1. 1

    The term “cirrhosis” is a neologism derived from the Greek kirrhós, which describes the yellowish discoloration of the liver during advanced stages of chronic liver disease, and the suffix –osis, which denotes a specific condition in medical terminology. Morphologically, cirrhosis reflects the consequences of chronic hepatic necroinflammatory activity with an incomplete and disorganized repair process that results in regenerative nodules and extensive fibrosis replacing normal hepatic parenchyma with disturbance of normal hepatic physiology. Cirrhosis can result from any etiology of chronic liver disease (Table 1). Activation of hepatic stellate cells into myofibroblasts and matrix deposition are key steps in the pathogenesis of cirrhosis.

    Table 1

    Etiologies of Cirrhosis

    Etiology                                   Examples

    Hepatitis B

    Hepatitis C

    Hepatitis D

    Autoimmune  and cholestasis


    hepatitis Biliary


    Primary biliary cholangitis

    Primary sclerosing cholangitis

    Secondary biliary cirrhosis Secondary  sclerosing cholangitis






    Nonalcoholic steatohepatitis

    Alpha-1 antitrypsin deficiency


    Wilson disease

    Glycogen storage diseases

    Lysosomal storage diseases



    Cardiac cirrhosis

    Budd-Chiari syndrome Sinusoidal  obstruction syndrome





    Cryptogenic Unrecognized nonalcoholic fatty liver disease, infections, or drugs


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  2. 2

    The prevalence of cirrhosis varies significantly in different regions of the world and is directly influenced by the epidemiology of individual chronic liver diseases that lead to progressive hepatic fibrosis. The estimated global prevalence of cirrhosis is 4.5% to 9.5%; however, this estimate likely underestimates the real magnitude of disease burden, as a sizeable proportion of asymptomatic individuals remain undiagnosed. Similarly, it is difficult to obtain accurate estimates of mortality related to cirrhosis, but countries in Central and South America and Southern Europe exhibit the highest mortality rates, particularly in males. Epidemiologic trends of cirrhosis have changed considerably over time in many countries, underscoring variations in the incidence and prevalence of specific etiologies of chronic liver disease. For instance, widespread immunization against hepatitis B virus (HBV) has markedly reduced its incidence, prevalence, and associated liver disease including cirrhosis. Alcohol consumption has varied strikingly across different regions of the globe over the past several decades. A steady decline in mortality due to cirrhosis has occurred in some European countries (mainly Mediterranean) as alcohol use has diminished. A similar trend has also been noted in North America; however, hospitalizations for alcoholic hepatitis have increased over the recent past in the United States. In contrast, a significant increase in mortality related to cirrhosis has been noted in some Eastern European countries with increased alcohol

    consumption. In addition, eradication of hepatitis C virus (HCV) is associated with a reduction in hepatic dysfunction, liver-related and all-cause mortality, complications of cirrhosis such as hepatocellular carcinoma (HCC), and portal hypertension. The impact of highly effective direct-acting antiviral agents against HCV on the epidemiology of cirrhosis and its complications has just started to become evident as these regimens have only been widely used in clinical practice for the past few years, although a decline in liver transplant listings for HCV has already been reported. In contrast, the growing prevalence of nonalcoholic fatty liver disease (NAFLD) is reflected in its current prominence as a cause of cirrhosis. NAFLD is anticipated to become the single most frequent cause of chronic liver disease and cirrhosis in the mid- to second half of this century.

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  3. 3
    Clinical findings

    In the absence of hepatic decompensation, the overwhelming majority of individuals with cirrhosis are asymptomatic and may only exhibit subtle clinical findings. Clues to the presence of cirrhosis can include elevated serum aminotransferases and/or bilirubin, decreased albumin, and prolongation of the prothrombin time. Approximately 10% to 17% of individuals with unexplained elevation of aminotransferases have unrecognized cirrhosis. Thrombocytopenia in the absence of a primary hematologic explanation is another clue to the presence of cirrhosis and primarily reflects hypersplenism due to portal hypertension but also diminished production of

    thrombopoietin, a platelet growth and development factor synthetized by the liver. A platelet count below 160 × 10/µL provides the highest diagnostic accuracy for cirrhosis amongst routine blood tests (sensitivity 74%, specificity 88%, positive likelihood ratio 6.3, negative likelihood ratio 0.29). Thrombocytopenia is also a component of noninvasive scoring systems that predict fibrosis, such as the AST (aspartate aminotransferase) to Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4).

    Physical examination may reveal somewhat diminished liver span by percussion and a firm liver edge on palpation. Splenomegaly is suggested by dullness to percussion in the left upper abdominal quadrant or a palpable spleen tip. Cutaneous signs of cirrhosis include palmar erythema, spider nevi, facial telangiectasia, decreased chest and/or axillary hair, inversion of the normal male pubic hair pattern, Terry nails (“ground glass” appearance of nails with absent lunula), and Muehrcke nails (paired, white, transverse bands separated by normal color). Nail clubbing may also be present in individuals with cirrhosis, particularly in those with hepatopulmonary syndrome.

    Dupuytren contracture is relatively common in alcoholic cirrhosis but its pathogenesis is not well understood. Palmar erythema due to altered sex hormone metabolism is more evident on the thenar and hypothenar eminences and typically spares the central portion of the palm. Hypogonadism in both sexes and gynecomastia and testicular atrophy in males can be detected, reflecting altered sex hormone metabolism (increased production of androstenedione, enhanced aromatization to estrone, and increased conversion to estradiol). The catabolic effects of advanced cirrhosis often result in marked sarcopenia, which adversely affects quality of life and survival and is also associated with poorer outcomes after liver transplantation.

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  4. 4
    Natural history of cirrhosis and prognostic models

    Cirrhosis may be broadly categorized into two distinct clinical phases, regardless of the etiology: compensated and decompensated.

    Compensated cirrhosis implies the absence of index complications such as jaundice, ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage. In contrast, hepatic decompensation indicates an advanced phase of the disease, which is rapidly progressive and characterized by development of one or more complications and diminished hepatocellular function with prolongation of the prothrombin time and hypoalbuminemia. Characterizing cirrhosis as compensated or decompensated is simple and reproducible, and offers useful prognostic information for clinical practice (Table 2).

    Table 2

    Stages of Cirrhosis Based on Clinical Complications and 1-Year Outcome Probabilities


    From D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies. J Hepatol   2006;44:217–31.

    More precise prognostic models such as the Child Turcotte Pugh (Table 3) and the Model for End-Stage Liver Disease (MELD) are also widely used, the latter being considered the most accurate predictor of short-term mortality for individuals with cirrhosis and serving as the basis for the current organ allocation system in liver transplantation in the United States and elsewhere (calculator available at

    Table 3

    Child-Turcotte-Pugh Classification

    The specific etiology of cirrhosis may help determine its prognosis.

