Article Text

Management of patients with cirrhosis awaiting liver transplantation
1. Andrés Cárdenas1,
2. Pere Ginès2
1. 1The GI Unit, Institut Clinic de Malalties Digestives i Metaboliques, Hospital Clinic, and University of Barcelona, Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Ciber de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
2. 2The Liver Unit, Institut Clinic de Malalties Digestives i Metaboliques, Hospital Clinic, and University of Barcelona, Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Ciber de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
1. Correspondence to Dr Pere Ginès, Liver Unit, Hospital Clinic, Institut Clinic de Malalties Digestives, Villarroel 170, Barcelona 08036, Spain; pgines{at}clinic.ub.es

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## Introduction

The first human orthotopic liver transplantation (OLT) was performed in the early 1960s by Thomas Starzl in the USA.1 Up until then there was little to offer patients with advanced liver disease with features of decompensation such ascites, hepatorenal syndrome (HRS), hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), gastro-oesophageal variceal bleeding, and/or hepatocellular carcinoma. These patients had a sinister prognosis because only palliative and symptomatic therapy was offered. The advent of OLT as an accepted therapy for advanced liver disease completely changed this scenario offering patients a cure to their diseased liver. In the initial years, significant advances were made in refining the indications and surgical technique. Nonetheless it took several years to realise that maximally optimising the pre-transplant status of patients would translate into better post-transplant outcomes.2 The most common conditions in decompensated cirrhosis that require aggressive management and alter pre- and post-transplant outcome include hyponatraemia, SBP as well as other bacterial infections, HE, HRS, and hepatocellular carcinoma.

In the USA and Europe, survival rates of patients who undergo OLT are near 85% and 86% at 1 year and 80% and 79% at 3 years, respectively.3 4 However, the high demand for organs and the steady availability of donors has led to increased morbidity and mortality in the waiting list in many transplant centres. Thus, proper care of patients on a liver transplantation list plays a fundamental role in reaching OLT in an adequate condition that ensures a good outcome after OLT. In this respect the appropriate selection of candidates plays a key role in determining waiting list morbidity and mortality. Patients who are selected for OLT undergo a thorough evaluation in order to exclude conditions that may preclude the operation (mainly serious comorbid conditions, metastatic cancer or those who will not survive or benefit are not candidates). The priority of listed patients is based on models that predict survival while on the waiting list. Although different models are used among different countries, the Model for End-stage Liver Disease (MELD) score is the model used in the USA and some countries in Europe. The score accurately predicts short-term mortality in independent cohorts of patients with different aetiologies of liver disease.5 However, despite improvements in organ allocation policy and medical care, patients continue to spend a long time on the waiting list. This is mainly due to a high demand of organs and small donation rates; however, this varies among different countries. For instance, in the USA the average waiting time on the list is 361 days whereas in the UK it is 149 days.6 7 This increase of time spent on the list places patients at risk of developing many of the complications listed above; therefore, an important goal within this timeframe is to optimise the patient's condition preventing further decompensation and treating specific complications that not only affect pre-transplant status but also post-transplant outcome. This article will focus on the above-mentioned complications in patients awaiting OLT. Hepatocellular carcinoma, which is commonly encountered in patients with compensated and decompensated cirrhosis, should also be managed aggressively, however, this topic is beyond the scope of this review, and has been discussed recently elsewhere.8

## Ascites

Ascites is the most common complication of cirrhosis and is associated with 50% mortality at 5 years if patients do not receive OLT.9 It is one of the most frequent reasons for referral for evaluation of OLT in the USA and Europe. Ascites is classified as Grade 1 ascites: fluid detected only by ultrasound; Grade 2: moderate ascites with symmetrical distention of the abdomen; Grade 3: large or tense ascites.10 The evaluation of patients with ascites involves several steps, but the most important is a diagnostic paracentesis and abdominal ultrasound. Diagnostic paracentesis is required in all patients listed for transplantation regardless of their INR value in order to exclude other causes different of cirrhosis and portal hypertension and rule out SBP.11 Mandatory tests in the ascitic fluid include cell count, culture in blood culture bottles (10 ml of fluid injected at the bedside), and total protein.11 A high polymorphonuclear (PMN) count indicates infection (see below). The protein level (which is usually low in cirrhosis) is a marker of prognosis. In cases where cirrhosis is not clearly evident, the difference between the serum albumin concentration and ascites albumin concentration (serum-ascites albumin gradient) in patients with cirrhosis and ascites is usually greater than 1.1 g/dl and indicates portal hypertension. Abdominal ultrasonography should be performed to rule out hepatocellular carcinoma and/or portal vein thrombosis. The importance of treating ascites properly relates to an overall better outcome in the pre-transplant phase by reducing the likelihood of renal and electrolyte complications, decreasing hospital admissions and providing a better quality of life for the patient.

