Chapter 24 Preoperative and postoperative nutrition in hepatobiliary surgery
Alterations in Liver Metabolism That Affect Nutritional Status
The liver plays a crucial role in the metabolism and assimilation of nutrients, and it is central in the orchestration of protein and carbohydrate metabolism. Any defect or disease of the liver results in significant metabolic derangements. Progression of liver dysfunction results not only in metabolic derangement from a decrease in the number of functioning hepatic cells but also in shunting of portal blood, which decreases the delivery of nutrients, growth factors, and hormones to the remaining cells. Patients with advanced liver disease and cirrhosis also have increased circulating serum levels of growth hormone, glucagon, epinephrine, and cortisol. The cause of this altered hormonal pattern is not completely understood but is typical of a catabolic state and results in carbohydrate intolerance and muscle proteolysis (Eigler et al, 1979; Sherwin et al, 1974). It is speculated further that the catabolic profile of patients with cirrhosis and ascites may be due in part to a defective gastrointestinal (GI) mucosal barrier, which leads to the escape of endotoxin from the lumen of the bowel into the peritoneal cavity (Helton, 1994). The transmigrated endotoxin stimulates peritoneal mononuclear phagocytic cells and Kupffer cells in the liver to release proinflammatory cytokines and mediators (interleukin [IL]-1, tumor necrosis factor [TNF], IL-6, eicosanoids, and nitric oxide). These mediators and cytokines modulate numerous metabolic functions of the liver, including amino acid, protein, lipid, carbohydrate, and trace mineral metabolism (Andus et al, 1991). The proinflammatory cytokines are produced by cells in the intestine and liver to mediate anabolic and catabolic functions and regulate hepatic blood flow, bile flow, liver regeneration, and the response to I/R injury.
TNF is the proximal cytokine signal produced by hepatic Kupffer cells in response to endotoxin or I/R injury. TNF initiates a cascade of inflammatory events that are important in the pathogenesis of many types of surgically induced liver injury, such as I/R injury that occurs with liver resection and transplantation. Endotoxemia occurring in response to manipulation of the biliary tree in patients with biliary obstruction also stimulates the release of TNF, which is believed to mediate in part the systemic sepsis response and subsequent increased organ failure rate associated with operating in the setting of biliary obstruction and infection (Nolan, 1981; Wilkinson et al, 1976). TNF and IL-6 cause a reprioritization of hepatic protein synthesis, a process involving accelerated production of acute-phase proteins at the expense of constitutive proteins. Some indirect evidence suggests that parenteral nutrition also weakens the intestinal barrier, allowing endotoxin to escape from the gut, where it then primes Kupffer cells for cytokine release in response to later infection (Fong et al, 1989).
Increased skeletal muscle proteolysis and muscle wasting in advanced cirrhosis may be related in part to the fact that the cirrhotic liver does not respond appropriately to growth hormone because of low levels of growth hormone–binding protein (Hattori et al, 1992). Growth hormone normally binds to growth hormone–binding protein on hepatocytes and stimulates the production of insulin-like growth factor-1 (IGF-1), the principal mediator of growth hormone–induced protein synthesis and IGF-1 binding proteins. Patients with advanced cirrhosis have low circulating plasma levels of IGF-1 and IGF-1 binding proteins (Hattori et al, 1992; Poggi et al, 1979). The net effect of this metabolic derangement is impaired glucose disposal by skeletal muscle and impaired skeletal muscle protein synthesis. Simultaneously, there is decreased protein synthesis by the diseased liver for the major secretory proteins, such as albumin, and proteins in the coagulation cascade (Nachbauer & Fischer, 1983). As a result of the aforementioned alterations, the administration of recombinant IGF-1, but not growth hormone, may enhance protein synthesis (Inaba et al, 1994) and may be an important adjunct to improving the nutritional state of patients with liver disease who are undergoing operation (Sato et al, 1994).
Subclinical steatorrhea is common in patients with cirrhosis or obstructive jaundice and leads to fat-soluble vitamin and trace element deficiencies (Gitlin & Heyman, 1984). These deficits are underappreciated in the nutritional assessment of patients with hepatobiliary disease who are undergoing surgery, and such deficits should be corrected.