    For instance, persistent viremia in individuals with chronic HBV or HCV infection is implicated in the development of decompensated cirrhosis. Effective antiviral therapy can abort progression of chronic viral hepatitis to cirrhosis and decompensation.

    Although cirrhosis per se is not an indication for liver transplantation, it is important to identify individuals with cirrhosis who should be considered for liver transplantation. Development of an index complication of cirrhosis such as gastroesophageal variceal hemorrhage, ascites, or hepatic encephalopathy is an indication to refer a patient for liver transplantation and initiate pretransplant evaluation. The MELD score provides objective and reproducible prognostication of short-term survival without liver transplantation (Figure 1), and data from a seminal study showed that liver transplantation is associated with improved survival in individuals with MELD scores greater than 17.

    FIGURE 1    Relationship between Model for End-Stage Liver  Disease (MELD) score and survival at 3 months. (From Sleisenger and Fordtran’s

    Gastrointestinal and Liver Disease, 10th ed., Chapter 97, page 1634. Elsevier; 2016.)

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  5. 5
    Major complications of cirrhosis

    Portal Hypertension

    Although portal hypertension can be inferred by clues such as splenomegaly with thrombocytopenia in a patient with cirrhosis, it is defined by a hepatic venous pressure gradient (HVPG) greater than 5 mm Hg. This gradient is calculated by subtracting the measured free hepatic vein pressure from the wedged hepatic venous pressure (a measurement that reflects portal venous pressure by using the same hemodynamic principle as the wedged pulmonary capillary pressure to assess left atrial pressure). Clinically significant portal hypertension typically occurs when the HVPG is 10 mm Hg or greater, at which threshold gastroesophageal varices and ascites occur. Unfortunately, accurate noninvasive measurement of portal pressure is not available, limiting its use in routine clinical practice as it requires passage of a transjugular catheter.

    Increased intrahepatic resistance to portal venous flow aggravated by increased splanchnic blood flow in cirrhosis leads to portal hypertension. In addition to cirrhosis, which is the most common cause of portal hypertension in Western countries (hepatic schistosomiasis is the leading cause in areas where this infection is common), other disorders may result in pre- or posthepatic portal hypertension. Portal vein thrombosis is a common cause of prehepatic portal hypertension. Cardiomyopathy, constrictive pericarditis, Budd- Chiari syndrome, and inferior vena cava webs may result in posthepatic portal hypertension. Ascites and gastroesophageal variceal hemorrhage are the two most common complications of portal hypertension in cirrhosis. Less common but clinically significant complications include portal hypertensive gastropathy, hepatic hydrothorax, hepatopulmonary syndrome, portopulmonary hypertension, and hepatorenal syndrome.

    Gastroesophageal Variceal Hemorrhage

    Portal hypertension leads to formation of multiple portosystemic collaterals, including gastroesophageal varices. Formation of gastroesophageal varices typically occurs when the HVPG is 10 mm Hg or greater, with the risk for variceal hemorrhage increasing once HVPG is greater than 12 mm Hg. Gastroesophageal varices are present in approximately 50% of patients with cirrhosis and are more common in patients with hepatic decompensation (Child-Turcotte- Pugh class C). Variceal hemorrhage is the most dramatic complication of cirrhosis and occurs at a rate of 5% to 15% per year. Risk factors for variceal hemorrhage include larger variceal size, more advanced hepatic decompensation, and presence of vascular “red wale” signs during endoscopic evaluation. Esophageal varices are classified according to their size as small (≤ 5 mm) or large (> 5 mm).

    Screening for gastroesophageal varices with esophagogastroduodenoscopy (EGD) is recommended when cirrhosis is suspected. Management strategies for patients with esophageal varices that have not previously bled (primary prophylaxis) are summarized in Table 4.

    Table 4

    Recommendations for Primary Prophylaxis Against Esophageal Variceal Hemorrhage

    Abbreviations: BB = beta-blocker; CTP = Child-Turcotte-Pugh; EGD = esophagogastroduodenoscopy; EVL = endoscopic variceal  ligation.

    Child-Turcotte-Pugh class obtained by adding points for each variable

    Class A: 5–6 points (compensated  cirrhosis)

    Class B: 7–9 points (decompensated cirrhosis) Class C: 10–15 points (decompensated  cirrhosis)

    Management of esophageal varices that have previously bled (secondary prophylaxis) includes a combination of a nonselective beta-blocker with endoscopic variceal ligation (EVL). The dose of the nonselective beta-blocker should be titrated to the maximal tolerated dose (resting heart rate of 55 to 60 beats/minute or 25% decrease from baseline) and EVL should be repeated frequently (every 2 weeks or so) until complete variceal obliteration. Recurrence of esophageal varices may occur following EVL; thus surveillance EGD is recommended at 6- to 12-month intervals.

    Gastric varices are classified according to relationship with esophageal varices and location (Table 5).

    Table 5

    Classification of Gastroesophageal and Gastric Varices and Recommendations for Primary Prophylaxis


    Type of Varices                 Characteristics                                                                    Primary Prophylaxis
    Gastroesophageal varices type 1 (GOV1) Extension of esophageal varices along the lesser curvature into the gastric cardia Similar to esophageal varices
    Gastroesophageal varices type 2 (GOV2) Extension of the esophageal varices along the greater curvature into the gastric fundus Similar to esophageal varices
    Isolated gastric varices type 1 (IGV1) Gastric varices localized in the fundus If high risk, consider beta-blocker (BB) or cyanoacrylate injection
    Isolated gastric varices type 2 (IGV2) Gastric varices localized in the antrum No data, consider BB if high risk

    Acute variceal hemorrhage occurs at a yearly rate of 5% to 15% and is associated with high mortality (at least 20% at 6 weeks). Adequate resuscitation is crucial in acute variceal hemorrhage with some additional precautions. Patients with variceal hemorrhage are at high risk for aspiration, and endotracheal intubation for airway protection should be performed prior to endoscopy. Overly aggressive expansion of blood volume should be avoided as it may result in increased portal venous pressure. A target hemoglobin level of approximately 8 g/dL is appropriate. Prophylactic broad-spectrum antibiotics (i.e., intravenous ceftriaxone [Rocephin]1) reduce bacterial infections, risk of rebleeding, and mortality. Administration of vasoactive drugs such as octreotide (Sandostatin)1 or terlipressin (Lucassin)5 result in increased rates of initial endoscopic control of bleeding but have no effect on overall patient survival. EGD is recommended within 12 hours and EVL is the endoscopic treatment of choice. Balloon tamponade (i.e., Sengstaken Blakemore, Minnesota, or Linton-Nachlas tubes) and transjugular intrahepatic portosystemic shunt (TIPS) are effective rescue therapies when variceal hemorrhage cannot be controlled with endoscopic therapy or recurs, respectively. Patients who survive an episode of variceal hemorrhage should receive secondary prophylaxis with a combination of a nonselective beta-blocker and repeated EVL until complete obliteration of the varices is achieved. For patients with esophageal varices at high risk for treatment failure (Child-Turcotte- Pugh class B or C but with MELD scores ≤ 13), early use of TIPS following control of bleeding with pharmacologic vasoactive therapy and EVL appears to be superior to beta-blocker plus EVL.14 Cyanoacrylate injection or TIPS are the treatments of choice for management of gastric variceal hemorrhage.