### Management

A cornerstone of therapy is implementation of a low sodium diet with 90 mmol/day as well as diuretics. Grade 1 ascites does not need to be treated, but is advisable that these patients refrain from excessive salt intake. Diuretics are indicated for all those patients with Grade 2 ascites. Patients with their first episode of ascites respond to spironolactone 50–100 mg/day and the dose may be increased progressively if needed. Patients with recurrent episodes of ascites should receive the combination of spironolactone 100 mg/day with furosemide 40 mg/day.10–14 If there is no response, compliance with diet and medications should be confirmed and diuretics may then be increased every 7 days by doubling doses to a maximal dose of spironolactone (400 mg/day) and a maximal dose of furosemide (160 mg/day). Patients with Grade 3 ascites are best managed by total paracentesis with albumin administration (8 g/l of fluid removed) after the tap in order to prevent the post-paracentesis circulatory dysfunction.10 11 15–17 This option is safe, effective, has significantly fewer side effects than diuretics and allows rapid treatment of patients. Albumin is better than other plasma expanders (dextran-70, polygeline, and saline) for large-volume paracentesis greater than 5 litres.18 Many of these patients have marked sodium retention and therefore need be started or continued on moderately high or high doses of diuretics after paracentesis.

About 10% of patients with ascites are refractory to treatment with diuretics.10 In refractory ascites, patients do not respond to highest doses of diuretics or develop side effects (electrolyte imbalances, HE, or renal failure) that prohibit their use. The median survival of such patients is approximately 6 months. Treatment options while patients are listed for OLT include repeated large-volume paracentesis plus albumin or transjugular intrahepatic portosystemic shunt (TIPS). Therapeutic paracentesis is the recommended initial treatment and patients, on average, require a tap every 2–4 weeks. The majority may be treated as outpatients, making this option easy to perform and inexpensive. TIPS by reducing portal pressure decreases ascites and its re-accumulation as well as diuretic requirements. Although TIPS is very effective, it frequently obstructs (50–70% in 1 year) and may cause HE and congestive heart failure.19 Newer polytetrafluoroethylene-covered prostheses seem to improve TIPS patency and decrease the number of clinical relapses and reinterventions without increasing the risk of encephalopathy but more information is needed about these types of shunts.20

Randomised controlled studies comparing TIPS with repeated therapeutic paracentesis demonstrate that TIPS is associated with a lower rate of ascites recurrence with discrepant findings in survival21–25 (two showed a survival benefit with TIPS22 25 and two demonstrated no difference in survival23 24). However, HE in these studies occurred in 30–50% of patients treated with TIPS. Meta-analyses of all randomised controlled studies conclude that TIPS is better at controlling ascites but does not improve survival compared to paracentesis.26 Current guidelines recommend large-volume paracentesis as the treatment of choice because of its wider applicability, lower cost and fewer side effects when compared to TIPS.10 27–30 TIPS may be an option for patients aged <70 years, with preserved liver function, without HE or severe cardiopulmonary disease who require very frequent paracentesis or in whom ascites cannot be adequately eliminated by paracentesis.10 27–30

