Ebook Oxford textbook of transplant anaesthesia and critical care: Part 2

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(BQ) Part 2 book Oxford textbook of transplant anaesthesia and critical care has contents: Anaesthesia for heart–lung transplantation, lung transplantation, geriatric transplant anaesthesia, coagulation and haemodynamic monitoring,.... and other contents. SECTION 6 Liver http://e-surg.com http://e-surg.com CHAPTER 19 Liver disease: epidemiology, pathophysiology, and medical management Andre De Wolf, Paul Martin, and Hui-Hui Tan Epidemiology of liver disease The true epidemiology and incidence of liver disease is difficult to ascertain, as most liver diseases are insidious, with a latent period between disease occurrence and detection (Kim, 2002) Hence, population-based studies are often used as surrogates to estimate disease burden The United States A population-based study by the CDC reported the incidence of newly diagnosed chronic liver disease in adults to be 63.9 per 100,000 population as seen by gastrointestinal specialists The most common aetiology of chronic liver disease was hepatitis C (hepatitis C virus (HCV)) (42%), followed by hepatitis C combined with alcohol-related liver disease (22%), non-alcoholic fatty liver disease (NAFLD) (9%), alcoholic liver disease alone (8%), and hepatitis B (hepatitis B virus (HBV)) (3%) Other aetiologies (primary sclerosing cholangitis, primary biliary cirrhosis, hereditary haemochromatosis, autoimmune hepatitis, α1-antitrypsin deficiency, and hepatocellular carcinoma (HCC)) accounted for less than 3% of all newly diagnosed cases of chronic liver disease (Bell, 2008) The prevalence of antibodies against HCV (anti-HCV) was 1.8% in the third National Health and Nutrition Examination Survey (NHANES III) study, which corresponds to approximately 3.9  million Americans infected with HCV Of these, approximately 70%, or 2.7 million, had evidence of chronic infection as determined by the presence of the viral RNA in serum (Alter, 1999) By 2007, HCV mortality had superseded that of HIV in the US, with HCV and HBV deaths occurring disproportionately in middle-aged persons (Ly, 2012) The prevalence of aminotransferase elevation in the general population in the NHANES III study was 7.9%—the majority of which could not be explained by alcohol consumption, viral hepatitis, or haemochromatosis Aminotransferase elevation was more common in men compared to women (9.3% vs 6.6%), in Mexican Americans (14.9%), and in non-Hispanic blacks compared to non-Hispanic whites (8.1% vs 7.1%) Unexplained aminotransferase elevation (69.0%) was strongly associated with adiposity (higher body mass index, higher waist circumference) and other features of the metabolic syndrome (higher triglycerides, higher fasting insulin, lower high-density lipoprotein (HDL); and type diabetes and hypertension in women) and thus may represent NAFLD (Clark, 2003) Other studies based on histological sources (liver biopsy, autopsy, and postmortem series) indicate that 10–40% (median ~ 20%) of the general population may have NAFLD (including steatosis alone) and 2–5% have non-alcoholic steatohepatitis (NASH) (Falk-Ytter et al., 2001) Based on NHANES III data, the seroprevalence of HBV surface antigen (HBsAg) or antibodies to HBV core antigen is 4.9% (McQuillan, 1999) HBV infection is more prevalent in non-whites than whites, regardless of age As the NHANES samples only civilian, non-institutionalized persons living in households, the true prevalence of disease may be underestimated (Kim, 2002) Approximately 240,000 new HBV infections occurred annually between 1988 and 1994 (Coleman, 1998), but in 1997 the estimated number of incident HBV cases was only 185,000 In both Europe and the US the incidence of primary biliary cirrhosis (PBC) among adults (aged > 20 years) has been estimated to be between and per 100,000 persons per year, with a strong female predominance While the incidence has remained unchanged since 1995, the prevalence has risen, suggesting that the survival is longer, which may be due to early diagnosis (Kim, 2002) The incidence of fulminant hepatic failure is estimated to be 2,300–2,800 cases per year in the US In earlier reports from the 1980s, viral hepatitis (hepatitis A virus (HAV), HBV, non-A non-B hepatitis) was the most common aetiology of fulminant hepatic failure in the US By the 1990s, drug-induced (especially acetaminophen) causes had become the most common cause of fulminant hepatic failure (Rakela, 1985; McCashland, 1996; Schiodt, 1999) Age-adjusted incidence rate of HCC increased from 1.4 per 100,000 during 1976–1980 to 4.7 per 100,000 during 1996–1997 (El-Serag and Mason, 1999) Asian-Americans have the highest incidence rates of HCC (up to 23 per 100,000 in Asian men > 60 years of age), followed by African-Americans, whose incidence is two to three times that of whites (El-Serag