    Ascites denotes pathologic accumulation of fluid in the peritoneal cavity (> 25 mL) and is the most common complication of cirrhosis. Portal hypertension is required for development of cirrhotic ascites, as individuals with HVPG less than 12 mm Hg do not develop this complication.16 Importantly, sinusoidal hypertension appears to be a requirement for development of ascites as prehepatic portal hypertension does not invariably result in development of this complication. Other relevant mechanisms include splanchnic vasodilatation and its consequences such as humorally mediated sodium retention and diminished free water excretion by the kidneys, hypoproteinemia and reduced oncotic pressure, and disruption of normal lymphatic drainage in the liver due to extensive fibrosis.

    Ascites can be demonstrated by physical examination when its volume is greater than 1500 mL, although ultrasonography can detect as little as 100 mL. Clinical signs include flank dullness on percussion, shifting dullness, and, if the amount of ascites present is large, demonstration of a fluid wave. A diagnostic paracentesis is mandatory in the following settings: new-onset ascites, change in clinical status including hospitalization of a patient with previously diagnosed ascites, and suggestion of spontaneous bacterial peritonitis (SBP). The following tests on the fluid are indicated: leukocyte count with differential (purple or lavender top tube with ethylenediaminetetraacetic acid [EDTA]), culture (on two blood culture bottles inoculated at the bedside), total protein, and albumin (red top tube). The appearance of the ascitic fluid may yield important clinical clues (Table 6). The serum-to-ascites albumin gradient (SAAG), obtained by subtracting the ascitic fluid albumin value from the serum albumin value, helps to make a distinction between transudative and exudative ascites. A gradient of 1.1 g/dL or greater confirms portal hypertension as the etiology of ascites, whereas a value less than 1.1 g/dL suggests etiologies other than portal hypertension. The absolute number of polymorphonuclear (PMN) cells in the ascitic fluid is an important clue to SBP.

    Table 6

    Characteristics of Ascitic Fluid and Differential Diagnosis



    Appearance      Differential Diagnosis                                                                        Biochemical Hints on Fluid Analysis

    Clear Uncomplicated transudative ascites due to cirrhosis WBC < 500 cells/µL, PMN < 250 cells/µL, SAAG ≥ 1.1
    Turbid/cloudy Infection PMN ≥ 250 cells/µL
    Bloody Traumatic  paracentesis, hemoperitoneum RBC > 10,000 cells/µL
    Milky Chylous ascites due to obstruction or trauma of lymphatic vessels or thoracic duct Triglycerides > 200 md/dL

    Abbreviations: PMN = polymorphonuclear cells; SAAG = serum-to-ascites albumin gradient; WBC = white blood cell.

    Cirrhotic ascites is unlikely to resolve without specific therapeutic intervention. Management of ascites is centered on sodium restriction rather than free water restriction; total dietary intake of sodium should be less than 2000 mg (88 mmol) per day and compliance with this intervention can be documented by monitoring urinary sodium concentrations. A sodium-to-potassium concentration ratio of greater than 1 on a random urine sample correlates well with a 24-hour sodium excretion greater than 78 mmol/day and implies compliance with sodium restriction. Nevertheless, dietary restriction of sodium is efficacious in only 10% of patients and enhanced natriuresis is typically needed to provide adequate control of ascites. Combining diuretics that work at different sites of the nephron is more effective than using a single agent. Aldosterone is upregulated in cirrhosis owing to diminished effective arterial blood volume and consequential increased renin and angiotensin activity, resulting in enhanced renal sodium and free water retention. Spironolactone (Aldactone) competitively inhibits aldosterone-dependent sodium- potassium exchange in the distal convoluted renal tubule and the collecting ducts. The recommended initial dose of spironolactone for patients with ascites due to portal hypertension is 100 mg orally daily. Administration of a loop-acting diuretic such as furosemide (Lasix)1 is recommended in addition to spironolactone as it potentiates natriuresis. The recommended initial dose for furosemide is 40 mg orally daily. Further increases in doses of diuretics should be made maintaining this 100/40 ratio to a maximum dose of 400 mg orally daily of spironolactone and 160 mg orally daily of furosemide, as it prevents hypo- or hyperkalemia. Renal function and electrolytes must be monitored regularly, particularly after dose modifications. Tender gynecomastia is an unpleasant side effect of spironolactone, and some patients may need to discontinue it, in which case amiloride (Midamor)1(10–40 mg orally daily) can be used. Two outcomes may occur in patients with ascites that is not adequately controlled with diuretics: (1) refractory ascites to maximum diuretic doses and sodium restriction, which typically recurs rapidly following large-volume paracenteses (LVP), and (2) inability to increase diuretic doses owing to symptomatic hypotension or deterioration in renal function as evidenced by increasing serum creatinine levels.

    Repeated LVP with removal of more than 5 liters of ascitic fluid per session is a safe and effective intervention to treat refractory ascites; however, mortality within 6 months is 20% once this develops, reflecting the severity of the underlying liver disease, and thus patients should be referred for evaluation for liver transplantation.

    Continued dietary restriction of sodium is necessary to avoid overly frequent LVP, and continuation of diuretics should be assessed on a case-by-case basis taking into consideration potential benefits and adverse reactions. Expansion of plasma volume for patients undergoing LVP is endorsed by current guidelines and supported by data demonstrating reduced postparacentesis circulatory dysfunction and improved survival. Plasma volume should be expanded with albumin at a dose of 6 to 8 g/liter of ascitic fluid removed during or immediately after LVP.

    Insertion of TIPS corrects portal hypertension and offers an attractive alternative for amelioration of refractory ascites in selected patients. TIPS is a minimally invasive technique in which an endovascular stent is used to create an intrahepatic portocaval shunt and has replaced surgical shunts. Transplant-free survival is superior with TIPS compared with repeated LVP. Assessment of systolic and diastolic heart functions is recommended prior to TIPS as significant hemodynamic changes occur following the creation of the portosystemic shunt that can result in post-TIPS heart failure in individuals with underlying systolic or diastolic dysfunction.

