesthesia has been used with success and should be considered.

Niemann-Pick disease results from the deficiency of sphingomyelinase and has an autosomal recessive pattern of inheritance. At least six phenotypes of NPD have been described; however, three forms make up the majority of cases.[198] Infantile neuropathic NPD (NPD type A) normally presents before 6 months of age and is characterized by hepatosplenomegaly, lymphadenopathy, seizures, and mental retardation. A progressive loss of intellectual capacity and motor function is noted secondary to increased deposition of sphingomyelin in the central nervous system.

Non-neuronopathic NPD (NPD type B) has a variable age of presentation and a more heterogenous expression. Nevertheless, most patients are diagnosed in childhood with hepatosplenomegaly. Unlike type A, patients with type B NPD are neurologically intact and systemic deposition of sphingomyelin is more prominent. Hepatic cirrhosis may develop and portal hypertension and ascites can complicate patient disease. Many type B patients develop pulmonary disease characterized by severe diffusion limitations. Such patients may have low Pao2 and develop cor pulmonale and right ventricular failure in the second decade of life.

Patients with type C NPD actually have a deficiency in cholesterol transport that leads to a disease that is phenotypically similar to type A and B NPD.[199] Patients with type C disease present with prolonged neonatal jaundice. Hepatosplenomegaly is less severe than in types A and B, and patients normally undergo slowly progressive neurodegeneration.

Airway management may be more difficult in patients with NPD.[200] Pulmonary disease may complicate perioperative care, especially in individuals with type B disease. Liver transplantation has successfully reduced some of the clinical manifestations in patients with type A and B NPD; however, morbidity and mortality of liver transplantation may be extremely high secondary to pulmonary and neurologic disease. [201] [202]

Other Lysosomal Storage Diseases

Mannosidosis results from the deficiency of α-mannosidase.[203] An infantile form of the disease is characterized by progressive mental retardation and hepatosplenomegaly. Cataracts and corneal clouding may also be observed. An adult form has a delayed onset and allows for longer survival. A small mouth and a large tongue may make intubation difficult. Death normally occurs before age 5. An autosomal recessive pattern of inheritance is noted in this extremely rare disease.

Wolman's disease results from the deficiency of acid lipase and is characterized by the deposition of cholesterol esters throughout the body.[204] Hepatosplenomegaly and eventual cirrhosis are among the more prominent manifestations; however, pulmonary disease with a high alveolar diffusion gradient may be severe. Adrenal calcification is a unique feature. Neonatal survival is impossible without total parental nutrition, and death occurs within the first year of life. Bone marrow transplantation has been successfully utilized to treat Wolman's disease.[205] There is no specific information regarding anesthesia in patients with Wolman's disease.


The porphyrias make up a family of inherited diseases resulting from deficiencies in one or more of the enzymes required for heme synthesis. The enzymatic deficit results in the accumulation of “upstream” metabolites and consequent symptoms ( Fig. 5-6 ). As more than 75% of heme synthesis takes place in the bone marrow, porphyrias are associated with variable hepatic disease. Traditionally, porphyrias are generally divided into erythropoietic or hepatic types, depending on whether the excess production of metabolic intermediates takes place in the liver or in the bone marrow. Porphyrias can be further divided into those with neurovisceral symptoms (acute porphyrias) and those characterized by photosensitivity and cutaneous symptoms (cutaneous porphyrias). Table 5-6 summarizes the characteristics of the various porphyrias.[206]


FIGURE 5-6  Heme synthesis and the enzymatic defects of porphyria.



TABLE 5-6   -- The Porphyrias


Enzyme Defect

Autosomal Inheritance

Site of Expression


Acute Porphyrias

ALA dehydratase deficiency

ALA dehydratase



Very rare

Acute intermittent porphyria (AIP)

PBG deaminase



Most common acute porphyria

Hereditary coproporphyria

Coproporphyrinogen oxidase



Similar to AIP

Variegate porphyria

Protoporphyrinogen oxidase



Common in South Africa

Cutaneous Porphyrias

Porphyria cutanea tarda

Uroporphyrinogen III decarboxylase



Most common porphyria

Hepatoerythropoietic porphyria

Uroporphyrinogen III decarboxylase


Liver, erythropoietic

Similar to CEP

Erythropoietic protoporphyria



Liver, erythropoietic

Mild hemolysis










Occasional liver disease

Congenital erythropoietic porphyria (CEP)

Uroporphyrinogen III cosynthase



Splenomegaly Hemolysis



Acute intermittent porphyria (AIP) is the most common type of porphyria, with a prevalence of about 1:10,000 to 1:20,000 people. Secondary to the disease's ability to cause neuronal damage, the incidence of AIP among patients with psychiatric disorders may be as high as 1:500. [207] [208] AIP may be considered the prototype for all acute porphyrias, as the presentation of all acute porphyrias is similar with specific diagnosis requiring laboratory analysis.

In AIP, patients suffer a deficiency of PBG deaminase activity. Because a complete deficiency would be incompatible with life, most patients have approximately 50% of normal PBG deaminase activity. The deficiency results in an increase in cellular 5-aminolevulinic acid (ALA). Most patients are generally asymptomatic until some event stimulates the production of ALA. The deficiency of PBG deaminase activity results in relative ALA overproduction and consequent symptoms. Precipitating factors that lead to an acute exacerbation include (1) stimulation of ALA synthetase production in the liver; (2) endocrine factors including the female reproductive cycle; (3) fasting, especially in combination with alcohol intake; (4) induction of hepatic cytochrome P450 that leads to ALA synthetase production through a reduction in inhibitory heme; and (5) emotional stress, including surgery and chronic illness.[206] Clinical onset occurs most often after puberty and is more common in women, likely secondary to the effects of hormones and corticosteroids on the liver.

An acute attack is normally heralded by the presence of colicky abdominal pain, nausea, and vomiting, followed by the appearance of dark urine.[209] Patients may also complain of diarrhea or constipation. Classically, neurologic symptoms follow the onset of visceral complaints and may be highly variable. Patients may experience seizures, peripheral neuropathy, and cranial nerve deficits. They may become psychotic. Hyponatremia may be observed secondary to the syndrome of inappropriate antidiuretic hormone release (SIADH).

The cornerstone of treatment in AIP, as all acute porphyrias, includes the recognition and avoidance of precipitating factors. Once precipitating factors have been eliminated, glucose therapy (400 g/day) and/or heme arginate (3 mg/kg/day for 3 days) may be instituted.[206] Glucose and heme arginate work to decrease ALA synthetase activity and have been found to reduce the urinary excretion of ALA and shorten the length of an acute attack.

In the patient with a history of acute porphyria, optimal perioperative care includes careful planning and communication between surgeons, anesthesiologists, and internists. Presurgical admission for intravenous hydration with glucose-containing fluids is an important step in the patient with a history of acute attacks. A large carbohydrate load may suppress the synthesis of ALA synthetase and may be beneficial.[210] The selection of appropriate anesthetics and analgesics is important, because many drugs frequently used in anesthesia have the capacity to induce ALA synthetase and cytochrome P450.[211] [212] Table 5-7 summarizes the safety of various drugs frequently used in anesthesia. Many otherwise asymptomatic patients with AIP (or any acute porphyria) may present for anesthesia with a misdiagnosed “surgical” abdomen. Patients should be kept warm, because cold-induced stress may precipitate an acute crisis. Regional anesthesia has been used with success.[213]

TABLE 5-7   -- Porphyria and the Safety Anesthetics

Generally Considered Safe


Generally Considered Unsafe

Intravenous Agents










Inhaled Agents

Nitrous Oxide













Muscle Relaxants







Local Anesthetics























Adapted from Jensen NF, Fiddler DS, Striepe V: Anesthetic considerations in porphyrias. Anesth Analg 1995;80:591–599; and Stevens JJ, Kneeshaw JD: Mitral valve replacement in a patient with acute intermittent porphyria. Anesth Analg 1996;82:416–418.



Liver transplantation has been used successfully to cure AIP.[214] Attempts to treat other porphyrias with liver transplantation have met with mixed success. [215] [216] [217] [218] [219]

Wilson's Disease (Hepatolenticular Degeneration).

Wilson's disease (WD) is an autosomal recessive disease that results in the abnormal accumulation of copper in the liver, kidney, and central nervous system. WD is one of the oldest diseases to be recognized as familial, being first described by Kinnear Wilson in 1912 as a progressive disease characterized by hepatic cirrhosis and softening of the lenticular nucleus.[220] Over the past century, WD has changed from a universally fatal familial disease to a treatable disease with multiple therapeutic options. WD is present in all populations and has an incidence of approximately 1:30,000 persons. The gene responsible has been located in chromosome 13. The disease is more common among Jewish eastern Europeans and certain Asian populations.[221]

Copper is an essential metal required for the normal function of a variety of enzymes including lysyl oxidase, superoxide dismutase, tyrosinase, and monoamine oxidase. [222] [223] Copper metabolism is a complex process.[224] Briefly, copper is absorbed from the small intestine and bound to albumin. Over 90% of copper-bound albumin is taken up by the liver.[223] In the liver, copper binds to apo-ceruloplasmin to form ceruloplasmin. It is noteworthy that the incorporation of copper into apo-ceruloplasmin is an ATP-dependent process. Saturated with six molecules of copper, ceruloplasmin is released into the blood. Ceruloplasmin is also an acute phase reactant, with increased levels found in various inflammatory conditions. Throughout the body, copper is taken up by cells and delivered to its target enzymes after binding to various thiol-rich metallochaperones.[225]

The only physiologic means of copper excretion is through the bile. In WD, patients lose the ability to effectively mobilize copper for biliary excretion.[226] This defect leads to increased serum levels of copper. High levels of copper induce metallochaperone production. As metallochaperones are able to sequester copper in a nontoxic form, patients normally remain asymptomatic until copper supply overwhelms the absorptive power of metallochaperones. Ceruloplasmin levels are low in patients with WD, as they are in patients with liver cirrhosis of any cause.[227]

The presentation of WD varies widely. In general, patients present with symptoms of liver disease before the onset of neurologic symptoms.[228] Normally, WD presents in children and young adults with nonspecific symptoms including nausea, vomiting, and abdominal pain. Patients may give a history of mild, intermittent jaundice, and some patients may present with hepatomegaly or hepatosplenomegaly. WD may also present as fulminant hepatic failure [229] [230] or an incidental, asymptomatic elevation of serum transaminases. WD can imitate a variety of liver diseases, including autoimmune hepatitis. WD should be considered in the differential diagnosis of established liver disease, even in the preschool-aged child.[231]

Most patients present with the neurologic manifestations of WD in adulthood. Pseudosclerosis is noted, and patients present with parkinsonian features or rigid dystonia. The classically described lenticular degeneration of WD tends to present in childhood and is more often associated with dystonia. Children are often described as having a “sardonic smile.” The clinical hallmark of WD is the presence of a Kayser-Fleischer ring, a yellow-brown ring around the cornea. The Kayser-Fleischer ring is caused by copper deposition in Descemet's membrane. The ring is best demonstrated under slit lamp examination; however, the ring may be plainly visible. The Kayser-Fleischer ring is present in over 98% of patients with neurologic manifestations of WD and over 80% of patients with WD.[223]Approximately 30% of patients with WD will have psychiatric symptoms. The most common symptoms include depression and irritability; however, patients may present with frank catatonia. [232] [233]

The diagnosis of WD requires a high index of suspicion, because the presentation is similar to many causes of cirrhosis. Indeed, WD may underlie coexisting liver disease. In general, the diagnosis should be considered in any patient younger than 40 with the signs and symptoms of hepatic dysfunction, especially in cirrhotic patients with unexplained central nervous system dysfunction. As noted earlier, the presence of a Kayser-Fleischer ring and a low serum ceruloplasmin level virtually seals the diagnosis. In patients with normal ceruloplasmin levels, high urinary copper and high copper on liver biopsy may support the diagnosis.

D-Penicillamine is considered the gold standard in the medical treatment of WD. D-Penicillamine is capable of reversing the hepatic, neurologic, and psychiatric manifestations of WD. Penicillamine therapy is not likely to be effective in patients with fulminant failure, dystonia, or severe lenticular degeneration. Adverse reactions to penicillamine including rashes, lymphadenopathy, and a lupus-like syndrome. Life-threatening thrombocytopenia[234] or leukopenia[235] is uncommon. Because penicillamine has an anti-pyridoxine effect, pyridoxine should be supplemented. Trientine may be effective in penicillamine-sensitive patients.[236] Zinc, which may induce more metallochaperone production, is also effective.[237]

Liver transplantation may be required in cases of fulminant failure and will reverse the hepatic manifestations of WD. [238] [239] Improvement of neurologic symptoms has been inconsistently reported. [238] [240]

Anesthesia in patients with WD should include a careful preoperative assessment with regard to the multiple organ systems that can be affected. A preoperative platelet count should be obtained in any patient taking penicillamine. Because metoclopramide may exacerbate a patient's extrapyramidal symptoms, it should be avoided. Droperidol, promethazine, and prochlorperazine should also be avoided because they may aggravate preexisting movement disorders.

Drug-Associated and Other Toxic Liver Disease

The central circulatory position and metabolic roles of the liver have already been discussed, but once again deserve mention from the perspective of toxic injury. The liver receives high concentrations of ingested compounds by portal blood flow from the splanchnic bed. Hepatocytes in turn take up such compounds and subject them to the metabolic processes discussed previously with detoxification and biotransformation. An exhaustive list of naturally occurring substances, manufactured chemicals, and pharmacologic agents has been implicated in liver disease, with pharmaceuticals being the most common. Table 5-8 is intended to provide examples of the types of damage caused by representative agents but is in no way a complete listing. Clinical manifestations range from minor asymptomatic biochemical changes to cholestatic signs and symptoms to massive liver necrosis, depending not only on the agent but also on the patient's pre-exposure condition, concurrent disease, and extent of exposure. Toxic injury can thus be included in virtually every differential diagnosis in the patient with liver disease.

TABLE 5-8   -- Types of Toxic Hepatic Injury

Hepatocellular Damage

Representative Agents

Microvesicular fatty change

Tetracycline, salicylates, yellow phosphorus, ethanol

Macrovesicular fatty change

Ethanol, methotrexate, amiodarone

Centrilobular necrosis

Bromobenzene, carbon tetrachloride, acetaminophen, halothane, rifampin

Diffuse or massive necrosis

Halothane, isoniazid, acetaminophen, methyldopa, trinitrotoluene, Amanita phalloides (mushroom) toxin

Hepatitis, acute and chronic

Methyldopa, isoniazid, nitrofurantoin, phenytoin, oxyphenisatin


Ethanol, methotrexate, amiodarone, most drugs that cause chronic hepatitis

Granuloma formation

Sulfonamides, methyldopa, quinidine, phenylbutazone, hydralazine, allopurinol

Cholestasis (with or without hepatocellular injury)

Chlorpromazine, anabolic steroids, erythromycin estolate, oral arsenicals contraceptives, organic arsenicals

Reproduced, with permission from Crawford JM: The liver and the biliary tract. In Cotran RS, Kumar V, Collins T (eds): Robbins Pathologic Basis of Disease, 6th ed. Philadelphia, WB Saunders, 1999, p 869.



Several distinctions are important in considering toxic liver disease. One issue concerns the type of toxicity of a substance. Although certain chemicals enter the body in toxic form, injury in most cases results from metabolites that, ironically, are usually the result of hepatic transformation. Another categorization of toxins is based on the consistency with which they cause disease. Intrinsic hepatotoxins consistently produce damage in a dose-dependent manner in otherwise healthy patients, most often with a short latency. Amanita mushrooms and trichlorethane are examples of intrinsic hepatotoxins. Idiosyncratic hepatotoxin exposure, in contrast, produces liver disease infrequently and to a variable severity after a variable latent period. The idiosyncratic pattern can obviously be extremely challenging diagnostically. Some idiosyncratic hepatotoxins produce mild symptoms or asymptomatic biochemical changes with routine exposure (e.g., isoniazid and halothane) but can cause severe liver disease in susceptible individuals and/or certain circumstances. Additionally, under certain conditions, even intrinsic hepatotoxins can produce variable injury in exposures otherwise considered safe (e.g., acetaminophen in the patient with alcoholic hepatic injury).

Inhalational Anesthetics.

Hepatic injury associated with the administration of inhalational anesthetic agents is, of course, especially important to the anesthesiologist. Halothane was introduced into practice in 1956, and was found to be rarely associated with hepatic necrosis. It is now accepted that halothane actually produces at least two types of hepatotoxicity. In up to 20% of adults who receive a halothane anesthetic, patients will have a milder effect with slight increases in aminotransferases and variable clinical complaints of fever, nausea, and malaise. Somewhere in the range of 1 in 7,000 to 35,000 patients, depending on risk factors, will have fulminant hepatic necrosis that has been termed halothane hepatitis. Transaminases and bilirubin levels are elevated, and the patient is jaundiced and often encephalopathic. The classic histologic examination reveals hepatitis with centrilobular necrosis; zonal, bridging, and panlobular necrosis have been described. Risk factors include age (very rare in childhood), gender (twice as common in women), repeated exposure within 3 months (as much as a 15-fold increase), and perhaps a history consistent with the milder postoperative hepatotoxic symptoms listed earlier. The mortality rate has been reported to be 10% to 50%, although recovery is typically complete in survivors.

Halothane hepatitis is a model for idiosyncratic hepatotoxicity, and thus its mechanisms have been extensively investigated. A variety of observations including increased risk from re-exposure and the often-reported fever, rash, arthralgias, and eosinophilia led to research that has supported the theory of an immunologic basis for halothane hepatitis. Cytochrome P4502E1 metabolizes halothane to trifluoroacetyl chloride. This reactive molecule was initially investigated as a direct hepatotoxin. The current immunogenic theory, however, focuses on its acetylation of endoplasmic reticulum proteins. These trifluoroacetylated (TFA) proteins, in turn, are thought to serve as neoantigens that elicit an antibody response to both the altered proteins and native hepatocyte proteins in susceptible patients. Corroborating evidence includes the detection of TFA proteins in patients with a history of halothane exposure as well as antibodies to the TFA hapten (and carrier protein components) in patients with actual halothane hepatitis. Further support can be found in reports of cross sensitization to methoxyflurane and perhaps enflurane by prior halothane exposure. Additionally, while as much as 20% of absorbed halothane may be metabolized, newer agents undergo orders of magnitude less biodegradation (approximate values: enflurane 2% to 3%, sevoflurane 1% to 2%, isoflurane 0.2%, and desflurane 0.02%) and in correlated fashion are believed to be rarely or never the cause of hepatitis.

Ischemic Liver Injury

The manifestations of ischemic injury to the liver have been labeled as hepatic infarction, shock liver, centrilobular necrosis, and, most commonly, the inaccurate term ischemic hepatitis. As might be expected, hypotension and/or hypoxemia are the usual precipitating factors and result from a variety of processes ranging from obvious situations such as cardiac dysfunction, intraoperative events, and trauma, to less intuitive causes such as obstructive sleep apnea and heat stroke.