and Mason, 1999) Chronic liver disease in 2008 was the twelfth commonest cause of mortality in the US, accounting for nearly 34,000 deaths annually (Kim, 2002; Kochanek, 2011) http://e-surg.com 184 SECTION 6  liver Europe In the EU an estimated 29 million people have chronic liver disease Alcohol consumption, viral hepatitis B and C, and the metabolic syndrome are reported to be leading causes of liver cirrhosis and primary liver tumours Liver cirrhosis is responsible for around 170,000 deaths in Europe annually, with wide variations between countries—ranging from about per 100,000 Greek women to 103 per 100,000 Hungarian men dying each year The mortality rate from alcohol-related liver diseases is as high as 47 per 100,000 inhabitants Liver cancer is responsible for almost 47,000 deaths in Europe annually, according to the WHO mortality database (Blachier, 2013) The mortality rate of primary liver cancer is very close to its incidence because of the lack of curative options for most patients (Blachier, 2013) The prevalence of NAFLD in the European population is 2–44% in the general population and 42.6–69.5% in patients with type diabetes The prevalence of chronic hepatitis C in the European population is 0.13–13.26%, whilst that of chronic hepatitis B is 0.5–0.7% (Anonymous, 2013; Blachier, 2013) Liver anatomy and physiology The liver is the largest internal organ of the human body It has a dual blood supply: the hepatic artery supplies oxygenated blood to the liver and the portal vein brings venous blood rich in the products of digestion that have been absorbed from the gastrointestinal tract, and also blood from the spleen and pancreas Under normal circumstances the portal vein supplies approximately 70% of the liver’s blood supply and the hepatic artery is responsible for the remaining 30% Blood from the hepatic artery and portal vein perfuse the liver sinusoids and is conducted to the central vein of each liver lobule Resistance to blood flow in the sinusoids is low under normal circumstances The central veins drain into hepatic veins that drain into the inferior vena cava The endothelial lining of the hepatic sinusoids is fenestrated and discontinuous Beneath this lining is a very narrow space between the endothelial cells and the hepatic cells called the space of Disse, where hepatic stellate cells (Ito cells) are found The spaces of Disse connect with lymphatic vessels in the interlobular septa, allowing excess fluid to be removed The liver plays a major role in metabolism, including plasma protein synthesis, carbohydrate homeostasis, lipid metabolism, and metabolism of toxins and drugs Pathophysiology of chronic liver disease Liver cirrhosis Chronic liver injury results in fibrosis and, if unchecked, liver cirrhosis, defined as the histological development of regenerative nodules, surrounded by fibrotic tissue that replaces normal hepatocytes Fibrosis represents an excessive healing response to injured liver tissue and is thought to be mediated by activation of hepatic stellate cells (Ito cells); activated stellate cells proliferate, contract, and secrete collagen The collagen deposits (forming fibrotic tissue: liver fibrosis) separate isolated hepatocyte islands and portal vessels, resulting in impaired hepatocyte function Liver fibrosis may progress to cirrhosis when the hepatic vasculature is significantly disrupted The intrahepatic resistance to blood flow is increased by fibrosis and regenerative nodules, and portal hypertension develops Thus the portal pressure increases as a result of an increased resistance to outflow through the liver (Gatta, 2008; Schuppan and Afdhal, 2008; Bosch, 2010; Thabut and Shah, 2010) (see Figures 19.1 and 19.2) Besides this disruption of hepatic architecture, there is a dynamic component of increased vascular resistance There is an intrahepatic decrease in the production of NO and an increase in the production of vasoconstrictors, both a result of endothelial dysfunction (Iwakiri and Groszmann, 2007; Poordad, 2009; Bosch, 2010) This results in vasoconstriction of smooth muscle cells in the wall of hepatic and portal veins and venules and of myofibroblasts located around the sinusoids and hepatic venules Myofibroblasts are derived from stellate cells under cirrhotic conditions It is estimated that about 30% of the increased portal resistance is the result of hepatic vasoconstriction and impaired response to vasodilators Finally, cirrhosis results in an increase in splanchnic circulation (including splenic blood flow), and this large increase in inflow contributes to portal hypertension The main mechanism of this increased splanchnic circulation is the dramatic increase in NO production in the intestinal microcirculation in the presence of portal hypertension; other vasodilators may contribute This vasodilation persists even when all vasoconstrictor systems are activated; this could