    The MELD score is a prognostic model that was initially developed to assess risk of death following TIPS placement, and data demonstrate that patients with a MELD score greater than 18 are at high risk of death; thus TIPS should be avoided in this population.

    TIPS results in hepatic encephalopathy in a high proportion of patients, but pharmacologic therapy typically provides adequate treatment for this complication.

    Spontaneous Bacterial Peritonitis

    Cirrhosis and portal hypertension are associated with abnormal intestinal permeability leading to bacterial translocation resulting in SBP. The most commonly isolated microorganisms responsible for SBP are Escherichia coli (43%), Klebsiella pneumoniae (11%), Streptococcus pneumoniae (9%), other streptococcal species (19%), Enterobacteriaceae (4%), Staphylococcus (3%), and miscellaneous organisms depending on the region of the world (10%). A small-volume diagnostic paracentesis (30–60 mL) rather than LVP (which can increase the risk of hepatorenal syndrome in the setting of SBP) is mandatory for diagnosis of SBP and should be performed prior to administration of antibiotic therapy. Aerobic and anaerobic blood culture bottles should be inoculated at the bedside to avoid contamination and to increase diagnostic yield. Diagnosis of SBP is supported by the presence of 250 PMN/µL or more in the ascitic fluid without an obvious source of infection. Based on the PMN count and the microbiologic analysis of the ascitic fluid, four clinical scenarios summarized in Table 7 may be encountered.

    Table 7

    Spontaneous Bacterial Peritonitis and Associated Conditions Based on Characteristics of the Ascitic Fluid

    Treatment of SBP is centered on administration of broad-spectrum empiric antibiotics with bactericidal activity against the likely infecting bacteria. Third-generation cephalosporins such as cefotaxime (Claforan) 2 g intravenously every 8 hours or ceftriaxone (Rocephin) 2 g intravenously daily offer appropriate antimicrobial coverage and are initial agents of choice for treatment of SBP. For patients allergic to beta-lactams, alternatives include fluoroquinolones such as levofloxacin (Levaquin),1 although this agent exhibits less penetration into the ascitic fluid compared with a third-generation cephalosporin.

    Current guidelines do not recommend routinely performing a follow-up paracentesis in patients with a typical initial presentation of SBP and when antibiotic therapy results in rapid clinical improvement. Repeat paracentesis, however, may be indicated to document sterility of ascitic fluid and reduction in the PMN count in patients with a slow or absent response to antibiotic therapy or in those with atypical microorganisms on initial culture results.

    Plasma volume expansion with albumin is an important adjunct to antibiotic therapy in patients with SBP as it decreases the incidence of acute kidney injury and reduces mortality. The physiologic effects of intravenous infusion of albumin include increased oncotic pressure with consequential expansion of the effective arterial blood volume, as well as its ability to bind a wide range of endogenous and exogenous ligands including bacterial lipopolysaccharides, reactive oxygen species, nitric oxide and other nitrogen reactive species, and prostaglandins, thus modulating the inflammatory response. Current guidelines recommend a selective approach for administration of intravenous albumin to patients with SBP. Specifically, this therapy should be reserved for high-risk individuals such as those with serum creatinine greater than 1 mg/dL, blood urea nitrogen greater than 30 mL/dL, or total serum bilirubin greater than 4 mg/dL. The recommended dosage of albumin1 is 1.5 g/kg of body weight within 6 hours of establishing the diagnosis of SBP and a second dose of 1 g/kg on day 3.

    Following an episode of SBP, recurrence occurs in 69% of individuals within 1 year; thus secondary prophylaxis is indicated and current guidelines recommend long-term use of norfloxacin (Noroxin)1 400 mg orally twice daily or trimethoprim/sulfamethoxazole (Bactrim DS)1 one double-strength tablet orally daily. Risk factors for recurrent SBP include ascitic fluid total protein concentration less than 1 g/dL and gastroesophageal variceal hemorrhage. Recommended antibiotic prophylaxis for patients hospitalized with gastroesophageal variceal hemorrhage include ceftriaxone1 1 g intravenously daily; once the patient is able to tolerate oral antibiotics, this may be changed to trimethoprim/sulfamethoxazole1 one double-strength tablet orally daily, ciprofloxacin (Cipro)1 500 mg orally daily, or norfloxacin400 mg orally twice daily for a total of 7 days of antibiotic therapy. Importantly, some data suggest an increased risk for SBP in patients with cirrhosis and ascites taking proton pump inhibitors; thus unnecessary use of these agents should be avoided. The exact mechanism by which acid suppression increases the risk of SBP in cirrhosis is unclear, but intestinal bacterial overgrowth, increased intestinal permeability, and altered intestinal immune response may play important roles.

    Hepatorenal Syndrome

    The ominous significance of impaired renal function as a predictor of mortality in patients with cirrhosis is reflected by inclusion of the serum creatinine level in the MELD score. Renal dysfunction is commonly encountered in patients with cirrhosis, particularly in those with hepatic decompensation. Some studies reported acute kidney injury (AKI) in approximately 20% of hospitalized patients with cirrhosis. The differential diagnosis of AKI in patients with cirrhosis is broad and includes common etiologies such as acute tubular necrosis and nephrotoxicity, but specific glomerulopathies associated with HBV and HCV must be considered (i.e., membranous and membranoproliferative glomerulonephritides). In addition, nonalcoholic steatohepatitis is characterized by a high prevalence of type 2 diabetes mellitus and systemic hypertension; thus patients are at increased risk for diabetic and hypertensive nephropathies.

    Hepatorenal syndrome (HRS) is one of several potential causes of AKI that occurs in patients with cirrhosis and portal hypertension but has also been recognized in patients with acute liver failure. Importantly, HRS is a diagnosis of exclusion and other etiologies of AKI should be considered. The pathophysiology of HRS includes splanchnic vasodilatation causing a decline in renal perfusion with consequent reductions in the glomerular filtration rate and renal excretion of sodium (typically < 10 mEq/L).

    There are two distinct types of HRS depending on the acuity and severity of renal dysfunction. Type I HRS is characterized by rapid deterioration of renal function with at least a twofold increase in serum creatinine to a level greater than 2.5 mg/dL in less than 2 weeks and is often precipitated by SBP, acute alcoholic hepatitis, or gastrointestinal hemorrhage. Type II HRS is more indolent and is associated with less severe renal impairment, typically resulting in ascites resistant to diuretics. Prognosis also differs significantly for both types of HRS, with the median survival in the absence of liver transplantation being 2 weeks for HRS type I and 6 months for HRS type II.