Diagnosis relies on identification of an offending episode and typical biochemical response. LDH usually shows very high elevations both in terms of absolute values and relative to transaminase elevations. Biopsy is not typically required but, when performed, demonstrates widespread necrosis of the central lobule with minimal inflammation. Severity ranges from subclinical biochemical changes to fulminant failure. Treatment is supportive with correction of instigating processes.

Liver Function in the Geriatric Patient

The liver exhibits functional and structural changes with aging. Decreased liver weight with fibrosis and proportionally decreased blood flow has been described. Functionally, reduced regenerative capacity, altered response to endocrine stimulation, and altered drug metabolism are relevant to the perioperative physician.[241] Overall function is relatively resilient to these changes, however. There is a paucity and conflict of data regarding the impact of age on risk in the geriatric patient undergoing anesthesia. For example, one series of patients in the 1980s undergoing portosystemic procedures showed better mortality in patients who were 55 and younger,[242] although differences in disease severities and comorbidities were either pronounced or not described. General survival of cirrhotics with bleeding varices in different eras have correlated with Child-Pugh classification but not age. [20] [243] There is little evidence that age is an important perioperative risk factor compared with actual hepatic function.

Biliary Cirrhosis

Biliary cirrhosis is simply cirrhosis caused by biliary obstruction of any type, regardless of location in the biliary tree. Primary biliary disease is a defined as immunogenic disease of the intrahepatic bile ducts. Secondary biliary cirrhosis occurs with prolonged obstruction from mechanical causes, sclerosing cholangitis, and diseases that promote cholestasis such as biliary atresia and cystic fibrosis.

Primary Biliary Cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune disease commonly occurring with other autoimmune diseases (e.g., rheumatoid arthritis, CREST syndrome, pernicious anemia, and sicca complex). In the modern era, PBC is often diagnosed before actual cirrhotic changes and the name has thus become something of a misnomer. PBC follows a progression through four stages. It is first characterized by periductular inflammation and interlobular duct injury with granuloma formation, and then reactive ductular proliferation with cholestasis. Following this, there is decreasing inflammation but development of septal fibrosis and architectural disruption with worsening cholestasis. Finally, cirrhosis occurs with obliteration of normal bile ducts, continued inflammation, and cholestasis.

PBC has a 10:1 predilection for females, usually of middle age. Although it has been found in populations throughout the world, PBC is more prevalent and increasing in incidence in western countries. Alkaline phosphatase elevations and symptoms of fatigue and pruritus are typical but nonspecific early in the disease. Diagnosis is based on antimitochondrial antibodies with confirmatory liver biopsy. A variety of autoantibodies may be present, especially rheumatoid factor, anti-smooth muscle, and thyroid specific; these may occur without obvious coexisting disease. Advanced disease leads to the portal hypertension and liver failure of end-stage cirrhosis.

Liver failure typically occurs 5 to 10 years after diagnosis. Prognostic models appear to be more accurate than in many types of progressive liver disease and are helpful in considering the appropriate time for consideration of liver transplantation. Immunosuppressive drugs have had limited success in controlling the progression of PBC. Ursodeoxycholic acid (UDCA, a hydrophilic bile acid) has been shown to increase survival time without transplantation in PBC patients.[244] A report from a multicenter trial, however, did not find this benefit. These patients, who were allowed to continue UDCA or switch from placebo to UDCA on completion of the trial, did not experience significant improvement of transplant-free survival.[245] UDCA currently remains a standard treatment for PBC, but further evaluation through large-scale studies is anticipated.[246]

Secondary Biliary Cirrhosis.

Prolonged biliary obstruction, whether intrahepatic or extrahepatic (also known as extrinsic or mechanical obstruction), can lead to cirrhosis regardless of etiology. Obviously, a multitude of diseases can cause secondary biliary cirrhosis. Primary sclerosing cholangitis is the most common cause of secondary intrahepatic cholestasis but is still less common than PBC. In infancy and early childhood, cholestatic syndromes associated with atresia of intrahepatic and/or extrahepatic ducts often demonstrate rapid progression to fibrosis. Even when relief of obstruction is possible, this progression is not reliably halted. Adults more typically suffer from extrahepatic cholestasis such as chronic pancreatitis with stricture, pancreatic cancer, and choledocholithiasis.

Presentation and diagnosis depend on the instigating process, but jaundice and pruritus are often present. Alkaline phosphatase is typically highly elevated both absolutely (greater than four times normal) and relative to other liver panel abnormalities. Treatment involves diagnosis and treatment of the cause of cholestasis. Extrahepatic obstruction is often successfully relieved by surgical or endoscopic procedures. Intrahepatic obstruction is more problematic with limited curative options. Biliary atresia is an example. In this disease of infants in which initially normal bile ducts are obliterated in the first 3 months of life, most children will not survive to their first birthday without treatment. The Kasai procedure (hepatoportoenterostomy), in which a hilar core is opened so as to allow the cut bile ducts to drain unobstructed, can delay cirrhosis until the age of 3 to 4 years. Biliary atresia, however, remains the most common reason for liver transplantation in younger children.

Pregnancy-Associated Liver Disease

One to 3 percent of gravid patients can be expected to have liver test abnormalities at some point during their pregnancy. Patients with preexisting liver disease may experience deterioration during pregnancy, and pregnant patients can develop coincident liver disease. This section will focus on liver processes uniquely associated with pregnancy.

Most biochemical tests remain within the normal ranges of the general population during pregnancy. Exceptions include alkaline phosphatase and albumin. Alkaline phosphatase production by the placenta causes elevations in early pregnancy, eventually reaching levels that are three to four times normal nongravid values. Although albumin production is thought to be normal in pregnancy, increased blood volumes result in serum albumin decreases of about 1 g/dL.

Intrahepatic Cholestasis of Pregnancy (IHCP).

IHCP occurs commonly in pregnancy, with great variation between populations. Its cause is unknown, but associated factors include a personal or family history of IHCP and history of cholestasis with oral contraceptives. Onset is usually in the third trimester, typically with symptoms of pruritus, nausea, and in some cases abdominal pain. Jaundice occurs in about one fourth of patients, typically weeks after the onset of pruritus. Alkaline phosphatase is usually elevated beyond the normal increases of pregnancy, and transaminases are usually normal but may occasionally be slightly elevated. In those rare cases in which liver biopsy is performed, histologic findings are usually limited to cholestasis without inflammatory or necrotic changes.

IHCP usually has minimal maternal impact; resolution of symptoms and laboratory abnormalities is typically complete within a month of delivery. The incidence of premature delivery and perhaps perinatal mortality is increased. Treatment includes observation of mother and fetus, ursodeoxycholic acid, which decreases pruritus and may slow IHCP progression, and prophylactic administration of vitamin K to compensate for cholestatic malabsorption.

Preeclampsia and Eclampsia.

Preeclampsia occurs in up to 10% of pregnancies in general. Preeclampsia is the triad of hypertension (greater than 140/90 mm Hg), proteinuria (greater than 300 mg/24 hr), and edema, usually occurring in the late second or third trimester that cannot be attributed to other causes. Eclampsia occurs when seizures are superimposed upon preeclampsia, which happens in about 0.3% of preeclamptic patients. The pathophysiology of preeclampsia is thus far undefined, although theories abound. Popular proposed mechanisms often overlap and include endothelial cell injury, abnormal spiral artery development with compromised placental perfusion, thromboxane imbalance with prostacyclin, intravascular volume contraction, and abnormal renal function. Recent attention has focused on disruption of endothelial production of nitric oxide, prostacyclin, and tissue plasminogen activator. This approach emphasizes the change in vascular tone as well as coagulation changes.

Serum transaminases ranging from several times normal to as high as 100 times normal are found in nearly 25% of preeclamptics and 90% of those with eclampsia. Symptoms include epigastric or right upper quadrant discomfort. Complications that are believed to be associated with preeclampsia and eclampsia are hepatic rupture and/or infarction, fulminant hepatic failure, and subcapsular hematoma. Biopsy has demonstrated periportal fibrin deposition and areas of necrosis. Treatment is delivery, after which rapid normalization of laboratory values is typical. This decision is relatively straightforward when the fetus has an adequate maturity profile to ensure viability with delivery but problematic earlier in pregnancy. Delay in delivery entails risk of progression of preeclampsia but is believed to confer improved outcome on the fetus.

HELLP Syndrome.

The syndrome of hemolysis, elevated liver enzymes, and low platelets occurs in late pregnancy and usually with at least some of the signs of preeclampsia. Moderate transaminase elevations and thrombocytopenia are defining conditions of HELLP. Microangiopathic hemolysis is thought to be related to fibrin deposition; it produces schistocytes and fragment cells on peripheral smear, elevated serum LDH, and decreased hemoglobin. Biopsy, although rarely required, reveals periportal or focal necrosis and sinusoidal fibrin deposition with hemorrhage.

Maternal complications of HELLP include seizures (eclampsia), placental abruption, and disseminated intravascular coagulation. Fetal complications include prematurity, intrauterine growth retardation, and increased perinatal mortality as high as 30% in some earlier series. Treatment, as with preeclampsia, is delivery. Liver transaminases typically normalize within 1 week, whereas platelet counts continue to decline for 24 to 48 hours post partum and eventually normalize in 2 weeks.

Hepatic Infarction or Rupture.

Hepatic rupture is thought to occur in about 1 in 200,000 pregnancies, most often in association with preeclampsia or eclampsia, less often with acute fatty liver of pregnancy or HELLP syndrome, and extremely rarely without associated hepatic disease. Clinically, infarction or rupture presents as acute abdominal pain and distention, vomiting, and shock in the third trimester or immediately postpartum. Elevated transaminases, anemia, and disseminated intravascular coagulation are common, but the diagnosis can be confirmed with magnetic resonance imaging or computed tomography when time allows. Bedside ultrasound may be invaluable as a time-saving diagnostic tool. Survival requires early diagnosis and rapid treatment. Surgical intervention has included packing of the liver, resection of the involved segment or lobe (usually right), and even transplantation. Radiographically guided embolization has also been described in cases limited to a single lobe.

Acute Fatty Liver of Pregnancy (AFLP).

AFLP occurs in the third trimester of pregnancy and is of variable severity but can be fatal. It occurs in about 1 in 15,000 pregnancies and is more likely to occur in preeclamptic patients. Clinical presentation reflects the severity of the disease and ranges from nausea, abdominal pain, and general malaise to progressive liver failure with jaundice, coagulopathy, encephalopathy, and uremia. Expected laboratory abnormalities include elevated transaminases, prolonged clotting times, hypoglycemia, and uremia. Liver biopsy will demonstrate centrilobular microvesicular fatty deposition with either absent or minimal inflammation and necrosis. Essential hepatic architecture is preserved and eventual regression to normal hepatic tissue is found in survivors. Treatment is delivery, the delay of which must include a thoughtful assessment of fetal viability balanced against the possibility of rapid deterioration. Liver transplantation has been described as a treatment for AFLP, but timely delivery appears to result in complete reversibility of the disease in most cases.

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The diseased liver's pervasive impact on the function of other organ systems might be predicted by its myriad roles in health. The discussion that follows is intended to briefly outline systemic abnormalities associated with hepatic dysfunction that are of particular concern in the perioperative period.

Cardiovascular Effects of Liver Disease

The impact of chronic liver disease on the cardiovascular system is extremely complex and variable from patient to patient and under different circumstances within the same patient. The special considerations of portal hypertension are discussed with ascites in a separate section.

The cardiovascular profile of the cirrhotic patient is classically described as a hyperdynamic state with markedly increased cardiac output, low systemic vascular resistance, and modestly reduced arterial blood pressure. Despite this sustained elevation in cardiac output, functional exercise capacity of the cirrhotic is decreased. Available data show that cirrhotic patients undergoing exercise testing respond with lower than normal peak heart rates, lack of increased left ventricular ejection fraction, abnormally increased end-diastolic volumes with subnormal maximal cardiac outputs, and autonomic reflex abnormalities.[247]

Absolute intravascular volume is usually increased in cirrhotic patients, but coexisting renal disease, the impact of synthetic failure via decreased oncotic pressures, treatment of ascites with paracentesis and/or diuretics, and other factors may dramatically affect intravascular volume. Even with increased intravascular volume, the actual clinical behavior of the patient is often that of relative hypovolemia. Generalized vasodilatation, widespread arteriovenous shunting, and depressed cardiac response are presumed to be major responsible factors. Decompensation with abrupt decreases in volume may be related to attenuated sympathetic effects on the heart and the systemic vasculature. Furthermore, while the healthy liver can displace a portion of its blood volume into the central circulation with sympathetic simulation, this compensatory mechanism is impaired or absent in the setting of cirrhosis.

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Portal Hypertension and Ascites

The appreciation of esophageal variceal bleeding from cirrhotic obstruction of portal blood flow and the actual term portal hypertension are over 100 years old. The consequences of portal hypertension such as ascites, variceal hemorrhage, and encephalopathy still cause significant morbidity and mortality in advanced liver disease today.

In western societies, portal hypertension is most often associated with cirrhosis. Portal hypertension can actually be found in a variety of situations, however, and its causes have been categorized by mechanism and location. This way of considering portal hypertension incorporates both the forward and backward models of portal hypertension that have been variously favored in the past. Elevated pressure can result primarily from increased flow, increased resistance to flow, or both. If increased resistance is present, it may be prehepatic, intrahepatic (presinusoidal, sinusoidal, or postsinusoidal), or posthepatic. Box 5-2 demonstrates this categorization schema with several examples. The relative resistance of portosystemic collateral pathways, while not causal, will affect the degree of portal hypertension.

BOX 5-2 

Categorization and Examples of Portal Hypertension Etiologies



Increased flow predominates (Arterial-portal fistula, splenic hemangiomatosis)



Increased resistance predominates



Prehepatic (portal vein thrombosis, splenic vein thrombosis)






Presinusoidal (schistosomiasis, azathioprine)



Sinusoidal (cirrhosis, alcoholic hepatitis, methotrexate)



Postsinusoidal (Budd-Chiari syndrome)



Posthepatic (caval web, cardiogenic: right-sided heart failure, tricuspid regurgitation)

Pressure within the portal vein is usually less than 10 mm Hg, although variability is introduced by the influence of intra-abdominal pressure on the absolute venous pressure. The hepatic venous pressure gradient (HPG) can be used to control for this variability and attempt to localize the cause of increased portal venous pressure. HPG is the gradient between hepatic venous pressure and the wedged hepatic venous pressure. The latter, in a manner analogous to pulmonary artery occlusion pressure, estimates the intrasinusoidal pressures of the liver. Shortcomings of this measurement include variable sinusoidal communications arising from different pathologic processes causing resultant variability in pressures, as well as measurement from the efferent vessel causing occlusion artifact. When available, HPG can be used to localize etiology (e.g., HPG would be normal if the cause of portal hypertension were prehepatic) and monitor therapeutic interventions (e.g., sequential HPG can be used to verify improvement after β blockade). Portal hypertension is typically defined as an absolute pressure greater than 10 mm Hg or an HPG of greater than 5 mm Hg. The HPG at which portosystemic collaterals begin to develop appears to be 10 to 12 mm Hg in alcoholic cirrhosis.[248] These are most commonly gastroesophageal varices. Variceal bleeding is believed to be possible with an HPG of greater than 12 to 15 mm Hg, although the degree of elevation above this threshold is poorly related to bleeding risk.

Whether by the development of varices or intentional portosystemic shunt procedures, significant portal blood flow can bypass the liver to the systemic venous circulation. This circumvention of hepatocyte processing has been implicated in the prolonged and exaggerated effects of medications with high hepatic extraction, persistence of endogenous vasodilating substances usually cleared by the liver, and hepatic encephalopathy (discussed later).

Ascites is often present in the setting of severe cirrhosis and portal hypertension. As described previously, the normal sinusoid is lined with fenestrated endothelium and has no basement membrane. The normal sinusoidal pressure is low enough as to be nearly balanced by oncotic pressure. With increasing sinusoidal pressure, however, protein and fluid move into the interstitium with increased volume and increasing protein content of hepatic interstitial fluid and lymph. This flow eventually exceeds lymphatic return and accumulates in the abdomen as ascites. Interestingly, as the sinusoids develop a pseudo–basement membrane (so-called capillarization as previously described) less protein transudates through the now partially obstructed fenestrations. As a result, the protein content of the ascitic fluid can decrease with advancing disease.

The long-standing treatment of ascites includes diuretic therapy and paracentesis in conjunction with sodium restriction. Intravenous infusion of albumin with paracentesis has decreased the rapidity of ascites reaccumulation in some patients, perhaps because of the sinusoidal changes mentioned earlier. In any case, the treatment of ascites results in some decrease of intravascular volume.

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Renal Effects of Liver Disease

Renal function is commonly reduced in advanced liver disease. Processes such as infection or immune-mediated disease may primarily affect both the liver and kidneys. However, in cirrhosis and sometimes in acute liver failure, renal function can deteriorate as a secondary consequence of liver dysfunction. This phenomenon is termed hepatorenal syndrome (HRS). Prerenal failure and acute tubular necrosis can also occur in the setting of severe liver disease. They are discussed briefly with emphasis on their sometimes difficult, but important, differentiation from hepatorenal syndrome.

HRS is the type of renal failure specifically associated with advanced liver disease. It usually occurs in patients with ascites. As previously discussed, advanced liver disease often produces a cardiovascular profile of high cardiac output with low peripheral resistance and a relative, if not absolute, hypovolemia. This can predictably result in renal dysfunction of hypoperfusion (“prerenal”) etiology. However, in HRS, the decrease in renal cortical flow appears exaggerated. The reduction in total renal and especially cortical blood flow is reduced before there is any clinical evidence of renal injury. Cortical blood flow can actually be significantly decreased even with normal glomerular filtration rates. Such patients, with an increased resistive index by Doppler studies, are at high risk to proceed to renal insufficiency.[249] The proposed sites and mechanisms of renal vasoconstriction occurring paradoxically in a patient with generalized vasodilation are active topics of discussion. Suggested mediators that are abnormally produced or become imbalanced within the kidney as a result of liver disease include prostaglandins, nitric oxide, catecholamines, and endothelins. [250] [251] HRS is commonly designated as type I or type II. Type I occurs acutely over days in patients with marginal hepatic function and is associated with instigating factors such as gastrointestinal bleeding, infection, or hypovolemia in about one half of cases. Type II HRS is slowly progressive and occurs in patients with better-preserved and more stable hepatic function who often have recalcitrant ascites. Diagnostic criteria[252] for HRS are (1) advanced liver disease with portal hypertension; (2) an elevated serum creatinine or decreased creatinine clearance; (3) absence of other etiology; (4) lack of response to volume expansion; and (5) absence of proteinuria, obstructive uropathy, or parenchymal renal disease. Despite specific criteria, accurate diagnosis appears to be problematic.[253] This has ramifications both for patients who may have a more reversible process that is not considered and for the interpretation of HRS series that may include (and exclude) misdiagnosed patients.