Identification of Patients at Risk for Postoperative Complications
To use nutritional support appropriately in a cost-effective and clinically efficacious manner, it is necessary to identify which patients are at risk for nutritionally related complications and which would benefit from nutritional intervention. Malnutrition is recognized as an important predisposing factor in the morbidity and mortality of patients undergoing major abdominal surgery (Table 24.1; Mullen et al, 1979). Approximately 48% to 70% of patients with obstructive jaundice (Foschi et al, 1986; Pitt et al, 1981; Padillo et al, 2001) and nearly all patients with advanced cirrhosis undergoing operation have significant malnutrition and are at risk for postoperative complications. Infection is the most common complication in patients undergoing liver and biliary surgery and occurs in 22% to 40% of all patients (Dixon et al, 1983; Foschi et al, 1986; McPherson et al, 1984; Pitt et al, 1981; Smith et al, 1985; Stimpson et al, 1987). Sepsis and sepsis-induced multiple organ failure are the most common causes of death in liver transplant recipients (Colonna et al, 1988; Yokoyama et al, 1989; Torbenson et al, 1998) and in patients with jaundice and cirrhosis undergoing abdominal operations (Armstrong et al, 1984; McPherson et al, 1984; Pitt et al, 1981, 1985). Because most patients with severe liver disease or jaundice are malnourished, and because malnutrition leads to infection, nutritional intervention and repletion may decrease postoperative morbidity and mortality rates in patients undergoing hepatobiliary surgery.
Table 24.1 Causes of Malnutrition in Cirrhosis
| Poor Dietary Intake |
| Anorexia, nausea, alcohol abuse, dietary restrictions (protein, fat, sodium, fluid) |
| Malabsorption/Maldigestion |
| Cholestasis, intraluminal bile deficiency, coexisting pancreatic exocrine insufficiency, fat malabsorption |
| Increased Catabolism |
| Muscle proteolysis |
| Decreased Protein Synthesis |
| Decreased hepatocyte growth hormone receptor, IGF-1 and IGF-BP, hepatic transport proteins, fibrinogen, coagulation factors, lipoproteins |
| Drug Therapy Effects |
IGF, insulin-like growth factor; BP, binding protein
Several prognostic scoring systems have been developed to identify malnourished patients at risk for developing postoperative complications (Buzby et al, 1980). Although no consensus has been reached on the best method for assessing the nutritional status of hospitalized patients, the Nutritional Risk Index (NRI), Maastricht Index (MI), Subjective Global Assessment (SGA), and Mini Nutritional Assessment (MNA) can all be safely applied in the clinical setting with no significant difference in predictive value (Kuzu et al, 2006; Clugston et al, 2006). Although the use of such scoring systems allows prediction of postoperative complications in specific patient groups, their applicability in patients with significant liver disease or cirrhosis is not well established (Shronts, 1988). The most recent (2009) guidelines from the European Society for Clinical Nutrition and Metabolism (ESPEN) recommend the use of simple bedside methods, such as the SGA, for patients with either liver or pancreas disease. Because conventional markers, such as weight status and serum protein levels, are altered and depend on nonnutritional factors, other subjective measures must be relied upon. A dietary and medical history combined with physical examination continues to be the most sensitive means of assessing nutritional risk in patients undergoing hepatobiliary surgery.
The evaluation of a patient’s nutritional status should begin with an initial baseline evaluation and continue throughout the patient’s course of treatment. A complete nutritional assessment includes 1) physical examination and clinical evaluation, 2) assessment of muscle mass and strength, 3) evaluation of serum albumin and C-reactive protein, 4) assessment of vitamin and mineral deficits, and 5) determination of nutrient requirements (Table 24.2; Shronts, 1988). Historical questions should focus on the patient’s nutritional intake, the degree and rate of weight loss over the previous 6 months (Windsor, 1993), use of alcohol, length of time with jaundice, and problems with diarrhea, which may indicate fat malabsorption and steatorrhea. This assessment, although not clinically tested in prospective trials in patients undergoing liver surgery, is similar to the global nutritional assessment scale of Baker and Detsky (Baker et al, 1982; Detsky et al, 1987) and should provide a sensitive means of detecting patients at risk for nutrition-related problems after surgery. Dixon et al (1983), Pitt (1981), and Halliday et al (1988) and their colleagues identified several nutritional risk factors in patients undergoing biliary tract surgery that were predictive of postoperative morbidity and mortality (Table 24.3). If these factors are identified in a patient being considered for an elective operation, preoperative nutritional repletion is probably indicated.