    Discontinuation of all diuretics and nephrotoxic agents is critical in patients with HRS. Plasma volume expansion with administration of intravenous albumin1 at a dose of 1 g/kg of body weight (up to a maximum of 100 g/day) to increase renal perfusion is recommended. HRS is characterized by absent or minimal proteinuria (< 500 mg/day) and normal urine sediment reflecting the lack of intrinsic renal disease. Renal ultrasonography is also recommended as it provides good assessment for chronic parenchymal changes that may suggest the presence of a chronic underlying renal disease and accurately rules out obstructive nephropathy.

    Patients with HRS require either improvement in hepatic function or liver transplantation for renal function to recover.

    Pharmacotherapy can be used as a bridge to liver transplantation. Based on the pathophysiology of HRS, vasoconstriction with alpha- adrenergic agonists (i.e., midodrine [ProAmatine]1 or norepinephrine [Levophed]1) or vasopressin analogs (i.e., terlipressin [Lucassin]5) is the therapy of choice along with plasma volume expansion achieved with intravenous albumin infusion. The use of norepinephrine is reserved for critically ill patients with HRS. Terlipressin is not licensed for use in the United States. The combination of the somatostatin analog octreotide1 along with oral midodrine and intravenous albumin infusion appears to have beneficial effects based on results from small clinical trials and is currently recommended in the United States for noncritically ill patients with type I HRS. Data from a metaanalysis support the efficacy of vasoconstrictor therapy (terlipressin, octreotide + midodrine, or norepinephrine) in combination with intravenous albumin in reducing short-term mortality in patients with type I HRS. The largest randomized clinical trial to date evaluating terlipressin in combination with albumin versus placebo plus albumin showed no difference in reversal of type I HRS, but the terlipressin group had greater improvement in renal function. Renal replacement therapy may be needed for patients with HRS not responding to pharmacologic therapy awaiting liver transplantation; however, mortality is exceedingly high and hypotensive episodes commonly occur during hemodialysis.

    Following liver transplantation, renal function improves in approximately 60% of patients with HRS.

    Hepatic Encephalopathy

    Hepatic encephalopathy (HE) is a clinical syndrome of reversible neuropsychiatric impairment of varying severity. There is continuing controversy about its exact pathogenesis, but gut-derived toxins, including ammonia, are clearly implicated. Features of HE may be subclinical (covert) or clinically evident (overt) and include a wide range of neuropsychiatric signs and symptoms. The prevalence of HE varies depending on the clinical subtype and the severity of liver disease, with cumulative prevalence rates of up to 80% for covert HE and 30% to 40% for overt HE in patients with cirrhosis. Although the West Haven criteria are widely used for grading the severity of HE (Table 8), current guidelines recommend using three additional axes to classify HE based on the etiology, time course, and presence or absence of a precipitating factor (Table 9).

    Table 8

    West Haven Criteria for Grading Hepatic Encephalopathy


    Table 9

    Classification of Hepatic Encephalopathy Based on Four Different Axes

    From Patidar KR, Bajaj JS. Covert and overt hepatic encephalopathy: Diagnosis and management. Clin Gastroenterol Hepatol  2015;13:2048–2061.

    Covert HE is considered preclinical and encompasses minimal HE (features of HE that are only diagnosed by specialized neuropsychiatric testing) and grade 1 HE as per West Haven criteria. In contrast, overt HE is characterized by clinical findings of HE ranging from subtle changes in orientation and presence of asterixis to hepatic coma (grades 2 to 4 per West Haven criteria).

    Specialized testing is necessary to establish a diagnosis of covert HE. The psychometric hepatic encephalopathy score is regarded as the gold standard, but additional assessments include the number connection test, computerized tests such as the inhibitory control test, the cognitive drug research battery, and electroencephalogram. These tests, however, are not applicable in routine clinical practice and usually require consultation with a specialist. A smartphone application that evaluates psychomotor speed and cognitive alertness has been developed and validated as a point-of-care screening tool for covert HE: EncephalApp Stroop.

    The diagnosis of overt HE is clinical and supported by the presence of a wide spectrum of global neurologic deficits. Severe HE, grades 3 and 4 West Haven criteria, should prompt attention to airway protection, and endotracheal intubation ought to be considered.

    There are no laboratory markers that can be accurately used to diagnose overt HE. Blood ammonia levels lack sensitivity and specificity and correlate poorly with the severity of encephalopathy. Furthermore, a normal ammonia level does not preclude the presence of HE, and venous ammonia levels are influenced by several other factors including phlebotomy technique and handling of the blood specimen. Efforts must be directed at identifying potential precipitating factors for HE such as compliance with treatment of HE, new medications, gastrointestinal bleeding, AKI, electrolyte imbalances, and infections.

    Management of covert and overt HE is centered on the use of nonabsorbable disaccharides and antibiotics. Lactulose (Enulose) is the most widely used nonabsorbable disaccharide. Although the exact mechanism responsible for its therapeutic efficacy is still unclear, this agent is degraded by colonic microbiota to short-chain organic acids, resulting in acidification of the intestinal lumen and increased conversion of absorbable ammonia to nonabsorbable ammonium. The starting dosage for lactulose depends on the acuity and severity of HE but must be titrated to achieve two to four soft bowel movements per day. For patients who cannot tolerate oral administration (i.e., high risk for aspiration or coma), lactulose can be administered as an enema (300 mL of lactulose solution 10 g/15 mL in 700 mL of saline or water). The cathartic effects of nonabsorbable disaccharides may result in profuse diarrhea, dehydration, and hypernatremia. Rifaximin (Xifaxan) is a broad-spectrum antibiotic with activity against gram- positive, gram-negative, and anaerobic enteric bacteria that can be used in addition to lactulose for prevention of recurrent episodes of HE. Data from clinical trials show marked reductions in HE-related hospitalization and significant improvements in health-related quality of life in patients treated with a combination of lactulose and rifaximin without an increased rate of adverse events.

    The efficacy and safety of other pharmacologic therapies such as probiotics,7branched-chain amino acids,7 L-ornithine L-aspartate (LOLA),7 ammonia scavengers, and other laxatives (i.e., polyethylene glycol [MiraLax]1) need to be further confirmed by clinical trials.

    Because of concerns about oto- and nephrotoxicity, neomycin is no longer used.

    Creation of a portosystemic shunt (now usually with TIPS) for management of complications of portal hypertension is associated with a 13% to 36% incidence of overt HE. Careful patient selection prior to insertion of TIPS and medical therapy with nonabsorbable disaccharides with or without additional rifaximin remain standard therapy; however, despite compliance, approximately 3% to 7% of patients have recurrent or persistent overt HE post-TIPS. For these patients, endovascular techniques aimed at decreasing the size of the shunt should be considered.