Although the kidney in HRS remains essentially unchanged histologically and function may return to normal after liver transplantation,[254] spontaneous recovery is rare and there is currently no other definitive treatment. Promising work with animal models using vasopressin analogs may be coming to fruition. The mechanism of this treatment appears to be related to vasoconstriction of the splanchnic circulation. This is theorized to improve effective blood volume and perhaps suppress rennin-angiotensin and sympathetic activity to more normal ranges. Simple volume expansion, interestingly, is not particularly effective,[255] but colloid infusion may improve the response to V1 vasopressin agonists.[256] Experience is thus far limited, [256] [257] [258] and ischemic complications were problematic in a series using ornipressin.[259]

The diagnosis of prerenal failure should be considered because it may well be reversible if treated promptly. The question of whether prerenal failure can progress to HRS in some patients is unanswered but must be of concern. Acute tubular necrosis (ATN), when it occurs, is often precipitated by a combination of sustained hypoperfusion and nephrotoxic agents such as nonsteroidal anti-inflammatory analgesics, contrast dye, and aminoglycoside antibiotics. Elevated bilirubin, which itself has been postulated to be nephrotoxic, is associated with an increased incidence of ATN.

Characteristics helpful in distinguishing prerenal failure and HRS are limited. HRS sometimes demonstrates tubular damage with proteinuria and, in fact, may progress to ATN. Urine sodium will be low in both processes, whereas urinary creatinine will be high compared with levels in the plasma. Proteinuria, high urine sodium, and low urine creatinine are typical of ATN. Volume challenge of the patient with renal dysfunction is a logical approach to diagnose and begin treatment of prerenal failure.

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Pulmonary Effects of Liver Disease

The diseased liver impacts lung function in a variety of ways, sometimes with obvious mechanisms. Nearly 10% of patients with cirrhosis, for example, will develop pleural effusion. Classically termedhepatic hydrothorax, such effusions are initially transudative and more commonly occur on the right side. Effusion can occasionally occur in isolation but is most typically associated with ascites. In the more typical latter case, transdiaphragmatic communications between the peritoneal and pleural cavities are thought to allow movement of fluid into the chest. The impact on lung mechanics includes decreased lung volumes and pulmonary compliance, as well as elevated pleural pressures (abnormalities also caused by massive ascites). Moderate hypoxemia, thought to be an effect predominately of intrapulmonary shunt, is common, but improvement after evacuation of the effusion is unpredictable.[260] Without resolution of the hepatic process, repeated thoracenteses and perhaps portosystemic shunting may be required.

Some diseases that affect the liver will also primarily affect the lung; examples include cystic fibrosis, α1-antitrypsin deficiency, sarcoidosis, and primary biliary cirrhosis. Several descriptions also exist of patients undergoing sclerosis of esophageal varices who develop a range of pulmonary deterioration. These problems range from worsening hypoxemia and decreased vital capacity to full-blown adult respiratory distress syndrome. The etiology of these problems may have been embolization of particular sclerosants.[261]

Two poorly understood syndromes that are sometimes confused but have very different findings and implications are hepatopulmonary syndrome and portopulmonary hypertension. Table 5-9 summarizes their contrasting definitions, signs and symptoms, and management. In hepatopulmonary syndrome, peripheral pulmonary vasculature (precapillary and capillary) has characteristic vascular dilatations. These dilatations are thought to increase the distance between enough centrally flowing red cells and the alveoli to impair oxygenation. This effect is exaggerated in the sitting position with increased basilar blood flow, accounting for the symptoms of platypnea (worsened shortness of breath in the upright position) and orthodeoxia. Supplemental oxygen will typically improve saturation, but no other medical treatments have been consistently effective. Liver transplantation is usually an effective treatment, although improvement may be seen only after several months. Portopulmonary hypertension is a distinctly different process that appears histologically similar to primary pulmonary hypertension with medial hypertrophy. Pulmonary artery pressures may respond to vasodilators such as intravenous or inhaled epoprostenol or inhaled nitric oxide. The mortality of liver transplantation in patients with portopulmonary hypertension and mean pulmonary artery pressures of greater than 40 mm Hg is considered to be prohibitively high, although there are scattered case reports of survivors.[262] At this time it appears that recent onset and aggressive preoperative therapy[263] of portopulmonary hypertension may be associated with improved outcome.

TABLE 5-9   -- Distinguishing Hepatopulmonary Syndrome and Portopulmonary Hypertension


Hepatopulmonary Syndrome

Portopulmonary Hypertension

Defining Characteristics

Liver dysfunction

Lack of general agreement Commonly cited criteria:


Intrapulmonary vascular dilatations (IPVD)

Portal hypertension


Abnormal alveolar-arterial oxygen gradient (>15 mm Hg with room air)

Resting PAPm > 25


Other cardiopulmonary causes excluded

PAOP < 15



Other causes excluded

Common Symptoms





Dyspnea on exertion


Arterial desaturation


Common Signs and Diagnostics


Hypoxemia with exertion


Decreased DLCO

Elevated PAP


CE-Echo positive



Oxygen supplementation

Vasodilator trial


Liver transplantation


PAP, pulmonary artery pressure; PAPm, mean PAP; PAOP, pulmonary artery occlusion pressure; DLCO, carbon monoxide diffusing capacity; CE-Echo positive, contrast enhanced echocardiography: positive when contrast appears in left side of heart within three to six cardiac cycles of appearance in right side of heart and in the absence of another cause.




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Hepatic Encephalopathy

Hepatic encephalopathy can be associated with either acute or chronic liver disease and can itself be slowly progressive or, usually with an instigating process, deteriorate rapidly. It is a neuropsychiatric disorder that should be a diagnosis of exclusion. Differential diagnoses include intracranial processes (e.g., hemorrhage, tumor, or abscess), hypoxemia, neurologic infection, sepsis, and metabolic encephalopathy. Primary neuropsychiatric disorders can have similar presentations.

Clinical observation and admittedly limited animal models have led to the generally accepted concept that hepatic encephalopathy is caused by the failure of the liver to clear neurotoxins or their precursors arising from the gut. Box 5-3 lists several substances currently being considered in the development of hepatic encephalopathy. A brief discussion of several of these theories will provide an opportunity to also explain justifications for current treatments used in hepatic encephalopathy. Ammonia is generally believed to play a central role in hepatic encephalopathy. It is produced by colonic bacterial activity and small bowel deamination of glutamine, absorbed into the portal circulation and, in health, removed by the liver. Hepatic dysfunction, especially in association with portosystemic shunting, allows increased systemic ammonia concentrations. Glutamine synthetase inhibition can blunt cerebral edema and intracranial hypertension in animals with portocaval shunting and ammonia infusions.[264] This observation has supported the concept that central nervous system metabolism of ammonia with resultant increases of glutamine leads to an osmotic gradient capable of causing cerebral edema. Ammonia is also capable of altering the blood-brain barrier and influencing glutamate-associated neurotransmission. Despite these interesting findings, blood ammonia levels have not consistently correlated with the severity of hepatic encephalopathy. Lactulose, however, is still a mainstay of treatment for hepatic encephalopathy. The therapeutic mechanisms of lactulose are purportedly both acidification of the gut and catharsis resulting in decreased ammonia absorption. Ammonia load can be further decreased with poorly absorbed antibiotics that decrease bacterial activity, decreased protein ingestion, and control of gastrointestinal bleeding. γ-Aminobutyric acid (GABA) has received attention because in animal models of hepatic encephalopathy both expression of GABA receptors and blood-brain GABA movement were found to be increased. With the introduction of flumazenil and other investigational benzodiazepine antagonists, interest was focused on the GABA receptor within the context of its interaction with benzodiazepines. Some patients with hepatic encephalopathy do, in fact, improve with benzodiazepine antagonists. The effect, however, is variable and of unpredictable duration. The false neurotransmitteror amino acid imbalance theory is based on the increased proportion of aromatic as compared with branched-chain amino acids often found in patients with hepatic encephalopathy. Increased aromatic amino acids are proposed to be the precursors for false neurotransmitters such as octopamine, tyramine, and phenethylamine. Clinically, branched-chain amino-acid supplementations have been reported to improve hepatic encephalopathy and investigation of the therapeutic mechanism is ongoing.[265]

BOX 5-3 

Theorized Pathogenic Substances in Hepatic Encephalopathy






γ-Aminobutyric acid (GABA)



True neurotransmitters



False neurotransmitters (aromatic amino acid excess)






Endogenous opioids




The severity of hepatic encephalopathy is assessed on the basis of cognitive function, behavior, motor function, and level of consciousness. As shown in Table 5-10 , a stage of 1 through 4 can be assigned according to these changes.

TABLE 5-10   -- Stages of Hepatic Encephalopathy






Cognitive Function

Decreased attention

Obvious memory deficits

Amnesia, disorientation, incoherence


Behavior Characteristics

Irritable, anxious

Inappropriate (disinhibition)

Angry, paranoid, seizures


Motor Function

Tremor, fine motor loss

Asterixis, dysarthria, repeated blinking and yawning

Babinski reflex, nystagmus, altered deep tendon reflexes

Dilated pupils, decorticate or decerebrate posturing

Level of Consciousness

Normal, with altered sleep patterns

Lethargic, with ataxia

Confused, delirious, or stuporous




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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier


Estimation of perioperative risk in the patient with liver disease is problematic. Available data are often either outdated, retrospective, nonspecific to etiology, and/or of limited subject size. While acknowledging these shortcomings, generally accepted guidelines are summarized in Table 5-11 , and expanded below.

TABLE 5-11   -- Approach to the Patient with Liver Disease for Elective Surgery

Acute Hepatitis

Postpone surgery until normalization of biochemical profiles.

Chronic Hepatitis

Proceed with surgery if clinical course and laboratory parameters have been stable. Unspecified increased perioperative risk.

Obstructive Jaundice

Proceed with surgery, with attention to fluid resuscitation. Endoscopic or percutaneous preoperative biliary drainage controversial.

Cirrhosis: Child's A or B

Optimize and proceed with surgery. (See text for special concern in cases requiring cardiopulmonary bypass.)


Coagulation: Goal of prothrombin time within 2 sec of normal. Parenteral vitamin K, if ineffective, then fresh frozen plasma and/or cryoprecipitate.


Ascites: If conservative management (fluid restriction and/or diuretics) ineffective, then paracentesis.


Encephalopathy: Evaluate and treat triggering processes (e.g., gastrointestinal bleeding, uremia, medications); consider lactulose.

Cirrhosis: Child's C

Postpone surgery while improving Child's classification or cancel surgery for nonsurgical management.

Adapted from: Rizvon MK, Chou CL: Surgery in the patient with liver disease. Med Clin North Am 2003;87:211–227.




Acute Hepatitis.

High mortality rates from older studies are often quoted for patients undergoing elective surgery who have acute hepatitis. Patients were predominately undergoing exploratory laparotomy for the possibility of surgically correctable jaundice in an era before the availability of accurate noninvasive diagnostic techniques. These studies showed a mortality rate of approximately 10% [266] [267] for viral hepatitis and nearly 55% [268] [269] for alcoholic hepatitis. Acute hepatitis has thus been considered a contraindication to elective surgery, although these outcomes have not been retested in the setting of modern anesthetics and techniques.

Chronic Hepatitis.

In chronic hepatitis, the patient's clinical and biochemical status should be used to assess perioperative risk. In the symptomatic patient with synthetic and/or excretory abnormalities, data from different eras indicate increased perioperative risk. [270] [271] Conversely, well-compensated, asymptomatic chronic hepatitis appears to add little perioperative risk.[272]


Fatty liver itself does not contraindicate elective surgery, whether of alcoholic or nonalcoholic etiology. It is important to verify that acute alcoholic injury is not also present and further to emphasize to the patient the importance of abstinence in avoiding direct parenchymal damage and worsening of perioperative liver abnormalities. Patients with severe steatohepatitis tend to show increased morbidity and mortality in major hepatobiliary surgery,[273] although other associated factors are surgical time and body mass index. Nonalcoholic steatohepatitis (NASH) has been presumed to be the etiology of increased cirrhosis in morbidly obese patients. Among patients undergoing gastric bariatric surgery, a voluntary multi-institutional survey[274] reported a previously undiagnosed cirrhosis incidence of nearly 6% and a mortality in this group of 4%, all deaths being postoperative. More recent data from a single institution's 48 consecutive bariatric patients found 33% to have NASH and a further 12% to have advanced fibrosis;[275] mortality figures were not reported, but NASH and fibrosis were both associated with diabetes mellitus but not body mass index in this obese population.


Cirrhosis is the liver abnormality for which most perioperative data exist and for which a generally accepted classification has been developed and verified. Specifically, the Child-Turcotte and Child-Pugh classifications of cirrhosis have been demonstrated to correlate well with perioperative mortality rates ( Table 5-12 ). Data from the 1980s[276] and 1990s[277] show remarkably similar mortalities of approximately 10% for Child's A, 30% for Child's B, and 80% for Child's C in patients undergoing open abdominal procedures. Recent experience indicates that laparoscopic cholecystectomy [278] [279] [280]is better tolerated in Child's A and B cirrhotics, even considering higher conversion to open procedures than controls. Endoscopic intervention is often chosen for Child's C patients.

TABLE 5-12   -- Child-Pugh Classification of Cirrhosis

Factor and Score




Serum Bilirubin (mg/dL)




Serum Albumin (g/dL)






Easily controlled

Poorly controlled

Prothrombin Time Prolongation








The Child-Pugh score is calculated by adding the scores of the five factors (possible scores therefore range from 5–15).

Child's Class is A (5 or 6), B (7, 8, or 9), or C (10 and greater).




The distinction between Child's A and Child's B disease may be important in patients undergoing cardiopulmonary bypass. Two very small series indicate that Child's A patients will experience a marginal increase in complications, but reported a 50% to 80% [281] [282] mortality in their Child's B patients.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier


Concern for liver function may arise in a variety of clinical scenarios. A patient presenting for any elective procedure may have previously undetected laboratory abnormalities with which no symptoms have been associated. The patient with obvious jaundice or ascites, on the other hand, may present for related diagnostic or therapeutic interventions. Patients with advanced and/or life-threatening hepatic dysfunction may require interventions such as biliary decompression, partial hepatic resection, and liver transplantation; alternatively, these patients may require unrelated emergency procedures such as appendectomy, fracture repair, or cesarean delivery, with significant risk posed by their hepatic process.

The dilemmas faced by clinicians in these situations have been already implied in earlier sections. Laboratory value profiles are helpful, but not specific, in diagnosing disease processes. Perioperative data for specific diseases are limited and often reflect a variety of diagnostic criteria, anesthetic management techniques, and eras. Additionally, assessment of hepatic reserve is problematic. Although extraction tests have been used to assess hepatic function (particularly in transplant candidates) [283] [284] and newer nuclear imaging techniques show promise for risk stratification in the future, [285] [286] neither are well correlated with operative risk, nor are they universally available.

Anesthetic management is discussed from two perspectives. First, management issues ranging from asymptomatic laboratory abnormalities to fulminate failure are addressed. Anesthetic considerations for procedures directly involving the liver are then discussed. Supporting data, when available, are cited. Management recommendations are otherwise based on common practice, available reports, and/or the authors' opinions.

Anesthetic Management for Patients with Liver Dysfunction

Newly Discovered Asymptomatic Abnormal Laboratory Values

Previous series have reported the incidence of elevated transaminases in asymptomatic patients without prior diagnostic abnormality to range from less than 1% to greater than 10%. In the 1970s, an often-quoted study[287] found that 11 of 7620 (0.14%) patients scheduled for elective surgery had unexpected significant elevations of liver function tests. Of particular interest, 3 of these 11 patients developed jaundice even though their surgical procedures were canceled. A large series of asymptomatic patients undergoing nondirected screening indicates that the prevalence of asymptomatic elevations may be much higher 3 decades later. Approximately 15% of 2294 patients were found to have transaminase levels greater than normal range, and nearly 4% had levels greater than twice normal.[288] The authors considered a high prevalence of nonalcoholic steatohepatitis as a likely cause for their findings. Other likely and important diagnoses are listed in Box 5-4 .

BOX 5-4 

Differential Diagnosis of New Asymptomatic LFT Abnormalities (See Table 5-1 for Typical Patterns)



False positive (especially likely in asymptomatic patients without risk factors)



Early and/or subclinical hepatitis



Nonalcoholic steatohepatitis



Drug or toxic effect



Ischemic injury



Infiltrative process



Biliary disease

Approximately one third of asymptomatic patients without risk factors will have normal values on repeated laboratory evaluation. Conversely, acute hepatitis is still considered a contraindication to elective surgery. The cautious and often recommended path would be to postpone elective surgery until further evaluation, signs, and symptoms allow either determination of etiology or resolution of the undefined process. Other authors[289] have advocated a tiered response. In the latter approach, for example, if transaminases were elevated less than two times normal, risk factors for acute hepatitis would be reassessed. If the absence of risk factors was confirmed, this algorithm would then proceed to elective surgery. Regardless of the approach chosen, careful reassessment of the patient's history is indicated as outlined in Box 5-5 . The divided opinion of experts reflects the unanswered dilemma for the clinician, which is to determine when acute hepatitis has been adequately excluded to justify the delivery of an anesthetic for elective surgery.

BOX 5-5 

Asymptomatic Laboratory Abnormalities: Critical Questions and Further Diagnostic Strategy to Discuss with Patient and/or Primary Medical Doctor



Reassess risk factors for acute hepatitis.



Viral hepatitis exposures



Toxic exposures



Alcohol history



Medication history



Repeat liver panel laboratory studies (LFTs).



Order viral hepatitis laboratory studies, especially with even marginal indication from history.



Consider hepatology consultation for:



Worsening LFTs and/or positive viral serology



Transaminases that remain more than twice normal

Suspected or Known Acute Hepatitis

Patients with acute hepatitis should not be subjected to an anesthetic for an elective procedure. Some patients will require urgent surgery (1) without time for a definitive diagnosis or resolution of asymptomatic laboratory abnormalities or (2) with known acute hepatitis. It seems prudent to manage the former group with the same principles that would be applied for known acute hepatitis, and so these situations will be discussed together. (Acute hepatic failure is an entirely different entity that is discussed separately.) It is generally accepted (with supporting data but without absolute proof) that decreased hepatic blood flow is an important cause of perioperative hepatic dysfunction in patients with acute hepatitis and that efforts should therefore be made to maintain total blood flow to the liver. Peripheral procedures will have less impact than abdominal procedures, but procedure location is usually mandated by circumstance. In animal models and humans, it appears that halothane decreases total hepatic blood flow by decreasing both portal venous and hepatic arterial blood flow [290] [291] and should be avoided. Isoflurane is the best studied alternative and appears to preserve hepatic blood flow markedly better than does halothane. Total intravenous anesthesia may prove to be another reasonable alternative in this setting. Positive-pressure ventilation and positive end-expiratory pressure of themselves would be expected to decrease liver flow,[292] but spontaneous ventilation with an elevated carbon dioxide and splanchnic sympathetic stimulation could also be detrimental. Drugs with known or suspected hepatotoxicity should be avoided, if possible. Examples are given in the prior discussion of hepatotoxins; an incomplete list is included in Box 5-6 .