Table 24.2 Nutritional Assessment
| Clinical Evaluation |
| Physical Examination |
| Protein Synthetic Function |
| Vitamin, Mineral, Trace Element Deficits |
Table 24.3 Nutritional Risk Factors for Postoperative Complications in Hepatobiliary Surgery
Data from Halliday A, et al, 1988: Nutritional risk factors in major hepatobiliary surgery. J Parenter Enteral Nutr 12:43-48; Harrison J, et al, 1997: A prospective study on the effect of recipient nutritional status on outcome in liver transplantation. Transplant Int 10:369-374; and Pitt H, et al, 1981: Factors affecting mortality in biliary tract surgery. Am J Surg 141:66-71.
Antioxidant Nutrient Depletion in the Pathogenesis of Liver Injury
Patients with liver disease, biliary obstruction, bacterial or viral infection, or malnutrition have impaired antioxidant defenses coupled with increased oxidant stresses (Bell et al, 1992; Burra et al, 1992). Additional factors that deplete hepatic antioxidants include smoking, alcohol ingestion, general anesthesia, and surgery (Bulger & Helton, 1998; Goode et al, 1994). This antioxidant depletion likely contributes to increased risk for postoperative infection and multiple organ dysfunction in this patient population. Data from animal studies suggest that a major pathophysiologic event in hepatocellular injury is depletion of endogenous antioxidants (Bell et al, 1992; Burra et al, 1992) at the time of increased oxidative stress from infection (Sugino et al, 1987, 1989), liver resection (Ouchi et al, 1991), or transplantation (Serino et al, 1990).
Patients with chronic liver disease are at particularly high risk for having depleted stores of fat-soluble vitamins. Patients with chronic liver disease (see Chapter 2) have altered bile salt pools and enterohepatic circulation of bile salts, leading to impaired micelle formation, which leads to malabsorption of fat and fat-soluble vitamins A, D, E, and K. Patients with advanced cirrhosis were found to have markedly depleted preoperative plasma levels of vitamin E, vitamin A, and carotene, and these decreased even further after transplantation (Goode et al, 1994).
Patients with cirrhosis have lower antioxidant defenses, which compounds the insult of reperfusion injury by oxygen free radicals. Also, plasma levels of vitamin E decrease significantly in the first hours after surgery or acute injury; a significant reduction in the levels of liver α-tocopherol, an active form of vitamin E, was observed during the first hour of reperfusion in a rat model of liver ischemia (Marubayashi et al, 1984; Maderazo et al, 1990, 1991). Low levels of vitamin E also have been reported in patients with varying levels of chronic liver damage (Goode et al, 1994). Obstructive jaundice often is associated with endotoxemia (Bailey, 1976; Ding et al, 1992), which leads to Kupffer cell production of oxygen free radicals and nitric oxide, which inhibit protein synthesis (Curran et al, 1990). Endotoxemia also reduces endogenous levels of the antioxidants glutathione, vitamin E, and coenzyme Q (Marubayashi et al, 1986).
Two of the most important components of the human antioxidant system are ascorbic acid (vitamin C) and α-tocopherol. Ascorbate is required as a cofactor for many enzymes involved in the scavenging of many free radicals; α-tocopherol has the ability to scavenge intermediate peroxyl radicals and therefore interrupt the chain reactions of lipid peroxidation (Birlouez-Aragon et al, 2003; Halliwell et al, 1990; Traber, 1994), and it is the most important inhibitor of the free-radical chain reaction of lipid peroxidation. Studies in rodents show that supplemental vitamin E significantly attenuates liver I/R injury and hepatic lipid peroxidation (Sugino et al, 1989). In vitro, physiologic concentrations of vitamin E inhibit lipopolysaccharide-stimulated TNF secretion by Kupffer cells, suggesting that subnormal tissue or plasma levels of vitamin E may potentiate macrophage cytokine release (McClain et al, 1994; see Chapters 9 and 10).