be the result of changes in receptor affinity or downregulation of receptors Patients with cirrhosis have an increased risk of developing hepatocellular carcinoma, probably the result of the development of regenerative nodules with small-cell dysplasia (D’Amico, 2006) Hepatocellular dysfunction The consequences of cirrhosis include hepatocellular insufficiency and/or failure (ESLD) and portal hypertension Hepatocellular dysfunction results in hyperbilirubinaemia, reduced synthesis of proteins such as albumin and coagulation factors, and reduced clearance of toxins or intestinal vasoactive substances In addition, drugs that undergo hepatic metabolism will have altered pharmacokinetics Portosystemic collateral circulation with portosystemic shunting contributes to the reduced clearance Other direct consequences of hepatocellular dysfunction are discussed later in this chapter Circulatory changes The pathophysiology of haemodynamic changes in cirrhosis is shown in Figure 19.3 The abnormalities in intrahepatic blood flow influence not only regional circulation (splanchnic blood flow) but also overall haemodynamics and specific organ blood flow Patients with cirrhosis have a hyperdynamic circulation (sometimes called hyperdynamic circulatory syndrome), i.e peripheral vasodilation, reduced arterial blood pressure, and increased heart rate and cardiac output (Møller and Henriksen, 2008; Henriksen and Møller, 2009) Mild liver dysfunction may result in circulatory changes that are clinically not readily apparent Vasodilation is the result of increased plasma concentrations of NO, prostacyclin, oestrogen, bradykinin, and vasoactive intestinal peptide, all a consequence of reduced metabolic activity by the liver and blood bypassing the liver through collateral vessels In addition, there may be an increased sensitivity to these substances, while there also is a reduced sensitivity to vasoconstrictors such as norepinephrine, vasopressin, and endothelin-1 (decreased number of receptors and postreceptor defects) http://e-surg.com Chapter 19  (A) liver disease: epidemiology, pathophysiology, and medical management (B) Artery TPV TPV Bile duct Endothelium TPV Terminal portal vein THV Terminal hepatic vein Myofibroblast Regenerative nodule of hepatocytes* THV THV Fibrous tissue Kupffer cell Hepatic stellate cell THV Fig. 19.1  Vascular and architectural alterations in cirrhosis Mesenteric blood flows via the portal vein and hepatic artery that extend branches into terminal portal tracts (A) Healthy liver: terminal portal tract blood runs through hepatic sinusoids where fenestrated sinusoidal endothelia that rest on loose connective tissue (space of Disse) allow for extensive metabolic exchange with the lobular hepatocytes; sinusoidal blood is collected by terminal hepatic venules that disembogue into one of the three hepatic veins and finally the caval vein (B) Cirrhotic liver: activated myofibroblasts that derive from perisinusoidal hepatic stellate cells and portal or central-vein fibroblasts proliferate and produce excess extracellular matrix (ECM) This event leads to fibrous portal-tract expansion, central-vein fibrosis, and capillarization of the sinusoids, characterized by loss of endothelial fenestrations, congestion of the space of Disse with ECM, and separation or encasement of perisinusoidal hepatocyte islands from sinusoidal blood flow by collagenous septa Blood is directly shunted from terminal portal veins and arteries to central veins, with consequent (intrahepatic) portal hypertension and compromised liver synthetic function (Reprinted from The Lancet, 371, Detlef Schuppan and Nezam H Afdhal, ‘Liver cirrhosis’, pp. 838–851, 2008, with permission from Elsevier.) It has recently been suggested that bacterial translocation with increased production of proinflammatory cytokines may contribute to the hyperdynamic circulation However, a large part of the reduced peripheral vascular resistance is the result of the reduction in splanchnic vascular resistance (the result of a massive increase in NO production in the splanchnic circulation) The disturbance of microcirculatory function causes arteriovenous shunting, increased cardiac output, and abnormal blood volume distribution, all in proportion to the severity of the underlying hepatic disease Not all the vascular beds are affected to the same degree, and there may even be areas with vasoconstriction as the result of compensatory mechanisms Despite the fact that total blood volume is increased, there is redistribution of total blood volume away from the circulation, mainly towards the splanchnic circulation (Møller and Henriksen, 2008; Møller, 2011) This central hypovolaemia is perceived by baroreceptors, and this leads to the activation of compensatory mechanisms to increase blood volume These compensatory mechanisms include activation of the sympathetic nervous system (including