    Liver transplantation offers definitive therapy for patients with end- stage liver disease, resulting in restoration of hepatic synthetic function and resolution of complications associated with portal hypertension. However, residual cognitive impairments may persist following liver transplantation, adversely impacting health-related quality of life.

    Hepatocellular Carcinoma

    Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy in adults, currently representing the fifth most common cancer and the second leading cause of cancer-related death worldwide. The epidemiology of HCC varies significantly by region and ethnicity. The majority of patients with HCC in Western populations (95%) have underlying cirrhosis (predominantly due to chronic HCV infection, alcoholic liver disease, and nonalcoholic steatohepatitis), thus limiting applicability of surgical resection (see later) as curative therapy. In contrast, only 60% of patients with HCC in Eastern populations have cirrhosis, largely reflecting the high prevalence of chronic HBV infection and its oncogenic potential.

    Regions of the world with intermediate to high incidence of this malignancy (more than 3 cases per 100,000 persons per year) include Asia, sub-Saharan Africa, and Western Europe. North and South America have been typically considered low-incidence regions; however, over the past two decades there has been a steady increase in the incidence of HCC, particularly in the United States.

    Current guidelines endorse implementation of surveillance strategies for early diagnosis of HCC in individuals at risk for this malignancy and recommend the use of ultrasonography every 6 months as the primary surveillance modality. Populations at risk for HCC that benefit from surveillance include individuals with cirrhosis of any etiology, Asian males with chronic HBV over age 40, Asian females with chronic HBV over age 50, patients with chronic HBV and family history of HCC, African/North American blacks with chronic HBV, and individuals with stage 4 primary biliary cholangitis.

    HCC can be accurately diagnosed without need for liver biopsy by contrast-enhanced multiphase cross-sectional imaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI) based on specific patterns of contrast enhancement of the tumor in relation to the hepatic parenchyma. Key diagnostic characteristics for HCC on CT or MRI are contrast enhancement of the tumor during the early arterial phase and “washout” of contrast from the tumor during the portal venous and delayed phases. Additional features include presence of a capsule and interval growth of the lesion when previous imaging studies are used for comparison. Biopsy of the tumor carries a small risk for tumor seeding in the biopsy-needle tract (approximately 3%) and is rarely required to diagnose HCC owing to high accuracy of CT and MRI. The use of serum alpha-fetoprotein (AFP) has been controversial for routine surveillance owing to its low sensitivity and poor specificity; however, once a focal liver lesion is identified on imaging studies, this marker should be obtained as an additional diagnostic tool. AFP levels greater than 200 ng/mL are highly specific for HCC, and longitudinal follow-up of serum levels permits evaluation of response to therapeutic interventions.

    Additional serologic markers for HCC under investigation include the L3 isoform of AFP (AFP-L3) and des-gamma carboxy prothrombin (DCP); however, further validation of these tests for surveillance of individuals at risk for HCC is still required.

    The Barcelona Clinic Liver Cancer (BCLC) staging system can be used to categorize patients with HCC and to assist with therapeutic decisions (Figure 2). Surgical resection of HCC is reserved for patients with a single lesion and no evidence of cirrhosis or portal hypertension. Locoregional therapies include radiofrequency ablation, percutaneous ethanol injection, transarterial chemoembolization, radioembolization, and microwave ablation. These modalities are typically used for patients with early and intermediate stages (BCLC stages A and B, respectively). Liver transplantation is an effective treatment for patients with cirrhosis and HCC within the so-called Milan criteria: a single lesion up to 5 cm or no more than three lesions with the largest one being less than 3 cm, and in the absence of portal venous invasion or metastatic disease. Liver transplantation for HCC within these limits results in long-term survival equivalent to that seen in patients with cirrhosis but no HCC. Under the current organ allocation policy in the United States, patients with HCC within Milan criteria are listed for liver transplantation with their biological MELD score (calculated by the MELD formula and without exception points) for 6 months, after which time they automatically accrue MELD exception points and the score increases to 28, with 10% increments thereafter every 3 months until the maximum score of 34 is reached.

    MELD exception points are granted to patients with HCC 2 cm or greater in an effort to balance risk of death that is not adequately represented by the degree of hepatic dysfunction. For patients with HCC listed for liver transplantation, the use of locoregional therapies is recommended to prevent tumor progression that may result in dropout from the waiting list. Furthermore, active surveillance is recommended to evaluate for tumor recurrence or progression, development of new lesions, and metastatic disease while awaiting liver transplantation.

    FIGURE 2    Barcelona Clinic Liver Cancer (BCLC) staging system  for hepatocellular carcinoma (HCC). CLT, cadaveric liver transplantation. LDL, living donor liver transplantation. OS, overall survival. PEI, percutaneous ethanol injection.

    PST, performance status. RF, radiofrequency ablation. TACE, transarterial chemoembolization. (From EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56[4]:908–43.)

    The only systemic chemotherapeutic agents licensed for use in patients with HCC are sorafenib (Nexavar), two multikinase inhibitors that reduce tumor angiogenesis. Sorafenib is currently recommended for patients with BCLC stage C and regorafenib is licensed to treat patients with HCC who have been previously treated with sorafenib; however, adverse reactions, tolerability, and potential benefits must be carefully weighed and individualized according to overall health and performance status, as well as severity of hepatic dysfunction.

    The survival benefit of both agents versus placebo is modest (nearly 3 months).

    Portopulmonary Hypertension

    Pulmonary artery hypertension in a patient with established portal hypertension is indicative of portopulmonary hypertension (PPHTN), but other etiologies of pulmonary hypertension must be excluded prior to establishing this diagnosis. The prevalence of PPHTN varies depending on the severity of liver disease and has been reported in 0.7% of patients with cirrhosis but can be as high as 12.5% in patients undergoing evaluation for liver transplantation.

    The exact pathophysiology of PPHTN remains enigmatic, but increased exposure to humoral vasoconstrictors in the pulmonary vasculature due to portosystemic shunting and hyperdynamic circulation is among the most widely accepted hypotheses. Histologic findings in the pulmonary vasculature of patients with PPHTN are indistinguishable from those found in idiopathic pulmonary arterial hypertension and include medial hypertrophy with remodeling of the pulmonary artery walls and occasional in situ microthrombosis.

    The majority of patients with PPHTN remain largely asymptomatic for extended periods of time. Symptoms associated with PPHTN are similar to those of other types of pulmonary arterial hypertension and include dyspnea on exertion, syncope, chest pain, fatigue, hemoptysis, and orthopnea. Physical examination may demonstrate jugular venous distention and lower extremity edema, the latter typically being out of proportion to the severity of ascites. Cardiopulmonary auscultation usually reveals normal clear breath sounds throughout both lung fields, an accentuated pulmonic component of the second heart sound, and a systolic murmur located along the left sternal border that is accentuated with inspiration (tricuspid regurgitation). Chest radiographs may demonstrate right ventricular enlargement and a prominent pulmonary artery.