Vitamin E has a variety of protective effects on the hepatobiliary system (Leo et al, 1995). It attenuates endotoxemia (Powell et al, 1991; Sugino et al, 1989) and hepatocellular membrane lipid peroxidation and cellular damage after I/R injury (Lee & Clemens, 1992; Marubayashi et al, 1986). In rodents with bile duct obstruction, the concentrations of vitamin E and other antioxidants are reduced in liver tissue (Singh et al, 1992; Sokol et al, 1991). Large doses of enterally administered vitamin E inhibit the release of TNF in models of infection (Bulger et al, 1997; Marubayashi et al, 1989). Under these conditions, vitamin E supplementation improves survival after a septic challenge (Yoshikawa et al, 1984). Pretreatment with α-tocopherol improved adenosine triphosphate (ATP) levels, prevented the increase in lipid peroxidation products, and decreased the loss of hepatic glutathione during the early phase of reperfusion after warm ischemia in rats (Giakoustidis et al, 2002); α-tocopherol also increased the survival of rats with steatotic liver that underwent warm liver ischemia, and it has shown beneficial effects in cold I/R injury (Gondolesi et al, 2002; Eum et al, 2002). These animal studies show a protective effect of vitamin E on liver function and survival during conditions commonly encountered in patients undergoing hepatobiliary surgery.
Vitamin C deficiency is evident in 50% of patients with alcoholic liver disease (Muller, 1995) and is probably even lower in alcoholics who smoke. Vitamin C recycles reduced α-tocopherol and is intimately linked to vitamin E’s ability to quench free radical–mediated cellular damage (Sardesai, 1995). The simultaneous administration of ascorbate and α-tocopherol is more effective in inhibiting oxidation than either alone (Niki et al, 1995). Ascorbate and vitamin E are located in different domains; vitamin C acts as a first defense, when the radicals are generated in the plasma, with vitamin E breaking the chain propagation at the cellular membrane level. The synergistic protective effects of vitamin C and vitamin E in preventing lipid peroxidation and cellular damage suggest that these vitamins should be administered together for maximal potential benefit (Bulger & Helton, 1998). A prospective randomized study in patients undergoing liver resection using an infusion containing 10 mg α-tocopherol acetate and 1 g ascorbate administered prior to reperfusion demonstrated that in the treated group, less plasma lipid peroxidation and acute liver damage occurred as assessed by measurement of the prothrombin time (PT) and aminotransferase levels. The treated group also had fewer postoperative complications (Cerwenka et al, 1999).
The administration of fish oils or omega-3 fatty acids also can influence cytokine and prostanoid release by the intestine (Ogle et al, 1995) and Kupffer cells of the liver (Bankey et al, 1989; Billiar et al, 1988). These observations show that hepatocellular function before and after hepatobiliary operations can be modulated by the administration of specific nutrients and vitamins (Helton, 1994; Marubayashi et al, 1989) and provide a potential opportunity whereby the hepatobiliary surgeon can influence patient outcome by nutritional means. In mice models, administration of omega-3 fatty acids demonstrates trends toward biochemical protection and a marked reduction of necrosis and inflammation after bile duct ligation (Lee et al, 2008). No clinical trials to date have shown that diets supplemented with fish oil, omega-3 fatty acids, or vitamin E improve the outcome of patients undergoing hepatobiliary operations, but this is an area of nutritional support that should be studied in patients undergoing hepatobiliary operations.
Specific Nutritional Problems in Patients with Hepatobiliary Diseases
Obstructive Jaundice
Patients with significant jaundice (see Chapters 2 and 7) often have anorexia and lose weight because of decreased oral intake. Approximately 45% to 70% of patients with obstructive jaundice present with malnutrition as evidenced by greater than 10% weight loss, albumin less than 3 g/dL, decreased triceps skin fold, and impaired delayed hypersensitivity reactivity (Foschi et al, 1986). The NRI is simple to use and can define a high-risk subgroup of patients with obstructive jaundice; an NRI less than 83.5 has been found to be significantly associated with an increased mortality risk and longer duration of hospital admission but not an increased complication rate in this population subgroup (Clugston et al, 2006). The primary nutritional deficit resulting from obstructive jaundice is malabsorption of fat and fat-soluble vitamins. In addition, there is loss of trace minerals, such as phosphate, calcium, magnesium, and zinc, owing to salt formation from unabsorbed dietary fat (Shronts, 1988).