BOX 5-6 

Acute Hepatitis for Urgent Surgery: Intraoperative Management



Preserve hepatic blood flow.



Avoid halothane (isoflurane is best-studied alternative and better preserves flow).



Consider regional anesthesia if procedure and coagulation allows.



Maintain normocapnia.



Avoid PEEP if possible.



Provide generous volume maintenance.



Avoid medications with situational potential hepatotoxicity whenever possible. Examples:






Acetaminophen, particularly in the alcoholic patient



Sulfonamides, tetracycline, and penicillins






Perform postoperative surveillance clinically and biochemically for progression of hepatic dysfunction.



Suspect infectious etiology.



Provider exposures treated as high risk for viral hepatitis


As previously described, cirrhosis is a sequela of many different types of liver injury and represents a histologic diagnosis rather than a single disease process. The key elements of disruption of normal architecture by scarring with nodules of regenerating parenchyma are common to all causes, but some causes have typical associated findings. Common causes of cirrhosis are listed in Box 5-7 . These and several less common causes are detailed in previous sections, and a more complete list can be found in Box 5-1 .

BOX 5-7 

Common Causes of Cirrhosis






Viral hepatitis



Hepatitis B, C, and D (Delta)



Nonalcoholic steatohepatitis






Wilson's disease






α1-Antitrypsin deficiency



Diabetes mellitus









Drug or toxin other than alcohol



Primary biliary cirrhosis



Cholestasis (prolonged)

Ironically, the cirrhotic patient often suffers more from extrahepatic manifestations of his disease than from loss of hepatic parenchyma, per se. Such issues as coagulopathy and altered drug metabolism are important considerations, to be sure, but the anesthesiologist must be cognizant of a wide range of comorbidities and complications that occur with cirrhosis. Several important considerations are listed inBox 5-8 .

BOX 5-8 

Comorbidities and Complications of Cirrhosis



Portal hypertension






Variceal bleeding









Renal dysfunction (hepatorenal syndrome as extreme presentation)



Central nervous system effects (hepatic encephalopathy as extreme presentation)



Hepatopulmonary syndrome



Pleural effusion(s)



Portopulmonary hypertension



Glucose intolerance



Circulatory changes: high cardiac output and low systemic vascular resistance

Portal hypertension has already been discussed in terms of its role in the development of significant varices and ascites. The patient's history should be reviewed for portosystemic shunts such as a surgical splenorenal shunt or the now more common TIPS (transjugular intrahepatic portal systemic shunt) procedure. Ascites is important preoperatively for many reasons. Its presence may have led to treatment with spironolactone, paracentesis, or, in resistant cases, even the placement of a peritoneal-systemic shunt. All of these treatment modalities may result in blood volume and electrolyte abnormalities, which should be assessed preoperatively. Enthusiastic paracentesis can also cause or exacerbate hypoalbuminemia, depending on the character of the ascites.

All patients with cirrhosis and especially known portal hypertension should be considered to be at risk for having esophageal varices. These dilated veins communicating blood from the hypertensive portal system to lower pressure systemic veins can be the source of massive bleeding. They may be treated with endoscopic sclerotherapy. Blind instrumentation of the esophagus should be undertaken with extreme caution if not avoided completely.

Abnormal PT and hypoalbuminemia reflect decreased synthetic reserve and/or increased loss or consumption. If time permits, the response to vitamin K can be determined, but otherwise fresh frozen plasma is often used to bring the PT within acceptable range. Hypofibrinogenemia or dysfibrinogenemia from altered synthesis and fibrinolysis may also be responsible for coagulopathy and may be treated with cryoprecipitate. Thrombocytopenia, thought to be caused by both splenic sequestration and decreased peripheral survival, should be addressed as required by the procedure in question. Qualitative abnormalities of platelet function, including abnormal activation, may also exist but are difficult to assess. Implications of the other listed comorbidities and complications of cirrhosis have been described in previous sections.

Review of the patient's history must recognize the multisystemic impact of cirrhosis. If time allows, correctable abnormalities of coagulation, metabolic status, and intravascular status, should be addressed preoperatively. Child's classification (see Table 5-12 and its earlier discussion) should be evaluated for some general sense of perioperative risk. It is important to remember that most patients with significant cirrhosis have at least some degree of cognitive dysfunction and memory lapse; verification of history and signs of early encephalopathy should be sought from objective observers. Other important considerations are listed in Box 5-9 .

BOX 5-9 

Critical Questions to Ask Patients and/or Their Primary Medical Doctor



Etiology of cirrhosis



Complications of cirrhosis, particularly related to Child's classification



History of disease progression



History of therapeutic interventions



Current medications



Deterioration of status associated with current illness



Seek reliable confirmation: suspect patient's cognitive function and memory

The course of cirrhosis can be stable for long periods, but this belies the minimal systemic reserve that is often present. Indeed, perturbations that would be minor and well tolerated in the healthy patient may precipitate decompensation in the cirrhotic patient. Dietary indiscretions, infection, minor trauma, and medication interruptions, for example, may not be tolerated. In the same sense, procedures that would be considered minor in most patients may be major challenges to the cirrhotic patient, especially in the case of high Child's classification and/or significant preoperative deterioration.

Cirrhotic patients should be managed perioperatively with many of the same considerations as the patient with acute hepatitis (see previous section). Box 5-10 includes common additional cardiovascular, coagulation, and metabolic abnormalities that must also be addressed. Correction of PT to within 2 seconds of normal is generally recommended for invasive procedures. If time allows, vitamin K can be administered parenterally. Typically, however, fresh frozen plasma is used initially. Cryoprecipitate can be added if necessary. Portal hypertension and ascites may be present. Changes in pharmacokinetics and pharmacodynamics should be expected but are unpredictable. Drugs with high hepatic extraction are especially affected by portosystemic shunting of blood; highly protein-bound medications are affected by hypoalbuminemia with variable offset by increased gamma globulins, and the effects of drugs such as vasopressors (decreased) and sedatives (increased) may be altered.

BOX 5-10 

Anesthetic Preparation and Management in Cirrhosis



Consider same issues as in acute hepatitis (see previous discussion):



Preserve hepatic blood flow.



Avoid halothane (Isoflurane is best studied alternative and better preserves flow).



Consider regional anesthesia if procedure and coagulation allows.



Maintain normocapnia.



Avoid PEEP if possible.



Provide generous volume maintenance.



Avoid medications with situational potential hepatotoxicity whenever possible. Examples:






Acetaminophen, particularly in the alcoholic patient



Sulfonamides, tetracycline, and penicillins









Anticipate presence or development of abnormalities of: Coagulation



Attempt to correct prothrombin time to within 2 seconds of normal.



Consider cryoprecipitate if fresh frozen plasma ineffective or fibrinogen abnormality.



Correct thrombocytopenia appropriately for procedure.



Anticipate higher than normal blood loss forprocedure.






Anticipate relative hypovolemia, worsened by treatment of ascites.



Assess for presence of high cardiac output, low peripheral resistance.



Suspect portal hypertension and/or variceal bleeding, even without history.



Anticipate depressed response to ionotropes andvasopressors.



Consider invasive monitoring.



Pharmacokinetics and pharmacodynamics



Altered volume of distribution may occur.



Decreased serum albumin, increased gamma globulins.



Intravascular volume is unpredictable, especially with ascites treatment.



Portosystemic shunted blood bypasses liver.



Drugs highly extracted by liver especially affected.



Increased sensitivity to sedative medications may be present.

Acute Liver Failure

Acute liver failure or fulminant hepatic failure can occur rarely with any number of insults to the liver that result in the loss of sufficient hepatic parenchyma to precipitate acute decompensation. Diagnosis of the syndrome requires acute hepatocellular failure (without prior significant liver disease) and encephalopathy. The time interval between onset of illness and progression to encephalopathy may be correlated with both etiology and prognosis. Ischemic hepatitis and many toxic injuries, for example, progress to encephalopathy in a matter of days; viral hepatitis and cryptogenic failure are more typically associated with a month between onset and the development of encephalopathy. Additionally, the presence of jaundice for more than a week before encephalopathy may indicate a poor prognosis. These observations have led to the use of various nomenclatures ( Box 5-11 ) for acute hepatic failure. The discussion here uses the original definition in an attempt to avoid confusion.

BOX 5-11 

Nomenclatures of Acute Hepatic Failure



Original definition of acute hepatic failure or fulminant hepatic failure



Hepatocellular failure (jaundice or coagulopathy)



No prior diagnosis of significant liver disease



Encephalopathy within 8 weeks of onset



Nomenclature refinements based on syndrome development



Subfulminant hepatic failure



Encephalopathy develops between 2 weeks and 3 monthsafter jaundice.



Fulminant hepatic failure



Encephalopathy develops within 2 weeks of jaundice



Hyperacute liver failure



Encephalopathy develops within 1 week of jaundice.



Acute liver failure



Encephalopathy develops between 1 and 4 weeks of jaundice.



Subacute liver failure



Encephalopathy develops between 5 and 12 weeks after jaundice.

Worldwide, the most common causes of acute liver failure are drugs, particularly acetaminophen, and viral hepatitis. Box 5-12 lists the more common causes in approximate order of likelihood for centers in the United Kingdom and United States. The causes listed as uncommon have been reported as the cause of acute failure. The differential diagnosis of acute liver failure is very limited. Sepsis may be associated with cholestasis, disseminated intravascular coagulation, and encephalopathy without actual hepatocellular destruction. Factor VIII will often be suppressed in disseminated intravascular coagulation of sepsis but not in acute liver failure. Decompensation of chronic liver disease can also be confused with acute liver failure, particularly when a reliable patient history is not available.

BOX 5-12 

Etiology of Acute Liver Failure






Acetaminophen toxicity



Hepatitis B






Hepatitis A (most common worldwide cause)



Toxicity other than acetaminophen






Wilson's disease



Vascular disease



Pregnancy associated






Reye's syndrome



Infections other than hepatitis A and B

Acute liver failure is a medical emergency, often of the gravest proportions. Etiology-specific therapy should be implemented when it exists. N-Acetylcysteine, for example, is used to treat acetaminophen toxicity, whereas emergency delivery is indicated for failure associated with fatty liver of pregnancy. A major dilemma occurs for the intensivist managing acute liver failure. Some patients, with appropriate supportive care, can survive with recovery of hepatic function. Patients with acetaminophen toxicity and hepatitis A are more likely to fall into this group. Others are unlikely to survive without liver transplantation. There has been much interest and effort expended in devising,[293] verifying, [294] [295] [296] and refining[297] methods to separate these two groups. The patient who may be a candidate for transplantation should be transported to an experienced transplant center without delay. This allows the dual processes of constant reassessment of prognosis for recovery and transplant candidacy to be implemented.

Anesthesia should not be administered to patients with acute liver failure except for potentially life-saving emergency procedures. Management issues encompass not only the issues previously discussed for acute hepatitis but also attention to often severe neurologic, hemodynamic, and metabolic derangements. Boxes 5-13 and 5-14 [13] [14] outline relevant systemic effects of acute liver failure and additional information that should be sought from the critical care team, respectively.

BOX 5-13 

Comorbidities and Complications Seen with Acute Liver Failure






Cerebral edema with elevated intracranial pressure



Other causes such as hypoxemia, electrolyte abnormality, hypoglycemia






Gastrointestinal: typically gastric ulceration and not



variceal origin






Respiratory failure



Adult respiratory distress syndrome



Pneumonia and/or aspiration in encephalopathic patient



Renal failure






Acute tubular necrosis



Hepatorenal syndrome









Relative hypovolemia



Generalized vasodilatation




BOX 5-14 

Critical Questions to Ask Patients and/or Medical Team



Any evidence of preexisting liver disease



Presumptive cause of acute liver failure



Treatment instituted if appropriate (e.g., acetaminophen poisoning)



Course of neurologic deterioration



Measures instituted to control intracranial pressure



Metabolic, cardiovascular, and coagulation support required thus far

Direct measurement of intracranial pressure (ICP) can be invaluable for advanced encephalopathy. Placement of a monitoring device does have substantial risk of bleeding and infection in this setting. Clinical indicators of damaging ICP increases under anesthesia, however, may be both delayed and insensitive. If direct monitoring is not available, patients should be presumed to have elevated ICP with poor intracranial elastance. Maintenance of adequate cerebral perfusion pressure may be problematic because of relative hypovolemia and generalized vasodilatation.

Hemorrhage should be anticipated in acute liver failure. Severe coagulopathy often requires extensive transfusion. Gastrointestinal bleeding tends to be related to stress ulcerations, rather than the variceal bleeding found in chronic liver disease. Hypoglycemia can be profound because of decreased intake and loss of hepatic release. Adult respiratory distress syndrome (ARDS) occurs frequently in acute liver failure and can present a dilemma in attempting to avoid hypercapnia for ICP concerns while avoiding ventilatory pressure and volume lung injury in ARDS. Renal failure has been attributed to prerenal mechanisms, hepatorenal syndrome, and acute tubular necrosis. Regardless of etiology, patients with acute liver failure frequently require hemofiltration or hemodialysis, and nephrotoxic medications should be avoided whenever possible.

Invasive hemodynamic monitoring, like ICP devices, must be considered to incur a higher than normal risk in the patient with acute liver failure. Considering the interplay of systemic abnormalities just outlined, however, management of these patients typically requires invasive monitoring. Finally, it is unlikely that coagulation abnormalities can be fully corrected. The possibility of large volume transfusion requirements should be anticipated with adequate venous access, fluid warming devices, personnel, and blood bank support.

Anesthetic management issues are summarized in Box 5-15 .

BOX 5-15 

Anesthetic Preparation and Management in Acute Liver Failure

Consider same issues as in acute hepatitis (see previous section):



Preserve hepatic blood flow.



Avoid halothane (isoflurane is best studied alternative and better preserves flow).



Consider regional anesthesia if procedure and coagulation allows.



Maintain normocapnia.



Avoid PEEP if possible.



Provide generous volume maintenance.



Avoid medications with situational potential hepatotoxicity whenever possible. Examples:






Acetaminophen, particularly in the alcoholic patient



Sulfonamides, tetracycline and penicillins






Suspicion of infectious etiology



Provider exposures treated as high risk for viral hepatitis.






Anticipate elevated intracranial pressure (ICP) with compromised cerebral perfusion pressure.



Assess with direct ICP monitoring if available.



Elevate the patient's head.



Consider osmotic diuresis.



Consider barbiturates.



Consider hypertonic saline.



Avoid systemic hypotension.



Consider electroencephalography to detect seizure activity perioperatively.



Anticipate hypoglycemia, sometimes profound, with added perioperative stress.



Prepare for adult respiratory distress syndrome.



Consider PEEP (in conflict with ICP concerns and hepatic perfusion).



Consider decreased tidal volumes with permissive hypercapnia (in conflict with ICP).



Anticipate hypotension.



Relative hypovolemia.






Extensive vasodilation.



Prepare for massive transfusion requirements.



Alert blood bank.



Secure adequate venous access.



Utilize invasive hemodynamic monitoring.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Anesthetic Management for Procedures Involving the Hepatobiliary System

Transjugular Intrahepatic Portosystemic Shunt (TIPS or TIPSS)

The TIPS procedure, in use since 1989, is sometimes referred to as transjugular intrahepatic portosystemic stent shunt in earlier literature. This terminology emphasized the importance of stenting open hepatic tissue to avoid the loss of patency that had been experienced with the original technique of ballooning without stent placement. With the refinement of this procedure, patients were provided with portosystemic shunting to relieve portal hypertension without undergoing major surgery. Characteristics of patients presenting for TIPS can be found in Box 5-16 . The essentials of TIPS involve placing a catheter into the hepatic vein via the right jugular approach, passage of a specialized needle and then guidewire into a major tributary of the portal vein, and then passage of an angioplasty balloon and metallic stent over this wire to create and maintain a tract through the hepatic tissue. Mortality is increased in patients undergoing emergency TIPS for variceal bleeding, renal insufficiency, marked elevations of bilirubin, and/or coagulopathy resistant to treatment. Early mortality may approach 80% in patients with more than one of these risk factors.[298] In one small series, patients with Child-Pugh class C disease not only failed to have resolution of ascites but also had worse mortality than patients randomized to repeated paracentesis.[299] In a larger series of 60 patients, mortality without liver transplant was similar in TIPS and paracentesis groups at 1 and 2 years, although multivariate analysis demonstrated association of TIPS with survival not requiring registration for liver transplantation.[300]Complications that can lead to significant morbidity have been reported. Puncture of the liver capsule or injury to a hepatic artery can occur with extensive bleeding. Increased central venous pressure has been observed after shunting, and the cirrhotic with poor cardiac function may decompensate: myocardial infarction has been reported. Encephalopathy is a risk of any portosystemic shunting procedure, for reasons described in the prior discussion of hepatic encephalopathy. Hemolysis from mechanical trauma was prevalent in some early series of TIPS but has become a less common issue in recent years. Modern TIPS procedures maintain a patency rate of greater than 90% per year. When necessary, revision or repeat TIPS have become commonplace in active centers.

BOX 5-16 

Characteristics of Patients Presenting for TIPS



Diagnoses in Patients Requiring TIPS



Portal hypertension, most commonly from cirrhosis, with:



Bleeding varices and/or



Ascites failing medical management



Comorbidities Common in Patients Requiring TIPS



Comorbidities of cirrhosis (see earlier discussion), especially:



Bleeding varices



Emergency procedure associated with increased mortality






Recent paracentesis and/or diuretic therapy may cause hypovolemia






Typically high cardiac output and low peripheral vascular resistance



Depressed response to inotropes and vasopressors

Anesthetic considerations for patients undergoing TIPS are, in essence, those of managing the patient with cirrhosis complicated by ascites and/or portal hypertension, except for the rare patient who presents with presinusoidal or venous causes of portal hypertension. The reader is referred to the earlier section dealing with this patient group; for convenience the summary of key points is duplicated inBox 5-17 . Although some centers perform TIPS with the patient under sedation, most cases are performed using general anesthesia. Sedated patients report significant pain during intrahepatic dilation and stent deployment. The unpredictable response of patients with advanced cirrhosis to sedative and narcotic medications should also be considered in choosing between sedation and general anesthesia.

BOX 5-17 

Anesthetic Management of Patients for TIPS (See section regarding management of patients with cirrhosis)



Preserve hepatic blood flow.



Avoid halothane (isoflurane is best studied alternative and better preserves flow).



Consider regional anesthesia if procedure and coagulation allows.



Maintain normocapnia.



Avoid PEEP if possible.



Provide generous volume maintenance.



Avoid medications with situational potential hepatotoxicity whenever possible. Examples:






Acetaminophen, particularly in the alcoholic patient



Sulfonamides, tetracycline, and penicillins






Suspect infectious etiology.



Provider exposures treated as high risk for viral hepatitis.



Anticipate presence or development of abnormalities of: Coagulation



Attempt to correct prothrombin time to within 2 seconds of normal.