    The diagnostic workup for PPHTN should begin with transthoracic echocardiography, which provides an estimate of right ventricular and pulmonary arterial pressures and rules out left ventricular dysfunction. An estimated right ventricular systolic pressure greater than 50 mm Hg is typically used as a threshold to obtain more accurate direct hemodynamic measurements through right heart catheterization. Hemodynamic criteria used to diagnose PPHTN include mean pulmonary artery pressure (mPAP) greater than 25 mm Hg, pulmonary capillary wedge pressure less than 15 mm Hg, and pulmonary vascular resistance greater than or equal to 240 dynes ● s ● cm− 5  by right heart catheterization.

    Pharmacologic therapy has been extrapolated from studies performed in patients with idiopathic pulmonary arterial hypertension and includes endothelin receptor antagonists (bosentan [Tracleer]1 and ambrisentan [Letairis]1), phosphodiesterase inhibitors (sildenafil [Revatio]1), and prostacyclin analogs (epoprostenol [Flolan]1  and iloprost [Ventavis]1).

    Survival in PPHTN correlates with the severity of right ventricular dysfunction, and the safety and efficacy of liver transplantation are reliant on the severity of pulmonary arterial hypertension. Liver transplantation may be offered to selected patients with PPHTN but is typically contraindicated in those with mPAP greater than 35 mm Hg despite medical management, particularly if right ventricular dysfunction is present, due to considerable perioperative mortality.

    Hepatopulmonary Syndrome

    Hepatopulmonary syndrome (HPS) is characterized by hypoxemia due to intrapulmonary vascular dilatations with right-to-left shunting in the setting of cirrhosis and portal hypertension. Although intrapulmonary vasodilatation is encountered in over 50% of patients with cirrhosis undergoing evaluation for liver transplantation, only 15% to 30% have hypoxemia and true HPS. The most widely accepted pathophysiologic mechanism responsible for HPS is increased pulmonary synthesis of nitric oxide. Similar to PPHTN, the majority of patients with HPS are largely asymptomatic.

    Clinical manifestations include dyspnea of insidious onset and two characteristic clinical findings: platypnea and orthodeoxia (worsening dyspnea and hypoxemia in upright posture, respectively). Other more obvious but nonspecific clinical findings include spider angiomata, digital clubbing, and cyanosis. Screening for HPS relies on point-of- care oximetry indicating peripheral arterial oxygen saturation (Spo2) less than 96% at rest and at sea level. Hypoxemia must be confirmed by arterial blood gas analysis demonstrating an arterial partial pressure of oxygen (Pao2) less than 70 mm Hg and a widened alveolar–arterial oxygen gradient greater than or equal to 15 mm Hg (≥ 20 mm Hg for patients 65 years of age or older). Importantly, blood for arterial gas analysis should be obtained with the patient sitting upright, at rest, and breathing ambient air. After establishing a diagnosis of hypoxemia, documentation of pulmonary vascular dilatations with right-to-left blood shunting is necessary. Two- dimensional contrast-enhanced transthoracic echocardiography offers high sensitivity and is widely available. Agitated saline to produce microbubbles is injected intravenously as contrast, and under normal cardiopulmonary physiology, the gas bubbles are rapidly seen in the right atrium and ventricle but then diffuse into alveoli during normal flow through the pulmonary capillaries. In patients with HPS, the presence of intrapulmonary right-to-left shunting due to vascular dilatations results in the presence of the microbubbles opacifying the left heart chambers at least three heartbeats after being seen in the right ventricle. Intracardiac right-to-left blood shunting (i.e., atrial or ventricular septal defects, patent foramen ovale) should be suspected if contrast is seen in the left heart within three heartbeats.

    Radionuclide lung perfusion scintigraphy using technetium-labeled macroaggregated albumin particles (99mTc-MAA scan) is less sensitive than contrast-enhanced echocardiography for diagnosis of HPS but is more specific and permits accurate quantification of the intrapulmonary shunt fraction, even in the presence of coexisting intrinsic lung disorders. Shunt fractions greater than 6% confirm the diagnosis of HPS in the appropriate clinical setting.

    HPS is associated with increased mortality and diminished quality of life compared with patients with cirrhosis but no HPS. Following the diagnosis of HPS, median survival is 10.6 months; thus patients with HPS should undergo prompt liver transplantation evaluation.

    Under current organ allocation policies by the United Network for Organ Sharing (UNOS), patients with HPS and Pao2  less than 60 mm Hg are eligible for standard MELD exception score of 22 points at the time of listing, regardless of their calculated (biological) MELD score, and a 10% mortality equivalent increase in points every 3 months.

    Liver transplantation remains the definitive therapy for HPS based on marked improvement or even resolution of hypoxemia in more than 85% of transplant recipients; however, clinically meaningful changes may be slow and take up to 1 year following transplantation.

    Hepatic Hydrothorax

    Hepatic hydrothorax is a transudative process leading to accumulation of more than 500 mL of fluid in the pleural space in patients with cirrhosis and portal hypertension in the absence of primary cardiopulmonary disease. Hepatic hydrothorax is thought to result from passage of ascitic fluid from the peritoneal cavity into the pleural spaces (typically on the right in up to 85% of patients) via subcentimeter defects and/or microscopic fenestrations in the tendinous portion of the diaphragm and is facilitated by negative intrathoracic pressure generated during inspiration. Clinical features include dyspnea, nonproductive cough, pleuritic chest pain, and even hypoxemia and hypotension in cases of tension hydrothorax. Fluid analysis demonstrates similar chemical characteristics than ascites: high serum–to–pleural fluid albumin gradient (> 1.1 g/dL) and low total protein concentration (< 2.5 g/dL).

    Management of noninfected hepatic hydrothorax follows the same principles as those for ascites: sodium restriction, diuretics, repeated thoracenteses, and placement of TIPS for refractory cases.

    Importantly, indwelling pleural catheters should be avoided because of the high risk for complications including severe infections that may jeopardize possible liver transplant candidacy in the future.

    In patients with fevers and worsening pleuritic chest pain, spontaneous bacterial empyema (SBEM) must to be excluded. Similar to the diagnostic criteria for SBP, a diagnosis of SBEM is established by a PMN count greater than 250 cells/µL and a positive bacterial culture in the absence of a parapneumonic effusion. In cases in which bacterial cultures are negative, a PMN count threshold of greater than 500 cells/µL should be used to diagnose SBEM. Microorganisms responsible for this infection are also similar to those responsible for SBP; thus third-generation cephalosporins remain the antibacterial agents of choice for empiric therapy.