Patients with obstructive jaundice may have ascites secondary to decreased serum albumin levels, but the metabolism of carbohydrates and proteins is rarely altered (Flannigan et al, 1985). Biliary sepsis in a patient with obstructive jaundice contributes to malnutrition by shifting protein synthesis from anabolic protein synthesis to acute-phase protein synthesis (O’Neill et al, 1997). This reprioritization of protein synthesis occurs as a result of endotoxin-stimulated Kupffer cell production of TNF, IL-6, eicosanoids, nitric oxide, and other inflammatory mediators that directly inhibit protein synthesis (Curran et al, 1990; Heinrich, 1990; see Chapters 9 and 10). Because of these derangements, some authors have advocated preoperative biliary drainage (PBD) in both liver and pancreas surgery. A Cochrane 2008 analysis demonstrated that PBD is not recommended in patients who need surgery for obstructive jaundice. However, another recent Cochrane review showed no evidence to support or refute routine endoscopic retrograde cholangiopancreaticography (ERCP) with stenting in patients with malignant pancreaticobiliary diseases awaiting surgery (Wang et al, 2008; Mumtaz et al, 2007). PBD in pancreatic adenocarcinoma should not be routine practice, as it is associated with a stent-related complication rate of 23% and has resulted in a twofold increase in postpancreatectomy infectious complications (Mezhir et al, 2009); however, trials have supported PBD in extended hepatectomy for hilar colangiocarcinoma, if the future liver remnant volume is anticipated to be less than or equal to 30%. To reverse the catabolic effects of chronic endotoxemia and restore hepatic protein synthesis, patients with biliary infection should be treated with biliary decompression for at least 4 weeks before major hepatobiliary surgery to allow hepatocytes to recover their protein synthetic capacity.
Cirrhosis and Liver Failure
Patients with cirrhosis (see Chapter 70A, Chapter 70B, Chapter 73, Chapter 74 ) provide the clinician with a major challenge, as they have multiple hormonal and metabolic alterations (see Chapter 2). Characteristics of cirrhotic patients include wasting symptoms, especially loss of fat and muscle mass; growth failure; glucose intolerance; hyperinsulinemia; insulin resistance; increased plasma glucagon and catecholamines; elevated serum free fatty acids; elevated glycerol; hypoproteinemia; hyperammonemia; hypophosphatemia; and alterations in plasma and cerebrospinal fluid amino acid profiles (Achord, 1987; Henriksen et al, 1985; Petrides & De Fronzo, 1989; Riggio et al, 1984). These hormonal and metabolic aberrations lead to altered metabolism of all three macronutrients: fat, protein, and carbohydrate. The hormonal and metabolic changes seen in cirrhosis also lead to an increased skeletal muscle proteolysis for energy provision, which leads to eventual muscle wasting. In addition, there is increased peripheral lipolysis with a decreased ability to use fat and carbohydrate, which leads to hyperglycemia and hyperlipidemia (Katz, 1986).
Compounding these metabolic alterations are issues that predispose patients with cirrhosis to malnutrition, including decreased dietary intake owing to nausea and vomiting, and the common practice of imposing protein restriction in an effort to prevent encephalopathy. This practice of protein restriction is questionable in an already malnourished patient. Protein restriction exacerbates the problems inherently associated with malnutrition and prohibits the goal of liver regeneration. An alteration of plasma and cerebrospinal fluid amino acid profiles caused by catabolism, impaired hepatocellular function, and portal shunting leads to decreased levels of branched-chain amino acids (BCAAs) valine, leucine, and isoleucine and preferred uptake into the brain of aromatic amino acids phenylalanine, tyrosine, and tryptophan. The increased uptake of aromatic amino acids is thought to alter the production of neurotransmitters, resulting in encephalopathy. This theory led to the use of BCAA as dietary treatment for patients with liver disease (Marchesini et al, 2005). Correcting the serum amino acid profile by BCAA administration aims to reverse mental status changes and promote anabolism (Fischer et al, 1976). Oral supplementation with a BCAA preparation that can be administered for a long period improves event-free survival, serum albumin concentration, and quality of life in patients with decompensated cirrhosis (Bianchi et al, 2005; Marchesini et al, 2003; Muto et al, 2005). Changes in Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores were smaller in a BCAA-administered group than in a control group, and serum total bilirubin and serum albumin were better preserved. The incidence of major cirrhotic complications was also lower in the BCAA group than in the control group (Kawamura et al, 2009). ESPEN upgraded the recommendation of BCAA supplementation in decompensated liver cirrhosis in the latest revision of its guidelines in 2006. Recent work has demonstrated that BCAA may affect microinflammation in hepatitis C–positive patients with cirrhosis, reducing the production of oxidative stress and possibly leading to a decrease in the occurrence of hepatocellular carcinoma (HCC) (Ohno et al, 2008). More studies are needed to identify those who might benefit and what the benefit may be from BCAA supplementation.