Consider cryoprecipitate if fresh frozen plasma is ineffective or fibrinogen abnormality.



Correct thrombocytopenia appropriately for procedure.



Anticipate higher than normal blood loss for procedure.






Anticipate relative hypovolemia, worsened by treatment of ascites.



Assess for presence of high cardiac output, low peripheral resistance.



Suspect portal hypertension and/or variceal bleeding, even without history.



Anticipate depressed response to inotropes and vasopressors.



Consider invasive monitoring.



Pharmacokinetics and pharmacodynamics



Altered volume of distribution



Decreased serum albumin, increased gamma globulins



Intravascular volume unpredictable, especially with ascites treatment



Portosystemic shunted blood bypasses liver



Drugs highly extracted by liver especially affected



Increased sensitivity to sedative medications may be present

Biliary Tract Procedures

Cholecystectomy, Choledochal Cyst Excision, and Biliary Tumor Resection.

General characteristics of patients undergoing procedures of the biliary tract are listed in Box 5-18 . Although open cholecystectomy is still performed in selected patients with anticipated technical difficulties or coexisting disease such as advanced cirrhosis or bleeding diathesis, most institutions now plan laparoscopic cholecystectomy in over 90% of cases. Indications for cholecystectomy are cholelithiasis, choledocholithiasis, and cholecystitis. Patients in this group are often otherwise healthy, although cirrhotic patients often require cholecystectomy and may present the challenges of coagulopathy and portal hypertension. Patients with severe cardiopulmonary disease may poorly tolerate the pneumoperitoneum required for laparoscopic surgery; conversely, postoperative pulmonary function after laparoscopy is superior to that of open, high abdominal surgery.

BOX 5-18 

Characteristics of Patients Undergoing Procedures of the Biliary Tract



Diagnoses in Patients Requiring Biliary Tract Procedures















Biliary duct tumor



Choledochal cyst



Comorbidities and Complications Associated with Biliary Tract Disease



Respiratory embarrassment from abdominal pain



Obstructive jaundice



Coagulopathy from vitamin K malabsorption with chronic biliary obstruction



Cholelithiasis increased with:



Female gender






Cystic fibrosis



Crohn's disease



Sickle cell anemia

The extrahepatic biliary tree may uncommonly be the site of primary tumors or cystic dilation (choledochal cysts) that may present as symptoms of cholangitis, pancreatitis, or cholecystitis. Surgical excision is required and, depending on location, may be technically challenging and result in extensive blood loss.

Endoscopic retrograde cholangiopancreatography (ERCP) has become a cornerstone in the assessment and often the management of patients with suspected biliary obstruction. It is typically implemented after suspicious ultrasound, computed tomography, and/or magnetic resonance imaging. There is a great deal of institutional variation in the management of patients undergoing ERCP, ranging from sedation to general anesthesia. Trends that appear to be emerging are the increased use of conscious sedation or general anesthesia in referral centers undertaking more complex procedures and the cooperative development by involved professional societies of national management guidelines.[301]

Anesthetic preparation ( Box 5-19 ) should focus on any coexisting diseases and complications, with medical optimization as time allows. Even healthy patients with biliary disease will often be profoundly hypovolemic and may be actively experiencing nausea and vomiting. Narcotics should be titrated with the awareness that their stimulation of the sphincter of Oddi may precipitate worsened pain in the conscious patient preoperatively and technical failure of cholangiography intraoperatively. Atropine, glycopyrrolate, naloxone, and glucagon have all been reported to reverse this narcotic-induced spasm. Transfusion is typically not required, and the procedure itself mandates no monitoring beyond that dictated by general patient condition.

BOX 5-19 

Anesthetic Preparation and Management for Biliary Tract Surgery



Check for elevated prothrombin time.



Vitamin K may correct if time allows, otherwise use fresh frozen plasma.



Pay attention to volume status when vomiting, decreased oral intake, or fever is present.



Consider rapid-sequence induction or awake intubation in patients with nausea and vomiting.



Perioperative opioids may cause spasm of sphincter of Oddi.



Blood loss typically is minimal unless complex biliary repair or coagulopathy.



Open procedures



Pain can significantly affect respiratory status and be difficult to manage.



Consider epidural analgesia or intercostals nerve blocks.



Laparoscopic procedures



Pneumoperitoneum associated with:



Increased incidence of pneumothorax and pneumomediastinum



Subcutaneous emphysema



Decreased venous return



Increased peak inspiratory pressures



Hypercapnia from insufflated CO2 and decreased pulmonary compliance

Hepatic Resection

A wide range of patients undergo hepatic resection ( Box 5-20 ). Living-directed donors are healthy individuals whose excised lobes will be transplanted into another patient. Most other patients have either benign or malignant primary hepatic tumors or metastatic tumors to the liver. This large group may have a variety of associated disease processes such as cirrhosis and, of course, any number of unrelated diseases. More rarely, patients near extremis may require resection for problems such as trauma or pregnancy-associated rupture with uncontrolled bleeding.

BOX 5-20 

Characteristics of Patients Undergoing Hepatic Resection



Diagnoses of Patients Requiring Hepatic Resection



Living directed donor



Hepatic tumor






Pregnancy-associated hepatic rupture



Comorbidities That May Be Seen in Patients Requiring



Hepatic Resection



Chronic hepatitis, particularly hepatitis C






Markedly decreases liver's regenerative capacity



Primary benign or malignant hepatic tumor with biliary






Numerous cancers with metastases to the liver

Recent technologic applications such as intraoperative sonography, ultrasonic suction aspiration, harmonic scalpels, and the argon laser coagulator have become a routine part of liver resections in many centers. Hepatic cryotherapy, originally as an open procedure[302] and now under radiologic guidance, has been utilized for lesions otherwise unresectable because of underlying liver disease or anatomic position. For whatever reasons, overall morbidity and mortality of tumor resection and/or destruction has improved remarkably in recent experience.

The anesthetic management of patients undergoing liver resection ( Box 5-21 ) does have two areas of interesting controversy. The first involves fluid management. The traditional school of thought has been that the patient should be kept relatively euvolemic or even slightly hypervolemic during dissection. The logic is that, as in any procedure with the risk of sudden blood loss, the patient can be more rapidly resuscitated when hemorrhage occurs from a point of euvolemia instead of already being hypovolemic. The other approach is to minimize fluids throughout dissection so as to generate a low central venous pressure (CVP). This is augmented by intermittent occlusion of vascular inflow by some surgeons. Here, the logic is that CVP is a critical determinant in hepatic venous pressures so that the lower the CVP, the lower the bleeding from cut hepatic surfaces. This approach has been adopted at many centers and has support in recent literature. [303] [304] [305] [306] [307] It should be emphasized that following resection and confirmation of hemostasis, fluid resuscitation is undertaken. Proponents of this approach believe that the presumed increased risks of organ hypoperfusion, possible hemorrhage in a hypovolemic patient, and even air embolism are outweighed by the improved surgical conditions and decreased blood loss and transfusion requirements that have been reported.

BOX 5-21 

Anesthetic Preparation and Management



Define volume management strategy (low central venous pressure vs. euvolemia).



Consider risk and benefits of epidural catheter placement.



Consider invasive hemodynamic monitoring.



Secure adequate intravenous access for massive transfusion.



Alert blood bank of potential for extensive transfusion requirements.



Consider use of cell salvage and rapid infusion device.



Anticipate possibility of postoperative hepatic insufficiency.









Anticipate common postoperative complications of atelectasis, effusion, and pneumonia.

Postoperative analgesia is another interesting area of discussion. [308] [309] [310] Many centers routinely place epidural catheters for pain management, whereas others do not. Although postoperative pain is significant in this upper abdominal chevron incision, many anesthesiologists fear that the postoperative fluctuations of coagulation that may be seen in any major abdominal procedure will be dangerously accentuated with the resection of large amounts of hepatic tissue. There are limited data to guide the clinician in weighing the risk of epidural catheter placement in a patient who may become coagulopathic against the presumed benefits, especially pulmonary, [311] [312] [313] of epidural analgesia.

The possibility of massive blood loss always exists in these procedures. The blood bank should be alerted, and appropriate venous access should be attained. Cell salvage may be used if cancer and infection are not present.

Liver Transplantation

Orthotopic Liver Transplantation.

Liver transplantation has, in two decades, made a remarkable transition from a procedure of desperate last resort to a commonly recommended therapy ( Table 5-13 ). In the United States, data indicate 80% to 90% one-year survival across all groups and 70% to 80% five-year survival. With improved survival, recurrences of infection (first hepatitis B, and now hepatitis C) as well as the morbidities of long-term immunosuppression have become management issues. Indeed, transplantation can be viewed as exchanging an otherwise untreatable disease (e.g., cirrhosis or acute liver failure) with the treatable disease of immunosuppression. The most common available diagnoses of current U.S. liver transplant candidates are listed for adult and pediatric patients in Box 5-22 . Box 5-23 briefly lists important anesthetic considerations in liver transplant cases.

TABLE 5-13   -- Anesthetic Management for Orthotopic Liver Transplantation

Management Issue and Common Practices


Hemodynamic Monitoring

Direct intra-arterial pressures: radial and/or femoral arteries

Two sites often utilized, heparin-free infusion in one for laboratory samples.

Pulmonary artery catheter

Continuous cardiac output and mixed venous saturation catheters allow rapid assessment of oxygen delivery and utilization.

Transesophageal echocardiography

Particularly useful for portopulmonary syndrome, reperfusion crisis, and suspected tamponade as well as general cardiac function and fluid status. Risk exists of variceal bleeding in coagulopathic patients with esophageal varices.

Central Nervous System Monitoring

Intracranial pressure monitoring

Indicated in fulminant liver failure with advanced encephalopathy if coagulopathy can be adequately corrected.

Laboratory monitoring

Standard coagulation profiles

Prothrombin and partial thromboplastin times, fibrinogen levels, fibrinogen degradation products, and platelet count.

Factor activity

Readily available in some centers, allows factor specific determinations of abnormalities and therapeutic response.

Thromboelastography (TEG)

TEG was commonly used in early transplantation series. Allows “bedside” evaluation of coagulation with patterns typical of factor and platelet deficiency and fibrinolysis.


Allows in-vitro assessment of factor and antifibrinolytic therapy. Still used in many centers.

Potential for Massive Transfusion and Veno-veno Bypass

Extensive venous access

Peripheral large bore (8.5 Fr or larger) catheters allow rapid volume infusion.

Blood bank protocol

10–20 units of packed red blood cells, fresh frozen plasma, and platelets should be available. Many cases require that several units of cells and plasma be verified and at the bedside.

Rapid infusion devices

Many centers use rapid infusion pump devices capable of infusing 1 L or more of fluid in a minute. Careful attention to overpressure alarms and catheter sites is important to avoid pressurized extravasation.

Cell salvage

Cell salvage is commonly used when cancer or infection is not suspected. Large volumes of processed cells will dilute platelets and coagulation factors. Impact on fibrinolysis is controversial.

Veno-veno bypass

Utilization ranges from routine to selected or rare in different centers. Flow from femoral and portal vein to axillary or internal jugular vein maintains venous return during caval interruption. (Piggyback transplantation requires partial or short caval occlusion, typically veno-veno bypass is not utilized.[59])



BOX 5-22 

Most Common Diagnoses of U.S. Patients Registered for Liver Transplantation






Cirrhosis from hepatitis C



Cirrhosis from alcohol



Cryptogenic cirrhosis



Primary biliary cirrhosis



Autoimmune cirrhosis



Cirrhosis from hepatitis B



Acute liver failure



Primary sclerosing cholangitis






Biliary atresia (extrahepatic)



Autoimmune cirrhosis



Acute liver failure



Obstructive biliary disease



Cystic fibrosis






Neonatal hepatitis



Congenital hepatic fibrosis



Inborn errors of metabolism

BOX 5-23 

Preoperative Considerations in the Liver Transplant Patient



Coagulation is almost universally abnormal; severity and direct causes are variable.



Decreased or abnormal factor synthesis






Disseminated intravascular coagulation






Metabolic abnormalities arise from variety of causes; overall picture is unpredictable.



Hypoglycemia in acute hepatic failure, glucose intolerance in cirrhosis



Respiratory alkalosis common with hypoxemia-driven tachypnea



Metabolic acidosis from peripheral shunting causing tissue hypoperfusion



Metabolic alkalosis from volume contraction of paracentesis, diuresis, vomiting






High cardiac output with low peripheral resistance is typical.



Peripheral arteriovenous shunting causes paradoxical tissue ischemia.



Increased endogenous vasodilators usually metabolized by liver.



Formation of true arteriovenous fistulas



Cardiomyopathy may occur with alcoholism, Wilson's disease, etc.



Cardiac reserve must be adequate to tolerate rigorous challenges of transplantation.



Pericardial effusion may require preoperative or early intraoperative drainage.



Portopulmonary hypertension confers exceptionally high perioperative risk.






Hypoxemia common



Ascites and pleural effusions with respiratory compromise



Intrapulmonary shunting from endogenous vasodilators



Hepatopulmonary syndrome associated with intrapulmonary vascular dilatations



ARDS may be present, particularly in acute failure






Encephalopathy common, severity variable



Encephalopathy of acute liver failure is often associated with critical intracranial pressure elevations.



Direct intracranial pressure measurement is invaluable for intraoperative management.






Dysfunction common; severity ranges from mild to hepatorenal syndrome.



Osmotic diuretics and dopamine are often used but without proven efficacy.



Preoperative or intraoperative hemofiltration should be considered for anuric patients.

The Previously Transplanted Patient.

The remarkable improvement in patients surviving liver transplantation and the number of transplantations performed means that more patients will present for surgery who have had a liver transplant. Many of these patients seek all health care at their transplant center. However, it is likely that for practical and economic reasons or medical urgency that many patients will seek care elsewhere. Faced with this situation, the anesthesiologist should evaluate the function of the transplanted liver through history, examination, and routine liver panel studies as described for patients in general. Within a few months of transplantation serum bilirubin and transaminase levels should return toward or to normal range. AST changes, in particular, are monitored as indications of graft rejection. Alkaline phosphatase and GGT are more likely to remain elevated after transplant and must be considered in their trends rather than absolute values.

Conservative management of the patient with the transplanted liver would be to apply the principles discussed for the patient with acute hepatitis. There are, however, little data to indicate that the transplanted liver is at particularly increased risk for perioperative dysfunction. Immunosuppressive protocols should be maintained and their pharmacologic interactions with perioperative medications considered.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Special Considerations

Postoperative Liver Dysfunction

Every anesthesiologist should be prepared to provide at least initial consultation and/or care for the postoperative patient with liver dysfunction. The specter of hepatic necrosis from halothane exposure still looms large in the minds and literature of many colleagues in other specialties. As discussed previously, halothane is rarely a cause of severe hepatic injury, and newer volatile agents have extremely rarely or never been convincingly implicated. With a balanced approach, the anesthesiologist can help to ensure that the more likely, although perhaps less dramatic, causes of postoperative dysfunction are considered with recognition of their relative probability.

The reported incidence of hepatic abnormalities after anesthesia depend on preexisting state of health, population, procedure, era, and the defining criteria for dysfunction. Studies report 25% to 75% of postoperative patients develop abnormal laboratory values, but a much smaller percentage progress to clinically significant disease and/or jaundice. A variety of causes of postoperative jaundice are summarized in Box 5-24 . Three general categories of postoperative abnormalities are increased bilirubin production, hepatocellular injury, and cholestatic disorders.

BOX 5-24 

Classification and Examples of Postoperative Jaundice



Preexisting limitation of capacity for bilirubin metabolism



Chronic liver disease



Gilbert's disease



Unappreciated preexisting disease with natural or accelerated progression



Viral hepatitis






Autoimmune hepatitis



Hepatocellular injury



Ischemic hepatitis



Viral hepatitis



Drug hepatotoxicity



Increased bilirubin load



Breakdown of hemoglobin from transfused erythrocytes



Resorption of large hematomas






Mechanical (e.g., stents, cell salvage processing)



Preexisting disease (e.g., glucose-6-phosphate dehydrogenase deficiency)



Transfusion reaction



Intrahepatic cholestasis



Benign postoperative cholestasis



Medication associated



Extrahepatic biliary obstruction



Postoperative pancreatitis



Biliary stricture



Cholecystitis, calculous or acalculous

Bilirubin overproduction can cause jaundice in the previously healthy patient when bilirubin production exceeds hepatic processing capacity. About 250 mg of bilirubin is usually conjugated daily, but the healthy liver can conjugate up to three times that amount. Several perioperative situations can exceed this production. About 10% of transfused red cells, if older than 2 weeks, are destroyed within 1 day of administration. Similarly, red cells within hematomas are rapidly hemolyzed during resorption. The placement of stents (as discussed with early TIPSS series, for example) and mechanical valves can result in fragmentation or so-called mechanical hemolysis. Laboratory values usually show a pattern of mildly elevated AST and LDH, reduced haptoglobin, unconjugated hyperbilirubinemia, and reticulocytosis. The peripheral smear may reveal schistocytes. Unrecognized preexisting diseases can result in a relative or absolute overproduction of bilirubin. The amount of y hemoglobin that can be conjugated decreases in Gilbert's disease. Glucose-6-phosphate dehydrogenase deficiency, sickle cell disease, and the thalassemias can result in increased hemolysis with what would usually be insignificant stress.Table 5-14 compares laboratory patterns that may be seen in postoperative liver dysfunction.

TABLE 5-14   -- Biochemical Patterns of Postoperative Liver Dysfunction



Alkaline Phosphatase




Overproduction of bilirubin

AST (↑)

Other medications


↑Reticulocytes schistocytes







Ischemic injury

↑ 5–100×

(↑) 2×


(↑) 2–3×


Viral infection

↑ > 10×



Serologies and RNA analysis

Anesthetic associated-severe

↑ to ↑↑



Leukocytosis, eosinophilia

Benign postoperative cholestasis


↑ 3×


↑ 3×

PT (↑)

Extrahepatic cholestasis



AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; PT, prothrombin time; unconj, unconjugated; NL, normal; (↑), mild or no increase; ↑, increased; ↑↑, marked increase; × = times normal.




Hepatocellular necrosis can account for postoperative jaundice and transaminase abnormalities. Ischemic liver injury typically manifests 1 to 10 days after the insult. Hypoperfusion from hypotension, cardiopulmonary bypass, and mechanical interruption of flow as well as hypoxemia have been associated with this type of injury. Venous congestion from right-sided heart failure may exacerbate the damage. As previously discussed, liver blood flow is decreased with most anesthetics. In the case of unrecognized chronic disease, small decreases in blood pressure and cardiac output may not allow the hepatic arterial flow to compensate for decreased portal venous flow to the liver. Aminotransferase levels are markedly elevated, as is LDH, as previously described in patterns of hepatic injury. If liver biopsy is performed, centrilobular or panlobular necrosis is found. The injury can progress to acute liver failure with its attendant derangements as previously outlined. Treatment is supportive with insurance of perfusion and oxygen delivery.