the release of norepinephrine from the adrenal glands), activation of the ADH–arginine–vasopressin pathway, activation of the renin–angiotensin–aldosterone system (RAAS), and increased concentrations of circulating endothelin The stimulation of these compensatory systems in combination with the low systemic vascular resistance (SVR) results in an increase in stroke volume and cardiac output With worsening liver failure, the compensatory mechanisms are maximally stimulated, and the increase in cardiac output and vasoconstriction in some vascular beds becomes insufficient to maintain an adequate central blood volume and effective cardiac output Blood pressure and effective tissue perfusion will progressively decrease, ultimately resulting in end-organ failure Assessing severity and prognosis in chronic liver disease The severity of liver disease has been assessed by the Child–Turcotte–Pugh (CTP) score (see Table 19.1) and more recently by the MELD score (see Table 19.2) (Wiesner, 2003) MELD = [9.57 × loge creatinine (mg/dL) + 3.78 × loge bilirubin (mg/dL) + 11.2 × loge INR + 6.43 × (constant for liver disease aetiology)] Prognostic tools in patients with chronic liver diseases, apart from CTP and MELD scoring, include disease-specific indices for primary biliary cirrhosis and sclerosing cholangitis and the impact of specific complications of cirrhosis on patient survival The CTP score is as effective as quantitative liver function tests in determining short-term prognosis among groups of patients awaiting liver transplantation (Oellerich, 1991) Although its limitations have been well described, the CTP score has been widely adopted for risk-stratifying patients before transplantation because of its simplicity and ease of use (Conn, 1981) The MELD was originally developed to assess short-term prognosis in patients undergoing transjugular intrahepatic portosystemic shunts (TIPS) Among patients who had undergone this procedure, serum bilirubin, INR of PT, and serum creatinine seemed to be the best predictors of 3-month postoperative survival (Malinchoc, 2000) Subsequent studies of this model demonstrated its usefulness as an effective tool for determining the prognosis of groups of patients with chronic liver disease (Kamath, 2001) A  modification of this model is now used to prioritize patients for donor allocation in the US and has been shown to be useful in predicting both short-term survival in groups of patients on the waiting list for liver transplantation and the risk of postoperative mortality (Wiesner, 2003; Freeman, 2004) A similar model http://e-surg.com 185 186 SECTION 6  liver Normal liver Cirrhotic liver Hepatocytes HSC HSC Blood vessel Fibrogenesis Endothelin (HSC contraction) PDGF (migration, proliferation, recruitment to vessels) NO (vasorelaxation HSC apoptosis) SEC VEGF sprouting TGF-β (Differentiation, fibrogenesis) Ang-1 vessel stabilization Fig. 19.2  Pathological sinusoidal remodelling in cirrhosis and portal hypertension Hepatic stellate cells (HSC) align themselves around the sinusoidal lumen in order to induce contraction of the sinusoids While in normal physiological conditions HSC contractility and coverage of sinusoids is sparse, in cirrhosis increased numbers of HSC with increased cellular projections wrap more effectively around sinusoids, thereby contributing to a high-resistance, constricted sinusoidal vessel At the cellular level a number of growth factor molecules contribute to this process through autocrine and paracrine signalling between HSC and sinusoidal endothelial cells (SEC) A number of these molecules are depicted, along with their proposed role in paracrine function PDGF, Platelet-derived growth factor; VEGF, vascular endothelial growth factor; Ang-1, angiopoietin-1; NO, nitric oxide; TGF-β , transforming growth factor β (This figure was published in Journal of Hepatology, 53, Dominique Thabut, Vijay Shah, ‘Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: New targets for the treatment of portal hypertension’, pp. 976–980, Copyright © 2010 Elsevier and the European Association for the Study of the Liver (EASL).) has been developed for paediatric end-stage liver disease (PELD) (Wiesner, 2001; McDiarmid, 2002) This model has been useful in predicting deaths of paediatric patients waiting for transplantation (Freeman, 2001) Calculation of individual MELD or PELD scores for patients can be determined at Management of chronic liver disease complications Portal hypertension and varices Portal hypertension is defined as a pressure >5  mm Hg higher than central venous pressure; once the gradient is >10 mm Hg, complications associated with cirrhosis become more prevalent (Toubia and Sanyal, 2008; Garcia-Tsao, 2009; Sass and Chopra, 2009) Portal hypertension can be classified as prehepatic, intrahepatic, and post-hepatic; others classify it as presinusoidal, sinusoidal, and postsinusoidal