Liver Resection
Metabolic alterations occur in the regenerating liver after liver resection (Diehl, 1991; see Chapters 5 and 64). Krebs cycle activity is depressed, as is the reduction–oxidation state of the hepatic mitochondria, with a switch from the use of glucose to fat as the preferred source of energy by way of β-oxidation (Nakatoni et al, 1981). Because hyperglycemia and hyperinsulinemia suppress the release of fatty acids from adipose tissue and decrease ketone body production by the liver (Riou et al, 1986), hypertonic glucose infusions and insulin administration should be avoided in the immediate (<6 hours) postoperative period (Ozawa, 1992).
These observations indicate that selective administration of fat or ketone bodies shortly after liver resection or transplantation may be beneficial. In rodents, the provision of intravenous fat (30% of total nonprotein calories) (Hamada, 1993; Nishiguchi et al, 1991) or the ketone body monoacetoacetate (Birkhahn et al, 1989) immediately after liver resection accelerates liver regeneration. The administration of medium-chain triglycerides after liver resection results in better hepatic energy charge and decreased lipid peroxidation compared with the effects of intravenous glucose or long-chain triglyceride infusions (Hamada, 1993).
Sarac and colleagues (1994) hypothesized that increasing fat oxidation preoperatively via fasting would improve liver function after extensive liver resection in rats. Rats subjected to 90% hepatectomy had improved survival to almost 100% when fasted 24 hours before operation and fed oral glucose immediately after operation. Greater use of ketone bodies was observed in the liver of fasted rats, suggesting that the enzyme machinery for using free fatty acids was induced by the previous fast. This and many animal models have demonstrated that glycogen is essential to maintaining hepatocellular integrity and function by supplying glucose for ATP generation. A recent trial that administered high concentrations of glucose to patients intravenously 24 hours before hepatic lesion resection with portal clamping found significantly improved liver function on the first and fifth days postoperatively by reducing liver I/R injury (Tang et al, 2007).
The regenerating liver has an increased demand for specific amino acids, and provision of these in the diet accelerates regeneration. Immediately after liver resection, an abrupt increase is seen in the synthesis of the system A amino acid transporter—which transports alanine, serine, and methionine—but not those of system N (glutamine, histidine, asparagine) or system ASC (e.g., cysteine) (Fowler et al, 1992). Increased system A activity depends on portal glucagon and insulin secretion and substrate amino acid supply (Dolais-Kitabgi et al, 1981); system N and system ASC are not similarly regulated (Fowler et al, 1992). This fact supports the argument by many liver surgeons that enteral administration of glucose is the preferred route of feeding because of the effect on insulin release, which is vital to the function of the regenerating liver (Ozawa, 1992; Ozawa et al, 1974).
Provision of adequate protein and calories is important to ensure adequate liver regeneration. Rats subjected to 50% of normal daily caloric intake for 1 week before and after liver resection had significantly impaired liver regeneration, even when administered exogenous IGF-I, compared with normally fed rats (Sato et al, 1994). Specific types of protein-supplemented diets, such as a nucleoside-nucleotide supplemented total parenteral nutrition (TPN) solution, may improve protein synthesis after hepatectomy (Ogoshi et al, 1989).
John and colleagues (1992) reported that postoperative TPN consisting of 45% fat calories significantly impaired hepatic regeneration and albumin synthesis, caused cholestasis, and increased mortality compared with the same diet administered by the enteral route after 70% hepatectomy in rats. Mortality was 68% in rats fed TPN, 9% in rats fed enterally, and 8% in rats fed chow. This increased mortality rate in TPN-fed rats could be due to increased bacterial translocation and lipopolysaccharide migration across the gut, which overwhelms the limited phagocyte capacity of the remnant Kupffer cell mass (van Leeuwen et al, 1991
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