Viral hepatitis is an unusual but important cause of postoperative jaundice. Some percentage of patients will have an acute infection with a time course that conspires to manifest perioperatively or a chronic infection that results in hepatic deterioration postoperatively. Transfusion-borne disease is less likely than preoperative infection in the current era. The disease can unfold anytime in the first 2 postoperative weeks with typical laboratory findings; previously discussed serologic studies and RNA analysis are indicated.

Anesthetic-associated injury was discussed with hepatotoxins, but a few important points are repeated here. Halothane can cause either a milder intrinsic hepatotoxicity or a severe idiosyncratic hepatotoxicity. The latter appears to occur in the range of 1 in 35,000 adult anesthetics, if the previously described risk factors are absent. Transaminases are elevated, bilirubin increases in correlation with severity, and eosinophilia is found in up to 30% of cases. The newer inhalational anesthetics are rarely, if ever, associated with hepatic injury of consequence. This is believed to be because of decreased biotransformation and improved hepatic perfusion as compared with halothane. Other drugs that should be considered in postoperative liver dysfunction are tetracycline, isoniazid, phenytoin, penicillin, acetaminophen, and sulfonamides.

Benign postoperative cholestasis occurs with or without jaundice. It tends to occur in critically ill patients. Its causes are believed to be multifactorial, having significant overlap with issues such as increased bilirubin load and hypoperfusion. Treatment is supportive, and mortality is related to processes other than cholestasis. Major infection can also cause intrahepatic cholestasis. Some authors, in fact, consider this to simply be another cause of benign postoperative cholestasis, whereas others distinguish the two. Regardless of nomenclature, infection should be considered in the differential diagnosis of postoperative cholestasis.

Extrahepatic cholestasis is a rare cause of postoperative jaundice but should be considered. Causes include cholecystitis (with or without cholelithiasis), postoperative pancreatitis, and complications of surgery that disrupt the biliary tract. Aminotransferases, alkaline phosphatase, and total bilirubin are typically mildly to moderately elevated. Total parenteral nutrition has been associated with both acalculous cholecystitis and cholelithiasis, as well as steatohepatitis and even micronodular cirrhosis with long-term administration.

A general approach to the patient with postoperative liver dysfunction is to review the history for any overlooked evidence of preexisting liver disease. A biochemical liver profile, complete blood cell count, and clotting times should be assessed. Elevations of unconjugated bilirubin can arise from breakdown of transfused red cells, hemolysis from mechanical devices or preexisting disease, hematoma resorption, or Gilbert's syndrome. Haptoglobin, reticulocyte count, and LDH can be used to help confirm the etiology. In the case of conjugated hyperbilirubinemia, further discriminating laboratory testing should be pursued. Markedly increased aminotransferases and LDH without evidence of obstruction are consistent with ischemic injury, drug-associated injury, or active viral infection. Abdominal sonography can be used to evaluate obstruction. Sepsis, total parenteral nutrition, medication effects, and acalculous cholecystitis can also cause cholestasis and conjugated hyperbilirubinemia.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier


The vital roles of the liver, even in health, are of a complexity and number beyond our current understanding. Patients with liver disease or undergoing procedures affecting the liver can present great challenges to the anesthesiologist. With the current surge of patients deteriorating from chronic and often undiagnosed hepatitis C and the limited number of organs available for transplantation, we can expect to care for an increasing number of patients with significant hepatic dysfunction. Recent history also demonstrates the rapid development and implementation of new procedures, often in such arenas as interventional radiology and from the experience of transplant surgery. Such innovation requires the application of basic management principles and critical review of accumulating experience.

The stated goals of this chapter included discussion of relevant hepatic structure and function, responses of the liver to injury, discussion of specific disease etiologies, and principles of anesthetic management. With these considerations, it is hoped that the anesthesiologist can more comfortably and rationally approach the management of patients with hepatic disease as well as those undergoing liver-related surgery.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier


  1. In: Cotran RS, Kumar V, Collins T, ed. Robbins Pathologic Basis of Disease,  6th ed. Philadelphia: WB Saunders; 1999.
  2. In: Feldman M, Friedman LS, Sleisenger MH, ed. Sleisenger & Fordtran's Gastrointestinal and Liver Disease,  7th ed. Philadelphia: WB Saunders; 2002.
  3. Schuchmann M, Galle PR: Apoptosis in liver disease.  Eur J Gastroenterol Hepatol2001; 13:785-790.
  4. Patel T, Steer CJ, Gores GJ: Apoptosis and the liver: A mechanism of disease, growth regulation, and carcinogenesis.  Hepatology1999; 30:811-815.
  5. Berenguer M, Wright T: Viral hepatitis.   In: Feldman M, Friedman L, Sleisenger M, ed. Sleisenger & Fordtran's Gastrointestinal and Liver Diseases,  7th ed. Philadelphia: WB Saunders; 2002.
  6. Ryder SD, Beckingham IJ: ABC of diseases of liver, pancreas, and biliary system: Acute hepatitis.  BMJ2001; 322:151-153.
  7. Cuthbert JA: Hepatitis A: Old and new.  Clin Microbiol Rev2001; 14:38-58.
  8. Bower WA, Nainan OV, Han X, et al: Duration of viremia in hepatitis A virus infection.  J Infect Dis2000; 182:12-17.
  9. Tomida S, Matsuzaki Y, Nishi M, et al: Severe acute hepatitis A associated with acute pure red cell aplasia.  J Gastroenterol1996; 31:612-617.
  10. Diwan AH, Stubbs JR, Carnahan GE: Transmission of hepatitis A via WBC-reduced RBCs and FFP from a single donation.  Transfusion (Paris)2003; 43:536-540.
  11. Mannucci PM, Gdovin S, Gringeri A, et al: Transmission of hepatitis A to patients with hemophilia by factor VIII concentrates treated with organic solvent and detergent to inactivate viruses. The Italian Collaborative Group.  Ann Intern Med1994; 120:1-7.
  12. Lednar WM, Lemon SM, Kirkpatrick JW, et al: Frequency of illness associated with epidemic hepatitis A virus infections in adults.  Am J Epidemiol1985; 122:226-233.
  13. Kemmer NM, Miskovsky EP: Hepatitis A.  Infect Dis Clin North Am2000; 14:605-615.
  14. Willner IR, Uhl MD, Howard SC, et al: Serious hepatitis A: An analysis of patients hospitalized during an urban epidemic in the United States.  Ann Intern Med1998; 128:111-114.
  15. Vento S, Garofano T, Renzini C, et al: Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C.  N Engl J Med1998; 338:286-290.
  16. Keeffe EB: Is hepatitis A more severe in patients with chronic hepatitis B and other chronic liver diseases?.  Am J Gastroenterol1995; 90:201-205.
  17. Glikson M, Galun E, Oren R, et al: Relapsing hepatitis A: Review of 14 cases and literature survey.  Medicine (Baltimore)1992; 71:14-23.
  18. Craig AS, Schaffner W: Clinical practice: Prevention of hepatitis A with the hepatitis A vaccine.  N Engl J Med2004; 350:476-481.
  19. Prevention of hepatitis A infections: Guidelines for use of hepatitis A vaccine and immune globulin. American Academy of Pediatrics Committee on Infectious Diseases.  Pediatrics.1996; 98:1207-1215.
  20. Avgerinos A, Armonis A, Manolakopoulos S, et al: Endoscopic sclerotherapy versus variceal ligation in the long-term management of patients with cirrhosis after variceal bleeding: A prospective randomized study.  J Hepatol1997; 26:1034-1041.
  21. Lai CL, Ratziu V, Yuen MF, et al: Viral hepatitis B.  Lancet2003; 362:2089-2094.
  22. Alter MJ, Mast EE: The epidemiology of viral hepatitis in the United States.  Gastroenterol Clin North Am1994; 23:437-455.
  23. Huo TI, Wu JC, Wu SI, et al: Changing seroepidemiology of hepatitis B, C, and D virus infections in high-risk populations.  J Med Virol2004; 72:41-45.
  24. Christensen PB, Krarup HB, Niesters HG, et al: Outbreak of hepatitis B among injecting drug users in Denmark.  J Clin Virol2001; 22:133-141.
  25. Kidd-Ljunggren K, Broman E, Ekvall H, et al: Nosocomial transmission of hepatitis B virus infection through multiple-dose vials.  J Hosp Infect1999; 43:57-62.
  26. Webster GJ, Hallett R, Whalley SA, et al: Molecular epidemiology of a large outbreak of hepatitis B linked to autohaemotherapy.  Lancet2000; 356:379-384.
  27. Schreiber GB, Busch MP, Kleinman SH, et al: The risk of transfusion-transmitted viral infections: The Retrovirus Epidemiology Donor Study.  N Engl J Med1996; 334:1685-1690.
  28. Brook MG: Sexually acquired hepatitis.  Sex Transm Infect2002; 78:235-240.
  29. Alter MJ, Margolis HS: The emergence of hepatitis B as a sexually transmitted disease.  Med Clin North Am1990; 74:1529-1541.
  30. Akbar SM, Horiike N, Onji M, et al: Dendritic cells and chronic hepatitis virus carriers.  Intervirology2001; 44:199-208.
  31. Chin R, Locarnini S: Treatment of chronic hepatitis B: Current challenges and future directions.  Rev Med Virol2003; 13:255-272.
  32. Rehermann B: Immune responses in hepatitis B virus infection.  Semin Liver Dis2003; 23:21-38.
  33. Hyams KC: Risks of chronicity following acute hepatitis B virus infection: A review.  Clin Infect Dis1995; 20:992-1000.
  34. Milich DR, Jones JE, Hughes JL, et al: Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?.  Proc Natl Acad Sci U S A1990; 87:6599-6603.
  35. Harpaz R, McMahon BJ, Margolis HS, et al: Elimination of new chronic hepatitis B virus infections: Results of the Alaska immunization program.  J Infect Dis2000; 181:413-418.
  36. Chang MH, Chen CJ, Lai MS, et al: Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group.  N Engl J Med1997; 336:1855-1859.
  37. Chernesky MA, Browne RA, Rondi P: Hepatitis B virus antibody prevalence in anaesthetists.  Can Anaesth Soc J1984; 31:239-245.
  38. Browne RA, Chernesky MA: Viral hepatitis and the anaesthetist.  Can Anaesth Soc J1984; 31:279-286.
  39. Browne RA, Chernesky MA: Infectious diseases and the anaesthetist.  Can J Anaesth1988; 35:655-665.
  40. Yuen MF, Lai CL: Treatment of chronic hepatitis B.  Lancet Infect Dis2001; 1:232-241.
  41. Niederau C, Heintges T, Lange S, et al: Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.  N Engl J Med1996; 334:1422-1427.
  42. Yuen MF, Hui CK, Cheng CC, et al: Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.  Hepatology2001; 34:139-145.
  43. Dienstag JL, Schiff ER, Wright TL, et al: Lamivudine as initial treatment for chronic hepatitis B in the United States.  N Engl J Med1999; 341:1256-1263.
  44. Dienstag JL, Goldin RD, Heathcote EJ, et al: Histological outcome during long-term lamivudine therapy.  Gastroenterology2003; 124:105-117.
  45. Allen MI, Deslauriers M, Andrews CW, et al: Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group.  Hepatology1998; 27:1670-1677.
  46. Marcellin P, Chang TT, Lim SG, et al: Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.  N Engl J Med2003; 348:808-816.
  47. Perrillo R, Schiff E, Yoshida E, et al: Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants.  Hepatology2000; 32:129-134.
  48. Rizzetto M, Canese MG, Arico S, et al: Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers.  Gut1977; 18:997-1003.
  49. Taylor JM: Replication of human hepatitis delta virus: Recent developments.  Trends Microbiol2003; 11:185-190.
  50. McCruden EA, Hillan KJ, McKay IC, et al: Hepatitis virus infection and liver disease in injecting drug users who died suddenly.  J Clin Pathol1996; 49:552-555.
  51. Navascues CA, Rodriguez M, Sotorrio NG, et al: Epidemiology of hepatitis D virus infection: Changes in the last 14 years.  Am J Gastroenterol1995; 90:1981-1984.
  52. Lettau LA, McCarthy JG, Smith MH, et al: Outbreak of severe hepatitis due to delta and hepatitis B viruses in parenteral drug abusers and their contacts.  N Engl J Med1987; 317:1256-1262.
  53. Wu JC, Chen CM, Sheen IJ, et al: Evidence of transmission of hepatitis D virus to spouses from sequence analysis of the viral genome.  Hepatology1995; 22:1656-1660.
  54. Hoofnagle JH: Type D (delta) hepatitis.  JAMA1989; 261:1321-1325.
  55. Rosina F, Cozzolongo R: Interferon in HDV infection.  Antiviral Res1994; 24:165-174.
  56. Lauer GM, Walker BD: Hepatitis C virus infection.  N Engl J Med2001; 345:41-52.
  57. Choo QL, Kuo G, Weiner AJ, et al: Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome.  Science1989; 244:359-362.
  58. Alter MJ, Kruszon-Moran D, Nainan OV, et al: The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.  N Engl J Med1999; 341:556-562.
  59. Donahue JG, Munoz A, Ness PM, et al: The declining risk of post-transfusion hepatitis C virus infection.  N Engl J Med1992; 327:369-373.
  60. Wasley A, Alter MJ: Epidemiology of hepatitis C: Geographic differences and temporal trends.  Semin Liver Dis2000; 20:1-16.
  61. Ohto H, Terazawa S, Sasaki N, et al: Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group.  N Engl J Med1994; 330:744-750.
  62. Conte D, Fraquelli M, Prati D, et al: Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women.  Hepatology2000; 31:751-755.
  63. Thomas DL, Villano SA, Riester KA, et al: Perinatal transmission of hepatitis C virus from human immunodeficiency virus type 1-infected mothers. Women and Infants Transmission Study.  J Infect Dis1998; 177:1480-1488.
  64. Granovsky MO, Minkoff HL, Tess BH, et al: Hepatitis C virus infection in the mothers and infants cohort study.  Pediatrics1998; 102:355-359.
  65. Paccagnini S, Principi N, Massironi E, et al: Perinatal transmission and manifestation of hepatitis C virus infection in a high risk population.  Pediatr Infect Dis J1995; 14:195-199.
  66. Zanetti AR, Tanzi E, Paccagnini S, et al: Mother-to-infant transmission of hepatitis C virus. Lombardy Study Group on Vertical HCV Transmission.  Lancet1995; 345:289-291.
  67. Lavanchy D: Hepatitis C: Public health strategies.  J Hepatol1999; 31:146-151.
  68. Kage M, Ogasawara S, Kosai K, et al: Hepatitis C virus RNA present in saliva but absent in breast-milk of the hepatitis C carrier mother.  J Gastroenterol Hepatol1997; 12:518-521.
  69. Soto B, Rodrigo L, Garcia-Bengoechea M, et al: Heterosexual transmission of hepatitis C virus and the possible role of coexistent human immunodeficiency virus infection in the index case: A multicentre study of 423 pairings.  J Intern Med1994; 236:515-519.
  70. Couzigou P, Richard L, Dumas F, et al: Detection of HCV-RNA in saliva of patients with chronic hepatitis C.  Gut1993; 34:S59-S60.
  71. Sagnelli E, Gaeta GB, Felaco FM, et al: Hepatitis C virus infection in households of anti-HCV chronic carriers in Italy: A multicentre case-control study.  Infection1997; 25:346-349.
  72. Bronowicki JP, Venard V, Botte C, et al: Patient-to-patient transmission of hepatitis C virus during colonoscopy.  N Engl J Med1997; 337:237-240.
  73. Esteban JI, Gomez J, Martell M, et al: Transmission of hepatitis C virus by a cardiac surgeon.  N Engl J Med1996; 334:555-560.
  74. Ross RS, Viazov S, Gross T, et al: Transmission of hepatitis C virus from a patient to an anesthesiology assistant to five patients.  N Engl J Med2000; 343:1851-1854.
  75. Poynard T, Yuen MF, Ratziu V, et al: Viral hepatitis C.  Lancet2003; 362:2095-2100.
  76. Poynard T, Marcellin P, Lee SS, et al: Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT).  Lancet1998; 352:1426-1432.
  77. Pawlotsky JM: Use and interpretation of virological tests for hepatitis C.  Hepatology2002; 36:S65-S73.
  78. NIH Consensus Statement on Management of Hepatitis C: 2002.  NIH Consensus & State-of-the-Science Statements2002; 19:1-46.
  79. Afdhal NH: Diagnosing fibrosis in hepatitis C: Is the pendulum swinging from biopsy to blood tests?.  Hepatology2003; 37:972-974.
  80. Gebo KA, Herlong HF, Torbenson MS, et al: Role of liver biopsy in management of chronic hepatitis C: A systematic review.  Hepatology2002; 36:S161-S172.
  81. Dienstag JL: The role of liver biopsy in chronic hepatitis C.  Hepatology2002; 36:S152-S160.
  82. Lindsay KL, Trepo C, Heintges T, et al: A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C.  Hepatology2001; 34:395-403.
  83. Fried MW, Shiffman ML, Reddy KR, et al: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.  N Engl J Med2002; 347:975-982.
  84. Manns MP, McHutchison JG, Gordon SC, et al: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial.  Lancet2001; 358:958-965.
  85. Jaeckel E, Cornberg M, Wedemeyer H, et al: Treatment of acute hepatitis C with interferon alfa-2b.  N Engl J Med2001; 345:1452-1457.
  86. Worm HC, van der Poel WH, Brandstatter G: Hepatitis E: An overview.  Microbes Infect2002; 4:657-666.
  87. Naik SR, Aggarwal R, Salunke PN, et al: A large waterborne viral hepatitis E epidemic in Kanpur, India.  Bull World Health Organ1992; 70:597-604.
  88. Robson SC, Adams S, Brink N, et al: Hospital outbreak of hepatitis E.  Lancet1992; 339:1424-1425.
  89. Khuroo MS, Dar MY: Hepatitis E: Evidence for person-to-person transmission and inability of low dose immune serum globulin from an Indian source to prevent it.  Indian J Gastroenterol1992; 11:113-116.
  90. Linnen J, Wages Jr J, Zhang-Keck ZY, et al: Molecular cloning and disease association of hepatitis G virus: A transfusion-transmissible agent.  Science1996; 271:505-508.
  91. Stapleton JT: GB virus type C/hepatitis G virus.  Semin Liver Dis2003; 23:137-148.
  92. Alter HJ, Nakatsuji Y, Melpolder J, et al: The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease.  N Engl J Med1997; 336:747-754.
  93. Pessoa MG, Terrault NA, Detmer J, et al: Quantitation of hepatitis G and C viruses in the liver: Evidence that hepatitis G virus is not hepatotropic.  Hepatology1998; 27:877-880.
  94. Polgreen PM, Xiang J, Chang Q, et al: GB virus type C/hepatitis G virus: A non-pathogenic flavivirus associated with prolonged survival in HIV-infected individuals.  Microbes Infect2003; 5:1255-1261.
  95. Craig P: Echinococcus multilocularis.  Curr Opin Infect Dis2003; 16:437-444.
  96. Lewis Jr JW, Koss N, Kerstein MD: A review of echinococcal disease.  Ann Surg1975; 181:390-396.
  97. Ersahin Y, Mutluer S, Guzelbag E: Intracranial hydatid cysts in children.  Neurosurgery1993; 33:219-224.discussion 224-225
  98. Pandey M, Chaudhari MP: Primary hydatid cyst of sacral spinal canal: Case report.  Neurosurgery1997; 40:407-409.
  99. Tekkok IH, Benli K: Primary spinal extradural hydatid disease: Report of a case with magnetic resonance characteristics and pathological correlation.  Neurosurgery1993; 33:320-323.discussion 323
  100. Angulo JC, Sanchez-Chapado M, Diego A, et al: Renal echinococcosis: Clinical study of 34 cases.  J Urol1997; 157:787-794.
  101. Snodgrass D, Blome S: Cardiac hydatid disease: Report of two cases.  Australas Radiol2002; 46:194-196.
  102. Lygidakis NJ: Diagnosis and treatment of intrabiliary rupture of hydatid cyst of the liver.  Arch Surg1983; 118:1186-1189.
  103. Khoury G, Jabbour-Khoury S, Bikhazi K: Results of laparoscopic treatment of hydatid cysts of the liver.  Surg Endosc1996; 10:57-59.
  104. Sola JL, Vaquerizo A, Madariaga MJ, et al: Intraoperative anaphylaxis caused by a hydatid cyst.  Acta Anaesthesiol Scand1995; 39:273-274.
  105. Khoury G, Jabbour-Khoury S, Soueidi A, et al: Anaphylactic shock complicating laparoscopic treatment of hydatid cysts of the liver.  Surg Endosc1998; 12:452-454.
  106. Wellhoener P, Weitz G, Bechstein W, et al: Severe anaphylactic shock in a patient with a cystic liver lesion.  Intensive Care Med2000; 26:1578.
  107. Kambam JR, Dymond R, Krestow M, et al: Efficacy of histamine H1 and H2 receptor blockers in the anesthetic management during operation for hydatid cysts of liver and lungs.  South Med J1988; 81:1013-1015.
  108. Alagille D, Estrada A, Hadchouel M, et al: Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): Review of 80 cases.  J Pediatr1987; 110:195-200.
  109. Krantz ID, Piccoli DA, Spinner NB: Clinical and molecular genetics of Alagille syndrome.  Curr Opin Pediatr1999; 11:558-564.
  110. Tzakis AG, Reyes J, Tepetes K, et al: Liver transplantation for Alagille's syndrome.  Arch Surg1993; 128:337-339.
  111. Emerick KM, Rand EB, Goldmuntz E, et al: Features of Alagille syndrome in 92 patients: Frequency and relation to prognosis.  Hepatology1999; 29:822-829.
  112. Bucuvalas JC, Horn JA, Carlsson L, et al: Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature.  J Clin Endocrinol Metab1993; 76:1477-1482.
  113. Adachi T, Murakawa M, Uetsuki N, et al: Living related donor liver transplantation in a patient with severe aortic stenosis.  Br J Anaesth1999; 83:488-490.
  114. Choudhry DK, Rehman MA, Schwartz RE, et al: The Alagille's syndrome and its anaesthetic considerations.  Paediatr Anaesth1998; 8:79-82.
  115. Muller C, Jelinek T, Endres S, et al: Severe protracted cholestasis after general anesthesia in a patient with Alagille syndrome.  Z Gastroenterol1996; 34:809-812.
  116. Luisetti M, Seersholm N: Alpha1-antitrypsin deficiency: I. Epidemiology of alpha1-antitrypsin deficiency.  Thorax2004; 59:164-169.
  117. Perlmutter DH, Joslin G, Nelson P, et al: Endocytosis and degradation of alpha 1-antitrypsin-protease complexes is mediated by the serpin-enzyme complex (SEC) receptor.  J Biol Chem1990; 265:16713-16716.
  118. Carrell RW, Lomas DA: Alpha1-antitrypsin deficiency a model for conformational diseases.  N Engl J Med2002; 346:45-53.
  119. Elliott PR, Lomas DA, Carrell RW, et al: Inhibitory conformation of the reactive loop of alpha 1-antitrypsin.  Nat Struct Biol1996; 3:676-681.
  120. Elliott PR, Stein PE, Bilton D, et al: Structural explanation for the deficiency of S alpha 1-antitrypsin.  Nat Struct Biol1996; 3:910-911.
  121. Callea F, Brisigotti M, Fabbretti G, et al: Hepatic endoplasmic reticulum storage diseases.  Liver1992; 12:357-362.
  122. Lomas DA, Evans DL, Finch JT, et al: The mechanism of Z alpha 1-antitrypsin accumulation in the liver.  Nature1992; 357:605-607.
  123. Dafforn TR, Mahadeva R, Elliott PR, et al: A kinetic mechanism for the polymerization of alpha1-antitrypsin.  J Biol Chem1999; 274:9548-9555.
  124. Piitulainen E, Eriksson S: Decline in FEV1 related to smoking status in individuals with severe alpha1-antitrypsin deficiency (PiZZ).  Eur Respir J1999; 13:247-251.
  125. Lindblad A, Glaumann H, Strandvik B: Natural history of liver disease in cystic fibrosis.  Hepatology1999; 30:1151-1158.
  126. Duthie A, Doherty DG, Williams C, et al: Genotype analysis for delta F508, G551D and R553X mutations in children and young adults with cystic fibrosis with and without chronic liver disease.  Hepatology1992; 15:660-664.
  127. Duthie A, Doherty DG, Donaldson PT, et al: The major histocompatibility complex influences the development of chronic liver disease in male children and young adults with cystic fibrosis.  J Hepatol1995; 23:532-537.
  128. Efrati O, Barak A, Modan-Moses D, et al: Liver cirrhosis and portal hypertension in cystic fibrosis.  Eur J Gastroenterol Hepatol2003; 15:1073-1078.
  129. Pozler O, Krajina A, Vanicek H, et al: Transjugular intrahepatic portosystemic shunt in five children with cystic fibrosis: Long-term results.  Hepatogastroenterology2003; 50:1111-1114.
  130. Bloom AI, Verstandig A: SCVIR 2002 Film Panel case 2: TIPS for bleeding varices in cystic fibrosis and liver cirrhosis.  J Vasc Interv Radiol2002; 13:533-536.
  131. Noble-Jamieson G, Barnes N, Jamieson N, et al: Liver transplantation for hepatic cirrhosis in cystic fibrosis.  J R Soc Med1996; 89:31-37.
  132. Pfister E, Strassburg A, Nashan B, et al: Liver transplantation for liver cirrhosis in cystic fibrosis.  Transplant Proc2002; 34:2281-2282.
  133. Knoppert DC, Spino M, Beck R, et al: Cystic fibrosis: Enhanced theophylline metabolism may be linked to the disease.  Clin Pharmacol Ther1988; 44:254-264.
  134. Kearns GL, Mallory Jr GB, Crom WR, et al: Enhanced hepatic drug clearance in patients with cystic fibrosis.  J Pediatr1990; 117:972-979.
  135. Waggoner DD, Buist NR, Donnell GN: Long-term prognosis in galactosaemia: Results of a survey of 350 cases.  J Inherit Metab Dis1990; 13:802-818.
  136. Widhalm K, Miranda da Cruz BD, Koch M: Diet does not ensure normal development in galactosemia.  J Am Coll Nutr1997; 16:204-208.
  137. Levy HL, Sepe SJ, Shih VE, et al: Sepsis due to Escherichia coli in neonates with galactosemia.  N Engl J Med1977; 297:823-825.
  138. Vogt M, Gitzelmann R, Allemann J: Decompensated liver cirrhosis caused by galactosemia in a 52-year-old man.  Schweiz Med Wochenschr1980; 110:1781-1783.
  139. Bosch AM, Bakker HD, van Gennip AH, et al: Clinical features of galactokinase deficiency: A review of the literature.  J Inherit Metab Dis2002; 25:629-634.
  140. Bevan JC: Anaesthesia in Von Gierke's disease: Current approach to management.  Anaesthesia1980; 35:699-702.
  141. Ogawa M, Shimokohjin T, Seto T, et al: Anesthesia for hepatectomy in a patient with glycogen storage disease.  Masui1995; 44:1703-1706.
  142. Shenkman Z, Golub Y, Meretyk S, et al: Anaesthetic management of a patient with glycogen storage disease type 1b.  Can J Anaesth1996; 43:467-470.
  143. Kakinohana M, Tokumine J, Shimabukuro T, et al: Patient-controlled sedation using propofol for a patient with von Gierke disease.  Masui1998; 47:1104-1108.
  144. Mohart D, Russo P, Tobias JD: Perioperative management of a child with glycogen storage disease type III undergoing cardiopulmonary bypass and repair of an atrial septal defect.  Paediatr Anaesth2002; 12:649-654.
  145. Matern D, Starzl TE, Arnaout W, et al: Liver transplantation for glycogen storage disease types I, III, and IV.  Eur J Pediatr1999; 158:S43-S48.
  146. Rosenthal P, Podesta L, Grier R, et al: Failure of liver transplantation to diminish cardiac deposits of amylopectin and leukocyte inclusions in type IV glycogen storage disease.  Liver Transpl Surg1995; 1:373-376.
  147. Stormon MO, Cutz E, Furuya K, et al: A six-month-old infant with liver steatosis.  J Pediatr2004; 144:258-263.
  148. Choi YK, Johlin Jr FC, Summers RW, et al: Fructose intolerance: An under-recognized problem.  Am J Gastroenterol2003; 98:1348-1353.
  149. Newbrun E, Hoover C, Mettraux G, et al: Comparison of dietary habits and dental health of subjects with hereditary fructose intolerance and control subjects.  J Am Dent Assoc1980; 101:619-626.
  150. Edwards CQ, Cartwright GE, Skolnick MH, et al: Genetic mapping of the hemochromatosis locus on chromosome six.  Hum Immunol1980; 1:19-22.
  151. Simon M, Bourel M, Fauchet R, et al: Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis.  Gut1976; 17:332-334.
  152. Feder JN, Gnirke A, Thomas W, et al: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.  Nat Genet1996; 13:399-408.
  153. Adams PC: Nonexpressing homozygotes for C282Y hemochromatosis: Minority or majority of cases?.  Mol Genet Metab2000; 71:81-86.
  154. Harrison SA, Bacon BR: Hereditary hemochromatosis: Update for 2003.  J Hepatol2003; 38:S14-S23.
  155. Fletcher LM, Dixon JL, Purdie DM, et al: Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis.  Gastroenterology2002; 122:281-289.
  156. Fletcher LM, Halliday JW: Haemochromatosis: Understanding the mechanism of disease and implications for diagnosis and patient management following the recent cloning of novel genes involved in iron metabolism.  J Intern Med2002; 251:181-192.
  157. Andrews NC: Disorders of iron metabolism.  N Engl J Med1999; 341:1986-1995.
  158. Feder JN, Penny DM, Irrinki A, et al: The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.  Proc Natl Acad Sci U S A1998; 95:1472-1477.
  159. Cardoso EM, Stal P, Hagen K, et al: HFE mutations in patients with hereditary haemochromatosis in Sweden.  J Intern Med1998; 243:203-208.
  160. Powell LW, George DK, McDonnell SM, et al: Diagnosis of hemochromatosis.  Ann Intern Med1998; 129:925-931.
  161. Bacon BR, Powell LW, Adams PC, et al: Molecular medicine and hemochromatosis: At the crossroads.  Gastroenterology1999; 116:193-207.