In the western world, liver cirrhosis is the cause in 90% of cases An example of prehepatic portal hypertension is portal vein thrombosis, while post-hepatic portal hypertension can be caused by Budd–Chiari syndrome or congestive heart failure Once the portal pressure–central venous pressure gradient increases above 10  mm Hg, collaterals will develop Indeed, portal hypertension results in the dilatation of pre-existing vascular channels between the portal circulation and the vena cava, while the release of vascular endothelial growth factor (VEGF) and PDGF promotes the development of new portosystemic collaterals (Poordad, 2009; Bosch, 2010) Varices are formed at the distal oesophagus/proximal stomach, retroperitoneum, umbilicus, and rectum (Garcia-Tsao and Bosch, 2010; Mehta, 2010) Thus one of the consequences of portal hypertension is the formation of gastro-oesophageal varices, which can result in life-threatening bleeding About one-third of patients with varices will develop variceal bleeding, and this is associated with a http://e-surg.com Chapter 19  liver disease: epidemiology, pathophysiology, and medical management Cirrhosis Portal hypertension Portosystemic shunting Hepatocellular failure Splanchnic blood flow ↑ Arteriolar vasodilatation Cardiac output ↑ Heart rate ↑ Systemic vascular resistance ↓ SNS ↑ RAAS ↑ Vasopressin ↑ ET-1 ↑ Arterial blood pressure ↓ Central blood volume ↓ Lung blood volume ↓ Fig. 19.3  Pathophysiology of haemodynamic changes in cirrhosis Peripheral arteriolar vasodilatation in cirrhosis is caused by portosystemic shunting or impaired hepatic degradation of vasodilators Reduced systemic and splanchnic vascular resistance leads to reduced central and pulmonary blood volumes and hence to activation of vasoconstrictor systems The haemodynamic and clinical consequences are increases in cardiac output, heart rate, and plasma volume, and decreased renal blood flow, low arterial blood pressure, and fluid and water retention SNS, Sympathetic nervous system; RAAS, renin–angiotensin–aldosterone system; ET-1, endothelin-1 (Reproduced from Liver Anesthesiology and Critical Care Medicine, 'The patient with severe co-morbidities: cardiac disease', 2012, pp 243–253, Shayan C and De Wolf AM, © Springer Science+Business Media New York 2012, with kind permission of Springer Science+Business Media.) Table 19.1  Child–Turcotte–Pugh (CTP) classification of cirrhosis (From The New England Journal of Medicine, Garcia-Tsao G and Bosch J, 'Management of Varices and Variceal Hemorrhage in Cirrhosis', 362, 9, pp 823–832 Copyright © 2010 Massachusetts Medical Society Reprinted with permission from Massachusetts Medical Society.) Pointsa Clinical and biochemical criteria MELD score None Mild to moderate (grade or 2) Severe (grade or 4) None Mild to moderate Large or refractory to diuretics Bilirubin (mg/dL) 3 Albumin (g/dL) > 3.5 2.8–3.5 < 2.8 Seconds prolonged 6 INR < 1.7 1.7–2.3 > 2.3 Encephalopathy Ascites Table 19.2  Three-month mortality based on MELD score (‘Mortality + too sick’ means ‘mortality or too sick to undergo liver transplantation’) (Reprinted from Gastroenterology, 124, 1, Wiesner et al, 'Model for end-stage liver disease (MELD) and allocation of donor livers', pp 91–96, Copyright 2003, with permission from Elsevier and the AGA Institute.) Prothrombin timeb aIn the CTP classification system, class A (5–6 points) indicates least severe liver disease; class B (7–9 points) indicates moderately severe liver disease; and class C (10–15 points) indicates most severe liver disease To convert the values for bilirubin to micromoles per litre, multiply by 17.1 bEither seconds prolonged or the INR is used mortality risk of 40% at year (Stokkeland, 2006) Although these portosystemic collaterals could be expected to result in a decompression of the portal circulation, portal hypertension persists because there is an increasing NO-mediated vasodilation of the spanchnic arterioles, resulting in an accelerating increase in portal 40 124 1,800 1,098 295 120 Mortality (%) 1.9 6.0 19.6 52.6 71.3 Mortality + too sick (%) 2.9 7.7 23.5 60.2 79.3 Number of patients blood flow (see Figure 19.4) (Poordad, 2009) Another similar consequence of portal hypertension is portal hypertensive gastropathy Portal hypertension results in splenomegaly through the increase in splenic venous pressure Sequestration of platelets followed by their destruction frequently results in thrombocytopaenia Intrasplenic production of autoantibodies may contribute to this complication Prophylaxes against and treatment of oesophageal variceal bleeding include non-selective β-blockers, endoscopic sclerotherapy or ligation, TIPS placement, and the creation of a surgical shunt (see Table 19.3) (Garcia-Tsao and Bosch, 2010; Mehta, 2010) Variceal ligation and non-selective β-blockers are probably equivalent in their efficacy and have been used in combination (Mehta, 2010) Non-selective β-blockers (propranolol, nadolol, timolol) reduce portal pressure by reducing cardiac output (β1-blockade effect) and by reducing portal blood inflow through splanchnic vasoconstriction (β2-blockade effect) However, non-selective http://e-surg.com 187 188 SECTION 6  liver Cirrhosis Increased resistance to portal flow (fixed and functional) Increased portal pressure Increased vasodilating factors (e.g nitric oxide) Increased angiogenic factor (e.g VEGF) Splanchnic vasodilatation Formation of new vessels Increased portal blood inflow Dillatation of pre-existing vessels Varices Variceal growth Increased flow through varices Variceal rupture Fig. 19.4  Pathogenesis of portal hypertension, varices, and variceal haemorrhage The initial mechanism in development of portal hypertension in cirrhosis is an increase in vascular resistance to portal flow Subsequent increase in portal venous inflow maintains the portal hypertensive state Portal hypertension leads to formation of portosystemic collaterals, of which the most clinically relevant are gastroesophageal varices Increase in flow through these collaterals, enhanced by presence of splanchnic vasodilatation and increased portal blood inflow, leads to variceal growth and rupture This process is modulated by angiogenic factors (From The New England Journal of Medicine, Garcia-Tsao G and Bosch J, 'Management of Varices and Variceal Hemorrhage in Cirrhosis', 362, 9, pp 823–832 Copyright © 2010 Massachusetts Medical Society Reprinted with permission from Massachusetts Medical Society) Table 19.3  Effect on portal flow, resistance, and pressure with different therapies for varices/variceal haemorrhage (Reproduced with permission from Garcia-Tsao et al., 'Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis', Hepatology, 46, 3, pp 922–938 Copyright © 2007 American Association for the Study of Liver Diseases.) Treatment Portal flow Portal resistance Portal pressure Vasoconstrictors (β-blockers) ↓↓ ↑ ↓ Venodilators (nitrates) ↓ ↓ ↓ Endoscopic therapy (band ligation/ sclerotherapy) — — — TIPS/shunt therapy ↑ ↓↓↓ ↓↓↓ β-blockers not prevent the formation of oesophageal varices and are associated with side effects (Groszmann, 2005; Sersté, 2010; Wong and Salerno, 2010) Selective β1-blockers (tenolol, metoprolol) are less effective in reducing portal pressure because they lack the β2-blockade effect Although non-selective β-blockers reduce the risk of variceal bleeding, in sicker patients (refractory ascites) their use may be associated with a higher mortality, possibly by reducing the capacity of the cardiovascular system to compensate (see Figure 19.5) (Sersté, 2010; Wong and Salerno, 2010) Nitrates in combination with non-selective β-blockers may further reduce the incidence of variceal haemorrhage (Mehta, 2010) Other interventions during acute variceal bleeding include the administration of vasopressin, terlipressin, somatostatin, octreotide, and the placement of a Sengstaken–Blakemore tube (Krag, 2008; Garcia-Tsao and Bosch, 2010) Ultimately the only definitive therapy is liver transplantation Ascites, hydrothorax, and spontaneous bacterial peritonitis Ascites is one of the most frequent complications of cirrhosis It results from the combination of increased splanchnic capillary pressure and sodium retention; sodium retention is caused by the activation of neurohumoral systems (see the section ‘Circulatory changes’) Initial medical treatment consists of diuretics and sodium restriction Despite sodium retention, hyponatraemia is frequently seen because there is even more water retention due to the release of vasopressin (Krag, 2010a) Massive ascites commonly results in dyspnoea and abdominal discomfort Refractory ascites is frequently associated with hepatorenal syndrome (HRS) type 2, spontaneous bacterial peritonitis, dilutional hyponatraemia, muscle wasting, and pleural effusion Refractory ascites, an independent http://e-surg.com Chapter 19  NSBB liver disease: epidemiology, pathophysiology, and medical management –ve ↓ Cardiac output +ve NSBB i) Reduction in portal pressure ↓ Renal perfusion Risk for developing HRS ↓ Risk of variceal bleeding ii) Reduction of bacterial translocation ↓ Risk of development of SBP Fig. 19.5  Proposed mechanisms of beneficial (right) and deleterious (left) effects of non-selective β-blockers (NSBB) in patients with advanced cirrhosis HRS, Hepatorenal syndrome; SBP, spontaneous bacterial peritonitis (Reproduced with permission from Wong and Salerno, ‘Beta-Blockers in Cirrhosis: Friend and Foe?’, Hepatology, 52, 3, pp. 811–813 Copyright © 2010 American Association for the Study of Liver Diseases.) predictor of short-term survival, requires large-volume paracentesis for control accompanied by albumin infusion in an effort to reduce the incidence of renal failure (Ginès, 1996; Salerno, 2010) Alternatively, drugs to reduce splanchnic