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    Liver transplantation

    Liver transplantation is effective in salvaging patients with acute liver failure (ALF) and decompensated cirrhosis, as well as selected patients with HCC (see earlier), with excellent short- and long-term outcomes. Survival after 1 and 5 years following liver transplantation is approximately 80% to 90% and 60% to 75%, respectively. Cirrhosis per se is not an indication to initiate evaluation for liver transplantation, as it is not associated with survival benefit in patients with low MELD scores. Consequently, patients should be referred for liver transplantation evaluation when the MELD score is 15 or higher or when an index complication of cirrhosis such as ascites or variceal hemorrhage occurs. Organ allocation in the United States and many other countries is based on disease severity as reflected by the MELD score for patients 12 years of age or older and the Pediatric End-Stage Liver Disease (PELD) score for patients younger than 12 years of age (includes international normalized ratio, bilirubin, albumin, and growth failure). The most recent modification of the MELD score now includes serum sodium in the mathematical equation (MELD-Na), as hyponatremia is an independent predictor of mortality in patients with cirrhosis. Some etiologies of cirrhosis result in diminished survival that is not accurately predicted by the MELD score or are associated with extremely poor quality of life; thus MELD exceptions exist. Standardized MELD exception criteria are summarized in (Table 10)For patients with complications related to liver disease and associated increased morbidity and mortality not adequately reflected by the MELD score and not qualifying for standard MELD exceptions, additional points may be petitioned by the transplant center to the regional review board on a case-by-case basis with no guarantee that they will be granted. Some examples of conditions that may receive additional MELD points include recurrent bacterial cholangitis in patients with primary sclerosing cholangitis, intractable and debilitating pruritus in patients with primary biliary cholangitis, ascites refractory to maximum-tolerated doses of diuretics, hepatic encephalopathy refractory to medical therapy, and recurrent variceal hemorrhage despite adequate therapy.

    Table 10

    Medical Conditions That Qualify for Standard MELD Exception Points

    Conditions                                      Remarks
    Hepatocellular carcinoma T2 lesions (at least 2 cm in diameter) within Milan criteria
    Hepatopulmonary  syndrome Pao2 < 60 mm Hg on ambient air
    Portopulmonary  hypertension Mean pulmonary arterial pressure < 35 mm Hg with treatment
    Familial  amyloid polyneuropathy Confirmed by DNA analysis and histology
    Primary hyperoxaluria Need  simultaneous  liver–kidney transplant
    Cystic fibrosis Forced expiratory volume in 1 s (FEV1) < 40%
    Hilar  cholangiocarcinoma Stage I or II, liver transplantation center must have a UNOS-approved protocol
    Hepatic artery thrombosis Within 14 days of liver transplantation, not meeting criteria for status 1A

    Abbreviations: MELD = Model for End-Stage Liver Disease; UNOS = United Network for Organ Sharing.

    Contraindications to liver transplantation continually evolve over time. Relative contraindications are usually associated with suboptimal outcomes following liver transplantation and vary widely across different transplant centers. Absolute contraindications imply that a successful outcome following liver transplantation is unlikely; thus it should not be pursued (Table 11).

    Table 11

    Absolute Contraindications to Liver Transplantation

    Contraindications to liver transplantation

    Uncontrolled sepsis

    Acquired immunodeficiency syndrome

    Active alcohol or substance abuse

    Advanced cardiac or pulmonary disease

    Intrahepatic cholangiocarcinoma

    Hepatic hemangiosarcoma

    Hepatocellular carcinoma with metastasis

    Extrahepatic malignancy

    Anatomic abnormalities that preclude liver


    Lack of social support

    Persistent nonadherence to medical care

    ALF is an uncommon but important indication for liver transplantation owing to the high mortality associated with this condition. Although a significant proportion of patients with ALF may have spontaneous recovery, its clinical course is usually unpredictable and early referral for liver transplantation is recommended, regardless of the etiology. Patients with ALF have the highest priority for organ allocation if they meet specific criteria for UNOS status 1A (Table 12).

    Table 12

    Criteria for Status 1A Designation in Patients With Acute Liver Failure

    Evaluation for liver transplantation is a multidisciplinary process carried out over multiple encounters aimed to unveil additional medical, surgical, behavioral, social, and economic issues that may affect liver transplantation candidacy and/or outcomes. Once the patient’s candidacy is deemed appropriate, formal listing occurs with UNOS. Blood type (ABO) is the major determinant for organ compatibility, and appropriate size (based on body weight) must be taken into consideration.

    Living-donor liver transplantation was developed as an alternative owing to ongoing shortage of deceased-donor organs; however, living donation carries important risks for the donor that must be carefully taken into consideration. The advantages and disadvantages of living- donor liver transplantation are summarized in Table 13.

    Table 13

    Advantages and Disadvantages of Living-Donor Liver Transplantation

    Advantages                                                                                                Disadvantages
    Thorough donor screening process Only offered in selected liver transplantation centers
    Elective timing of liver transplantation permitting optimization of therapies Donor morbidity and mortality

    Diminished wait time with consequent reduction in dropout from the waiting list

    Minimal cold ischemia time

    Higher risk for biliary complications in the donor and recipient

    Additional approaches to try to expand donor organ supply include donation after cardiac death, using grafts from hepatitis B core antibody–positive and hepatitis C–positive donors, and splitting a graft for use in adult and pediatric recipients.

    Adequate long-term immunosuppression prevents graft rejection and is currently centered on the use of calcineurin inhibitors (tacrolimus [Prograf] primarily, and less often cyclosporine [Neoral]) with or without concomitant antimetabolite agents such as mycophenolic acid (Myfortic) or its prodrug mycophenolate mofetil (CellCept). Additional agents include inhibitors of the mammalian target of rapamycin (mTOR) such as sirolimus (Rapamune)1 and everolimus (Zortress).

    Long-term care of liver transplant recipients should not by any means focus exclusively on graft function and prevention of rejection, but rather be comprehensive and aimed at maintaining an overall good state of health by instituting preventive health strategies and monitoring for other complications that may ensue, such as diabetes mellitus, hypertension, dyslipidemia, renal dysfunction, obesity, and alcohol relapse, among many others.

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  7. 7

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    1  Not US Food and Drug Administration (FDA) approved for this   indication.

    5  Investigational drug in the United  States.

    1 Not FDA approved for this indication.

    1 Not FDA approved for this indication.

    1 Not FDA approved for this indication.

    1  Not FDA approved for this  indication.

    5  Investigational drug in the United  States.

    7  Available as dietary supplement.

    1 Not FDA approved for this indication.

    1 Not FDA approved for this indication.

    1  Not FDA approved for this  indication.

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