  162. Edwards CQ, Cartwright GE, Skolnick MH, et al: Homozygosity for hemochromatosis: Clinical manifestations.  Ann Intern Med1980; 93:519-525.
  163. Nichols GM, Bacon BR: Hereditary hemochromatosis: Pathogenesis and clinical features of a common disease.  Am J Gastroenterol1989; 84:851-862.
  164. Britton RS: Metal-induced hepatotoxicity.  Semin Liver Dis1996; 16:3-12.
  165. Bacon BR, Britton RS: The pathology of hepatic iron overload: A free radical mediated process?.  Hepatology1990; 11:127-137.
  166. Bonkovsky HL, Lambrecht RW: Iron-induced liver injury.  Clin Liver Dis2000; 4:409-429.vi-vii
  167. Niederau C, Fischer R, Sonnenberg A, et al: Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.  N Engl J Med1985; 313:1256-1262.
  168. Brandhagen DJ: Liver transplantation for hereditary hemochromatosis.  Liver Transpl2001; 7:663-672.
  169. Prieto-Alamo MJ, Laval F: Deficient DNA-ligase activity in the metabolic disease tyrosinemia type I.  Proc Natl Acad Sci U S A1998; 95:12614-12618.
  170. Stoner E, Starkman H, Wellner D, et al: Biochemical studies of a patient with hereditary hepatorenal tyrosinemia: Evidence of glutathione deficiency.  Pediatr Res1984; 18:1332-1336.
  171. Gilbert-Barness E, Barness LA, Meisner LF: Chromosomal instability in hereditary tyrosinemia type I.  Pediatr Pathol1990; 10:243-252.
  172. De Braekeleer M, Larochelle J: Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay-Lac-St-Jean.  Am J Hum Genet1990; 47:302-307.
  173. Scriver CR: Human genetics: Lessons from Quebec populations.  Ann Rev Genom Hum Genet2001; 2:69-101.
  174. Mitchell G, Larochelle J, Lambert M, et al: Neurologic crises in hereditary tyrosinemia.  N Engl J Med1990; 322:432-437.
  175. Holme E, Lindstedt S: Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione).  J Inherit Metab Dis1998; 21:507-517.
  176. Grompe M: The pathophysiology and treatment of hereditary tyrosinemia type 1.  Semin Liver Dis2001; 21:563-571.
  177. Terlato NJ, Cox GF: Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature.  Genet Med2003; 5:286-294.
  178. Man TT, Tsai PS, Rau RH, et al: Children with mucopolysaccharidoses three case reports.  Acta Anaesthesiol Sin1999; 37:93-96.
  179. Baines D, Keneally J: Anaesthetic implications of the mucopolysaccharidoses: A fifteen-year experience in a children's hospital.  Anaesth Intensive Care1983; 11:198-202.
  180. Walker RW, Allen DL, Rothera MR: A fibreoptic intubation technique for children with mucopolysaccharidoses using the laryngeal mask airway.  Paediatr Anaesth1997; 7:421-426.
  181. Walker RW, Colovic V, Robinson DN, et al: Postobstructive pulmonary oedema during anaesthesia in children with mucopolysaccharidoses.  Paediatr Anaesth2003; 13:441-447.
  182. Vas L, Naregal F: Failed epidural anaesthesia in a patient with Hurler's disease.  Paediatr Anaesth2000; 10:95-98.
  183. Yoskovitch A, Tewfik TL, Brouillette RT, et al: Acute airway obstruction in Hunter syndrome.  Int J Pediatr Otorhinolaryngol1998; 44:273-278.
  184. Busoni P, Fognani G: Failure of the laryngeal mask to secure the airway in a patient with Hunter's syndrome (mucopolysaccharidosis type II).  Paediatr Anaesth1999; 9:153-155.
  185. Vogler C, Barker J, Sands MS, et al: Murine mucopolysaccharidosis VIL: Impact of therapies on the phenotype, clinical course, and pathology in a model of a lysosomal storage disease.  Pediatr Dev Pathol2001; 4:421-433.
  186. Tokieda K, Morikawa Y, Natori M, et al: Intrauterine growth acceleration in the case of a severe form of mucopolysaccharidosis type VII.  J Perinat Med1998; 26:235-239.
  187. Gillett PM, Schreiber RA, Jevon GP, et al: Mucopolysaccharidosis type VII (Sly syndrome) presenting as neonatal cholestasis with hepatosplenomegaly.  J Pediatr Gastroenterol Nutr2001; 33:216-220.
  188. Toda Y, Takeuchi M, Morita K, et al: Complete heart block during anesthetic management in a patient with mucopolysaccharidosis type VII.  Anesthesiology2001; 95:1035-1037.
  189. Charrow J, Andersson HC, Kaplan P, et al: The Gaucher registry: Demographics and disease characteristics of 1698 patients with Gaucher disease.  Arch Intern Med2000; 160:2835-2843.
  190. Cox TM, Schofield JP: Gaucher's disease: Clinical features and natural history.  Baillieres Clin Haematol1997; 10:657-689.
  191. Hollak CE, Corssmit EP, Aerts JM, et al: Differential effects of enzyme supplementation therapy on manifestations of type 1 Gaucher disease.  Am J Med1997; 103:185-191.
  192. Hollak CE, Aerts JM, Goudsmit R, et al: Individualised low-dose alglucerase therapy for type 1 Gaucher's disease.  Lancet1995; 345:1474-1478.
  193. Hollak CE, Levi M, Berends F, et al: Coagulation abnormalities in type 1 Gaucher disease are due to low-grade activation and can be partly restored by enzyme supplementation therapy.  Br J Haematol1997; 96:470-476.
  194. Kita T, Kitamura S, Takeda K, et al: Anesthetic management involving difficult intubation in a child with Gaucher disease.  Masui1998; 47:69-73.
  195. Tobias JD, Atwood R, Lowe S, et al: Anesthetic considerations in the child with Gaucher disease.  J Clin Anesth1993; 5:150-153.
  196. Garcia Collada JC, Pereda Marin RM, Martinez AI, et al: Subarachnoid anesthesia in a patient with type I Gaucher disease.  Acta Anaesthesiol Scand2003; 47:106-109.
  197. Dell'Oste C, Vincenti F: Anaesthetic management of children with type II and III Gaucher disease.  Minerva Pediatr1997; 49:495-498.
  198. Kolodny EH: Niemann-Pick disease.  Curr Opin Hematol2000; 7:48-52.
  199. Liscum L, Klansek JJ: Niemann-Pick disease type C.  Curr Opin Lipidol1998; 9:131-135.
  200. Bujok LS, Bujok G, Knapik P: Niemann-Pick disease: A rare problem in anaesthesiological practice.  Paediatr Anaesth2002; 12:806-808.
  201. Daloze P, Delvin EE, Glorieux FH, et al: Replacement therapy for inherited enzyme deficiency: Liver orthotopic transplantation in Niemann-Pick disease type A.  Am J Med Genet1977; 1:229-239.
  202. Smanik EJ, Tavill AS, Jacobs GH, et al: Orthotopic liver transplantation in two adults with Niemann-Pick and Gaucher's diseases: Implications for the treatment of inherited metabolic disease.  Hepatology1993; 17:42-49.
  203. Cantz M, Ulrich-Bott B: Disorders of glycoprotein degradation.  J Inherit Metab Dis1990; 13:523-537.
  204. Wolman M: Wolman disease and its treatment.  Clin Pediatr (Phila)1995; 34:207-212.
  205. Krivit W, Peters C, Dusenbery K, et al: Wolman disease successfully treated by bone marrow transplantation.  Bone Marrow Transplant2000; 26:567-570.
  206. Gross U, Hoffmann GF, Doss MO: Erythropoietic and hepatic porphyrias.  J Inherit Metab Dis2000; 23:641-661.
  207. Crimlisk HL: The little imitator porphyria: A neuropsychiatric disorder.  J Neurol Neurosurg Psychiatry1997; 62:319-328.
  208. Gonzalez-Arriaza HL, Bostwick JM: Acute porphyrias: A case report and review.  Am J Psychiatry2003; 160:450-459.
  209. Elder GH, Hift RJ, Meissner PN: The acute porphyrias.  Lancet1997; 349:1613-1617.
  210. Harrison GG, Meissner PN, Hift RJ: Anaesthesia for the porphyric patient.  Anaesthesia1993; 48:417-421.
  211. Jensen NF, Fiddler DS, Striepe V: Anesthetic considerations in porphyrias.  Anesth Analg1995; 80:591-599.
  212. Stevens JJ, Kneeshaw JD: Mitral valve replacement in a patient with acute intermittent porphyria.  Anesth Analg1996; 82:416-418.
  213. McNeill MJ, Bennet A: Use of regional anaesthesia in a patient with acute porphyria.  Br J Anaesth1990; 64:371-373.
  214. Soonawalla ZF, Orug T, Badminton MN, et al: Liver transplantation as a cure for acute intermittent porphyria.  Lancet2004; 363:705-706.
  215. Nguyen L, Blust M, Bailin M, et al: Photosensitivity and perioperative polyneuropathy complicating orthotopic liver transplantation in a patient with erythropoietic protoporphyria.  Anesthesiology1999; 91:1173-1175.
  216. Meerman L, Haagsma EB, Gouw AS, et al: Long-term follow-up after liver transplantation for erythropoietic protoporphyria.  Eur J Gastroenterol Hepatol1999; 11:431-438.
  217. Bloomer JR, Rank JM, Payne WD, et al: Follow-up after liver transplantation for protoporphyric liver disease.  Liver Transpl Surg1996; 2:269-275.
  218. Lock G, Holstege A, Mueller AR, et al: Liver failure in erythropoietic protoporphyria associated with choledocholithiasis and severe post-transplantation polyneuropathy.  Liver1996; 16:211-217.
  219. de Torres I, Demetris AJ, Randhawa PS: Recurrent hepatic allograft injury in erythropoietic protoporphyria.  Transplantation1996; 61:1412-1413.
  220. Wilson S: Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver.  Brain1912; 34:295-509.
  221. Riordan SM, Williams R: The Wilson's disease gene and phenotypic diversity.  J Hepatol2001; 34:165-171.
  222. Gitlin N: Wilson's disease: The scourge of copper.  J Hepatol1998; 28:734-739.
  223. El-Youssef M: Wilson disease.  Mayo Clin Proc2003; 78:1126-1136.
  224. Cox DW: Genes of the copper pathway.  Am J Hum Genet1995; 56:828-834.
  225. Valentine JS, Gralla EB: Delivering copper inside yeast and human cells.  Science1997; 278:817-818.
  226. Schaefer M, Roelofsen H, Wolters H, et al: Localization of the Wilson's disease protein in human liver.  Gastroenterology1999; 117:1380-1385.
  227. Cauza E, Maier-Dobersberger T, Polli C, et al: Screening for Wilson's disease in patients with liver diseases by serum ceruloplasmin.  J Hepatol1997; 27:358-362.
  228. Saito T: Presenting symptoms and natural history of Wilson disease.  Eur J Pediatr1987; 146:261-265.
  229. McCullough AJ, Fleming CR, Thistle JL, et al: Diagnosis of Wilson's disease presenting as fulminant hepatic failure.  Gastroenterology1983; 84:161-167.
  230. Tissieres P, Chevret L, Debray D, et al: Fulminant Wilson's disease in children: Appraisal of a critical diagnosis.  Pediatr Crit Care Med2003; 4:338-343.
  231. Wilson DC, Phillips MJ, Cox DW, et al: Severe hepatic Wilson's disease in preschool-aged children.  J Pediatr2000; 137:719-722.
  232. Dening TR, Berrios GE: Wilson's disease: A prospective study of psychopathology in 31 cases.  Br J Psychiatry1989; 155:206-213.
  233. Dening TR, Berrios GE: Wilson's disease: Psychiatric symptoms in 195 cases.  Arch Gen Psychiatry1989; 46:1126-1134.
  234. Klepach GL, Wray SH: Bilateral serous retinal detachment with thrombocytopenia during penicillamine therapy.  Ann Ophthalmol1989; 13:201-203.
  235. Umeki S, Konishi Y, Yasuda T, et al: D-Penicillamine and neutrophilic agranulocytosis.  Arch Intern Med1985; 145:2271-2272.
  236. Brewer GJ: Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammation.  J Cell Mol Med2003; 7:11-20.
  237. Askari FK, Greenson J, Dick RD, et al: Treatment of Wilson's disease with zinc: XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc.  J Lab Clin Med2003; 142:385-390.
  238. Geissler I, Heinemann K, Rohm S, et al: Liver transplantation for hepatic and neurological Wilson's disease.  Transplant Proc2003; 35:1445-1446.
  239. Sutcliffe RP, Maguire DD, Muiesan P, et al: Liver transplantation for Wilson's disease: Long-term results and quality-of-life assessment.  Transplantation2003; 75:1003-1006.
  240. Suzuki S, Sato Y, Ichida T, et al: Recovery of severe neurologic manifestations of Wilson's disease after living-related liver transplantation: A case report.  Transplant Proc2003; 35:385-386.
  241. Popper H: Aging and the liver.  Prog Liver Dis1986; 8:659-683.
  242. Lacaine F, LaMuraglia GM, Malt RA: Prognostic factors in survival after portasystemic shunts: Multivariate analysis.  Ann Surg1985; 202:729-734.
  243. Hosking SW, Bird NC, Johnson AG, et al: Management of bleeding varices in the elderly.  BMJ1989; 298:152-153.
  244. Poupon RE, Lindor KD, Cauch-Dudek K, et al: Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis.  Gastroenterology1997; 113:884-890.
  245. Combes B, Luketic VA, Peters MG, et al: Prolonged follow-up of patients in the U.S. multicenter trial of ursodeoxycholic acid for primary biliary cirrhosis.  Am J Gastroenterol2004; 99:264-268.
  246. Levy C, Angulo P: Ursodeoxycholic acid and long-term survival in primary biliary cirrhosis.  Am J Gastroenterol2004; 99:269-270.
  247. Grose RD, Nolan J, Dillon JF, et al: Exercise-induced left ventricular dysfunction in alcoholic and non-alcoholic cirrhosis.  J Hepatol1995; 22:326-332.
  248. Roberts LR, Kamath PS: Pathophysiology of variceal bleeding.  Gastrointest Endosc Clin North Am1999; 9:167-174.
  249. Platt JF, Ellis JH, Rubin JM, et al: Renal duplex Doppler ultrasonography: A noninvasive predictor of kidney dysfunction and hepatorenal failure in liver disease.  Hepatology1994; 20:362-369.
  250. Lang F, Tschernko E, Haussinger D: Hepatic regulation of renal function.  Exp Physiol1992; 77:663-673.
  251. Salo J, Fernandez-Esparrach G, Gines P, et al: Urinary endothelin-like immunoreactivity in patients with cirrhosis.  J Hepatol1997; 27:810-816.
  252. Arroyo V, Gines P, Gerbes AL, et al: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club.  Hepatology1996; 23:164-176.
  253. Watt K, Uhanova J, Minuk GY: Hepatorenal syndrome: Diagnostic accuracy, clinical features, and outcome in a tertiary care center.  Am J Gastroenterol2002; 97:2046-2050.
  254. Gonwa TA, Klintmalm GB, Levy M, et al: Impact of pretransplant renal function on survival after liver transplantation.  Transplantation1995; 59:361-365.
  255. Gines P, Guevara M, De Las Heras D, et al: Review article: Albumin for circulatory support in patients with cirrhosis.  Aliment Pharmacol Ther2002; 16:24-31.
  256. Ortega R, Gines P, Uriz J, et al: Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: Results of a prospective, nonrandomized study.  Hepatology2002; 36:941-948.
  257. Ganne-Carrie N, Hadengue A, Mathurin P, et al: Hepatorenal syndrome: Long-term treatment with terlipressin as a bridge to liver transplantation.  Dig Dis Sci1996; 41:1054-1056.
  258. Le Moine O, el Nawar A, Jagodzinski R, et al: Treatment with terlipressin as a bridge to liver transplantation in a patient with hepatorenal syndrome.  Acta Gastroenterol Belg1998; 61:268-270.
  259. Guevara M, Gines P, Fernandez-Esparrach G, et al: Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion.  Hepatology1998; 27:35-41.
  260. Agusti AG, Cardus J, Roca J, et al: Ventilation-perfusion mismatch in patients with pleural effusion: Effects of thoracentesis.  Am J Respir Crit Care Med1997; 156:1205-1209.
  261. Bindrim SJ, Schutz SM: Respiratory function after injection sclerotherapy of oesophageal varices.  Gastrointest Endosc1995; 42:191-193.
  262. Tominaga M, Furutani H, Segawa H, et al: Perioperative management of living-donor liver transplantation in two patients with severe portopulmonary hypertension.  Masui2003; 52:729-732.
  263. Tan HP, Markowitz JS, Montgomery RA, et al: Liver transplantation in patients with severe portopulmonary hypertension treated with preoperative chronic intravenous epoprostenol.  Liver Transpl2001; 7:745-749.
  264. Blei AT, Olafsson S, Therrien G, et al: Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis.  Hepatology1994; 19:1437-1444.
  265. Iwasa M, Matsumura K, Watanabe Y, et al: Improvement of regional cerebral blood flow after treatment with branched-chain amino acid solutions in patients with cirrhosis.  Eur J Gastroenterol Hepatol2003; 15:733-737.
  266. Harville DD, Summerskill WH: Surgery in acute hepatitis.  JAMA1963; 184:257-261.
  267. Powell-Jackson P, Greenway B, Williams R: Adverse effects of exploratory laparotomy in patients with unsuspected liver disease.  Br J Surg1982; 69:449-451.
  268. Greenwood SM, Leffler CT, Minkowitz S: The increased mortality rate of open liver biopsy in alcoholic hepatitis.  Surg Gynecol Obstet1972; 134:600-604.
  269. Mikkelsen WP, Kern WH: The influence of acute hyaline necrosis on survival after emergency and elective portacaval shunt.  Major Probl Clin Surg1974; 14:233-242.
  270. Hargrove Jr MD: Chronic active hepatitis: Possible adverse effect of exploratory laparotomy.  Surgery1970; 68:771-773.
  271. Higashi H, Matsumata T, Adachi E, et al: Influence of viral hepatitis status on operative morbidity and mortality in patients with primary hepatocellular carcinoma.  Br J Surg1994; 81:1342-1345.
  272. Runyon BA: Surgical procedures are well tolerated by patients with asymptomatic chronic hepatitis.  J Clin Gastroenterol1986; 8:542-544.
  273. Behrns KE, Tsiotos GG, DeSouza NF, et al: Hepatic steatosis as a potential risk factor for major hepatic resection.  J Gastrointest Surg1998; 2:292-298.
  274. Brolin RE, Bradley LJ, Taliwal RV: Unsuspected cirrhosis discovered during elective obesity operations.  Arch Surg1998; 133:84-88.
  275. Beymer C, Kowdley KV, Larson A, et al: Prevalence and predictors of asymptomatic liver disease in patients undergoing gastric bypass surgery.  Arch Surg2003; 138:1240-1244.
  276. Garrison RN, Cryer HM, Howard DA, et al: Clarification of risk factors for abdominal operations in patients with hepatic cirrhosis.  Ann Surg1984; 199:648-655.
  277. Mansour A, Watson W, Shayani V, et al: Abdominal operations in patients with cirrhosis: Still a major surgical challenge.  Surgery1997; 122:730-735.discussion 735-736
  278. Puggioni A, Wong LL: A meta-analysis of laparoscopic cholecystectomy in patients with cirrhosis.  J Am Coll Surg2003; 197:921-926.
  279. Fernandes NF, Schwesinger WH, Hilsenbeck SG, et al: Laparoscopic cholecystectomy and cirrhosis: A case-control study of outcomes.  Liver Transpl2000; 6:340-344.
  280. Yeh CN, Chen MF, Jan YY: Laparoscopic cholecystectomy in 226 cirrhotic patients: Experience of a single center in Taiwan.  Surg Endosc2002; 16:1583-1587.
  281. Klemperer JD, Ko W, Krieger KH, et al: Cardiac operations in patients with cirrhosis.  Ann Thorac Surg1998; 65:85-87.
  282. Hayashida N, Shoujima T, Teshima H, et al: Clinical outcome after cardiac operations in patients with cirrhosis.  Ann Thorac Surg2004; 77:500-505.
  283. Oellerich M, Armstrong VW: The MEGX test: A tool for the real-time assessment of hepatic function.  Ther Drug Monit2001; 23:81-92.
  284. Petrolati A, Festi D, De Berardinis G, et al: 13C-methacetin breath test for monitoring hepatic function in cirrhotic patients before and after liver transplantation.  Aliment Pharmacol Ther2003; 18:785-790.
  285. Hwang EH, Taki J, Shuke N, et al: Preoperative assessment of residual hepatic functional reserve using 99mTc-DTPA-galactosyl-human serum albumin dynamic SPECT.  J Nucl Med1999; 40:1644-1651.
  286. Onodera Y, Takahashi K, Togashi T, et al: Clinical assessment of hepatic functional reserve using 99mTc DTPA galactosyl human serum albumin SPECT to prognosticate chronic hepatic diseases validation of the use of SPECT and a new indicator.  Ann Nucl Med2003; 17:181-188.
  287. Schemel WH: Unexpected hepatic dysfunction found by multiple laboratory screening.  Anesth Analg1976; 55:810-812.
  288. Patt CH, Yoo HY, Dibadj K, et al: Prevalence of transaminase abnormalities in asymptomatic, healthy subjects participating in an executive health-screening program.  Dig Dis Sci2003; 48:797-801.
  289. Maze M, Bass NM: Anesthesia and the hepatobiliary system.   In: Miller R, ed. Anesthesia,  Philadelphia: Churchill Livingstone; 2000:1964.
  290. Gelman S, Dillard E, Bradley Jr EL: Hepatic circulation during surgical stress and anesthesia with halothane, isoflurane, or fentanyl.  Anesth Analg1987; 66:936-943.
  291. Gatecel C, Losser MR, Payen D: The postoperative effects of halothane versus isoflurane on hepatic artery and portal vein blood flow in humans.  Anesth Analg2003; 96:740-745.
  292. Brienza N, Revelly JP, Ayuse T, et al: Effects of PEEP on liver arterial and venous blood flows.  Am J Respir Crit Care Med1995; 152:504-510.
  293. O'Grady JG, Alexander GJ, Hayllar KM, et al: Early indicators of prognosis in fulminant hepatic failure.  Gastroenterology1989; 97:439-445.
  294. Pauwels A, Mostefa-Kara N, Florent C, et al: Emergency liver transplantation for acute liver failure: Evaluation of London and Clichy criteria.  J Hepatol1993; 17:124-127.
  295. Anand AC, Nightingale P, Neuberger JM: Early indicators of prognosis in fulminant hepatic failure: An assessment of the King's criteria.  J Hepatol1997; 26:62-68.
  296. Shakil AO, Kramer D, Mazariegos GV, et al: Acute liver failure: Clinical features, outcome analysis, and applicability of prognostic criteria.  Liver Transpl2000; 6:163-169.
  297. Farmer DG, Anselmo DM, Ghobrial RM, et al: Liver transplantation for fulminant hepatic failure: Experience with more than 200 patients over a 17-year period.  Ann Surg2003; 237:666-675.discussion 675-676
  298. Russo MW, Jacques PF, Mauro M, et al: Predictors of mortality and stenosis after transjugular intrahepatic portosystemic shunt.  Liver Transpl2002; 8:271-277.
  299. Lebrec D, Giuily N, Hadengue A, et al: Transjugular intrahepatic portosystemic shunts: Comparison with paracentesis in patients with cirrhosis and refractory ascites: A randomized trial. French Group of Clinicians and a Group of Biologists.  J Hepatol1996; 25:135-144.
  300. Rossle M, Ochs A, Gulberg V, et al: A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites.  N Engl J Med2000; 342:1701-1707.
  301. Faigel DO, Baron TH, Goldstein JL, et al: Guidelines for the use of deep sedation and anesthesia for GI endoscopy.  Gastrointest Endosc2002; 56:613-617.
  302. Littlewood K: Anesthetic considerations for hepatic cryotherapy.  Semin Surg Oncol1998; 14:116-121.
  303. Jones RM, Moulton CE, Hardy KJ: Central venous pressure and its effect on blood loss during liver resection.  Br J Surg1998; 85:1058-1060.
  304. Chen H, Merchant NB, Didolkar MS: Hepatic resection using intermittent vascular inflow occlusion and low central venous pressure anesthesia improves morbidity and mortality.  J Gastrointest Surg2000; 4:162-167.
  305. Chen CL, Chen YS, de Villa VH, et al: Minimal blood loss living donor hepatectomy.  Transplantation2000; 69:2580-2586.
  306. Otsubo T, Takasaki K, Yamamoto M, et al: Bleeding during hepatectomy can be reduced by clamping the inferior vena cava below the liver.  Surgery2004; 135:67-73.
  307. Smyrniotis V, Kostopanagiotou G, Theodoraki K, et al: The role of central venous pressure and type of vascular control in blood loss during major liver resections.  Am J Surg2004; 187:398-402.
  308. Kwan AL: Epidural analgesia for patient undergoing hepatectomy.  Anaesth Intensive Care2003; 31:236-237.
  309. Greenland K: Epidural analgesia for patient undergoing hepatectomy.  Anaesth Intensive Care2003; 31:593-594.author reply 594
  310. Takaoka F, Teruya A, Massarollo P, et al: Minimizing risks for donors undergoing right hepatectomy for living-related liver transplantation.  Anesth Analg2003; 97:297.author reply 297-298
  311. Liu S, Carpenter RL, Neal JM: Epidural anesthesia and analgesia: Their role in postoperative outcome.  Anesthesiology1995; 82:1474-1506.
  312. Ballantyne JC, Carr DB, deFerranti S, et al: The comparative effects of postoperative analgesic therapies on pulmonary outcome: Cumulative meta-analyses of randomized, controlled trials.  Anesth Analg1998; 86:598-612.
  313. Jayr C, Thomas H, Rey A, et al: Postoperative pulmonary complications: Epidural analgesia using bupivacaine and opioids versus parenteral opioids.  Anesthesiology1993; 78:666-676.discussion 22A
  314. Moreno-Gonzalez E, Meneu-Diaz JG, Fundora Y, et al: Advantages of the piggy back technique on intraoperative transfusion, fluid consumption, and vasoactive drugs requirements in liver transplantation: A comparative study.  Transplant Proc2003; 35:1918-1919.