blood flow have been used (terlipressin, octreotide, midodrine) A TIPS can be placed but this increases the risk of hepatic encephalopathy and congestive heart failure (Salerno, 2010) Still, TIPS results in better elimination of persistent ascites, improved renal function, and better nutritional status In patients with recurrent ascites it may actually improve survival (Salerno, 2010) A new type of drug has been used in this situation: vaptans, selective antagonists of vasopressin-2 receptors Definitive therapy is obviously liver transplantation Hepatic hydrothorax, defined as a pleural effusion of 500 mL, occurs in about 5–12% of patients with advanced cirrhosis (Kiafar and Gilani, 2008) It is virtually always seen in patients who already have ascites, and it occurs predominantly on the right side (85%) It reflects diaphragmatic defects that allow fluids to shift from the peritoneal cavity to the pleural cavity These defects may be microscopic, may be created by stretching of the diaphragm (due to ascites), and are more prevalent in the right hemidiaphragm Symptoms include dyspnoea and chest pain Therapy is the same as for ascites, including TIPS, but there are a few additional options available:  thoracentesis, thoracoscopic repair of diaphragmatic defects, and pleurodesis Spontaneous bacterial peritonitis (SBP) is the result of intestinal oedema that disrupts the gut mucosal barrier that normally prevents the crossing of enteric bacteria SBP caused by Gram-negative bacteria can result in the release of endotoxins in the bloodstream; this may induce monocytes to produce the cytokine TNF-α TNF-α reduces cardiac function, stimulates further release of NO, and reduces vascular reactivity to vasopressors Bacterial translocation in the gut is thought to result in complications such as SBP and HRS Proper treatment includes the use of selected antibiotics, and prophylactic antibiotics reduce the recurrence of SBP Non-selective β-blockers increase intestinal transit and decrease bacterial translocation (Senzolo, 2009; Mehta, 2010) Ascites but especially SBP frequently precipitates HRS (Venkat and Venkat, 2010) Hepatorenal syndrome The compensatory systems (⇑RAAS, ⇑ADH–arginine–vasopressin pathway, sympathetic nervous system activation, increased concentrations of circulating endothelin) result in vasoconstriction of the coronary, cerebral, and renal arterioles This is especially apparent in the kidneys and may result in the development of HRS (Wong, 2008) (see Figure 19.6) Cytokines (TNF-α, endogenous cannabinoids) contribute to renal injury Renal blood flow is reduced, despite activation of prostaglandin-mediated protective mechanisms in the kidney; there are no discernible structural changes in the kidneys Sudden decreases in preload (bleeding, vomiting, diarrhoea) can result in further reduction in effective renal perfusion, and bacterial infections (such as SBP) can result in additional renal injury through release of cytokines Also, NSAIDs impair renal function by decreasing the intrarenal synthesis of vasodilating prostaglandins HRS results in fluid and sodium retention and ascites formation Diagnosis of HRS is usually based on excluding other causes of renal failure Serum creatinine concentration does not necessarily inversely correlate with the significant reduction in glomerular filtration rate, because there is decreased creatinine generation by skeletal muscle due to wasting seen in severe liver disease Type HRS is the acute, rapid progressive form of renal failure and type HRS is associated with a more moderate and slow loss of renal function (Wong, 2008) Still, the prognosis is poor for both types: 80% 2-week mortality for type and a median survival of type of 3–6 months In decompensated cirrhosis, renal vasodilators not improve renal perfusion, but splanchnic vasoconstrictors such as terlipressin, midodrine, octreotide, and norepinephrine in combination with volume restoration (albumin) (Møller, 2005; Krag, 2008; Wong, 2008) Other management options include paracentesis combined with volume expansion with intravenous albumin, treatment of SBP, TIPS (mainly in the presence of refractory ascites), and renal replacement therapy Ultimately the only curative therapy is liver transplantation; if prolonged (> 8–12 weeks), pretransplant dialysis is required and simultaneous liver–kidney transplantation is likely indicated Alternatively, renal dysfunction can be the result of overtreatment with diuretics (prerenal effect), and acute tubular necrosis may be seen in patients with acute hepatic failure or sepsis Renal impairment is a strong predictor of sepsis and mortality TIPS TIPS was used for the first time by Rösch and colleagues in 1969 in dogs and in a cirrhotic patient by Colapinto in 1982 (Rösch, 1969; Colapinto, 1982) It is an expandable flexible metal shunt prosthesis that is placed through the internal jugular vein and connects the portal vein with a hepatic vein This results in a http://e-surg.com 189 190 SECTION 6  liver Cirrhosis Portal hypertension ↑ Resistane to portal flow Systemic arterial vasodilation Splanchnic arterial vasodilation Activation of vasoconstrictor systems Relative insufficient cardiac output Abnormal renal autoregulation Cirrhotic cardiomyopathy ↑ Renal sensitivity to vasoconstrictors Renal vasoconstriction Hepatorenal syndrome Fig. 19.6  Pathophysiology of hepatorenal syndrome (Reproduced from Current Gastroenterology Reports, 10, 2008, ‘Hepatorenal syndrome: Current management’, pp. 22–29, Florence Wong, with kind permission from Springer Science and Business Media.) portacaval intrahepatic shunt that functions as a side-to-side portacaval shunt (Wong, 2006) Over the years, polytetrafluoroethylene (PTFE)-covered stents have replaced bare metal stents as they markedly improved the long-term patency of the shunt and also prevent portobiliary fistulae (Cejna, 2001; Angermayr, 2003; Bureau, 2007) One of the main complications of TIPS placement is new or worsening hepatic encephalopathy (20–30%) Other complications include worsening liver function, cardiac failure (especially in patients with cirrhotic cardiomyopathy) due to the sudden increase in venous return to the heart, and HRS, despite the fact that TIPS has been successfully used in the treatment for type HRS Absolute contraindications to TIPS procedure include right-sided heart failure, biliary tract obstruction, uncontrolled infection, pulmonary hypertension, recurrent chronic hepatic encephalopathy (in the absence of known precipitants), and hepatocellular carcinoma involving the hepatic veins Relative contraindications include severe liver failure (CTP score > 12), portal vein thrombosis, and multiple hepatic cysts (Pomier-Layrargues, 2012) TIPS has typically been used as treatment for uncontrolled oesophageal variceal bleeding (Sanyal, 1996; Azoulay, 2001; D’Amico and Luca, 2008) However, a recent randomized controlled trial evaluating the use of emergent TIPS as compared to standard medical therapy in patients with severe portal hypertension found that early TIPS was associated with less treatment failure and better survival rates (García-Pagán, 2010) This approach could justify the use of TIPS early after bleeding episodes in patients with moderate or severe liver failure and severe portal hypertension Meta-analyses have demonstrated that TIPS was more efficient than β-blockers or variceal band ligation in preventing variceal rebleeding, but it was more frequently followed by episodes of encephalopathy, and survival was not different between groups (Papatheodoridis, 1999; Burroughs and Vangeli, 2002; Zheng, 2008) Therefore TIPS is not recommended as a first-line therapy for secondary prophylaxis of oesophageal variceal bleeding The first-line treatment for bleeding gastric varices is endoscopic sclerotherapy with cyanoacrylate (Irani, 2011), although TIPS has been used successfully in patients in whom endoscopic therapy failed (Chau, 1998; Barange, 1999) TIPS is more efficient than obturation of the varices through cyanoacrylate (glue) injection in secondary prophylaxis of bleeding from large gastric varices (Lo, 2007) and has also been shown to be effective treatment for ectopic varices (Vangeli, 2004; Vidal, 2006) TIPS has been used successfully to treat medically refractory ascites (Lebrec, 1996; Rössle, 2000; Ginès, 2002; Sanyal, 2003; Salerno, 2004; Narahara, 2011) Although hepatic encephalopathy is observed more frequently, and survival is not improved in the majority of trials (Albillos, 2005; D’Amico, 2005; Deltenre, 2005), a meta-analysis showed different results after analysing individual patient data (Salerno, 2007) The risks of severe hepatic encephalopathy and/or liver failure following TIPS for patients with hepatic hydrothorax are similar to those observed in ascitic patients (Gordon, 1997; Siegerstetter, 2001; Dhanasekaran, 2010) TIPS is effective treatment for type HRS TIPS has no role in type HRS, except for highly selected cases as a bridge to liver transplantation, as it may aggravate the liver insufficiency (Spahr, 1995; Guevara, 1998a; Brensing, 2000) http://e-surg.com ... 1999 and 20 07 Ann Intern Med, 156(4) :27 1 27 8 Malagó M, Hertl M, Testa G, Rogiers X, Broelsch CE (20 02) Split-liver transplantation: future use of scarce donor organs World J Surg, 26 (2) :27 5 28 2... liver transplantation Clin Transplant, 12( 2): 123 – 129 Bilbao I, Dopazo C, Lazaro JL, et al (20 08) Our experience in liver transplantation in patients over 65 yr of age Clin Transplant, 22 : 82 88... 50(6) :20 22 20 33 Henriksen JH, Møller S (20 09) Cardiac and systemic hemodynamic complications of liver cirrhosis Scan Cardiovasc J, 43(4) :21 8 22 5 Hopkins WE, Waggoner AD, Barzilai B (19 92) Frequency
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