## Hyponatraemia

In the majority of patients with advanced cirrhosis, hyponatraemia develops in the setting of ascites where there is an expanded extracellular fluid volume along with increased renal sodium retention. This type of hyponatraemia is known as hypervolaemic hyponatraemia. The pathogenesis of hyponatraemia is directly related to the impairment of solute-free water excretion in cirrhosis. This is mainly due to a high non-osmotic secretion of arginine vasopressin31 which increases water reabsorption in the kidney due to the presence of V2 receptors located on the basolateral membrane of the collecting ducts. In most patients, hyponatraemia is asymptomatic, but recent data indicate that hyponatraemia is associated with a higher risk of HE.32 33 The mechanism by which hyponatraemia is associated with HE is believed to be due to changes in serum osmolality that lead to astrocyte swelling and then to a cellular release of solutes as a response to prevent cell swelling and cerebral oedema. These changes are relevant because the underlying pathogenesis of HE considers that in cirrhosis, ammonia and other toxins induce a low-grade cerebral oedema due to astrocyte swelling secondary to increased intracellular levels of glutamine that alter astrocyte function.33 Consequences of astrocyte swelling include alterations in gene expression and oxidative stress that alter glioneuronal communication and disturb neurological function, leading to HE.33 34 Therefore the presence of hyponatraemia in combination with hyperammonaemia, by favouring astrocyte swelling, may increase the risk of HE. The typical classical symptoms of acute hyponatraemia rarely occur in cirrhosis.

Hypervolaemic hyponatraemia is defined as a serum sodium concentration less than 130 meq/l in the presence of ascites or oedema.35 The presence of hyponatraemia is associated with a poor prognosis in cirrhosis; in patients with cirrhosis and ascites the risk of developing hyponatraemia is 15% at 1 year with a 25% probability of survival at 1 year.9 It is estimated that 22% of patients with advanced cirrhosis have serum sodium levels <130 meq/l; however, in patients with refractory ascites or HRS, this proportion may increase up to 50%.23 36 Hyponatraemia in cirrhosis has gained attention because serum sodium concentration improves the prognostic ability of the MELD score in patients awaiting OLT.37–39 It has also gained notice because the vaptans (V2 receptor antagonists—see below) for the treatment of hypervolaemic hyponatraemia were recently approved in the USA and Europe.

Hyponatraemia has important clinical consequences in patients undergoing OLT. Liver transplantation may be associated with a rapid correction of low serum sodium levels in hyponatremic patients and a new normonatraemic state may place patients at risk for deleterious effects on the brain. In fact, severe neurological complications, in particular osmotic demyelination syndrome may occur in patients with cirrhosis and hyponatraemia submitted to OLT but the incidence is low.40 Some studies indicate patients that undergo OLT with hyponatraemia might be at risk of developing renal failure, bacterial infections during the first month after transplantation, and have increased 3-month mortality with respect to patients without hyponatraemia,41 42 Nonetheless, another study found that hyponatraemia before OLT had no impact on survival following OLT.40

Management of hypervolaemic hyponatraemia includes water restriction of approximately 1–1.5 l/day but this measure is rarely effective and although it may halt the progressive decrease in serum sodium concentration in some patients it does not correct hyponatraemia. The administration of hypertonic saline solutions may be effective in some patients but is not recommended because it may cause more accumulation of ascites and oedema. The V2 receptor antagonists (vaptans) increase solute-free water excretion and improve serum sodium concentration in hyponatraemic patients with cirrhosis and ascites.43 44 There is very scarce data regarding their use in patients awaiting OLT.45 The short-term administration of vaptans is associated with an increase in serum sodium concentration that usually occurs within the first 4–5 days of treatment with normalisation of serum sodium concentration occurring in 30–55% of patients.43–45 Conivaptan is approved in the USA for short-term (4–5 days) intravenous use (dose 20 mg/day),45 whereas tolvaptan is approved as an oral compound (dose starting at 15 mg/day with sequential 15 mg increments up to 60 mg/day).43 A drawback of both of these agents is their elevated cost which averages between 200–450 US$per day. The most frequent side effect of vaptans in patients with cirrhosis is thirst which can occur in up to 30% of patients.43 44 Other side effects are uncommon; however, these drugs need to be used with caution and the patient must be carefully monitored as very rapid correction of hyponatraemia (eg, >12 meq/l/24 h) can theoretically cause osmotic demyelination. The use of these agents in cirrhosis was assessed in short-term studies; notwithstanding this, long-term controlled studies are needed to evaluate the safety, efficacy and applicability of these agents in patients with cirrhosis, ascites and hyponatraemia. Recommendations for the treatment of hyponatraemia are outlined in box 1. Box 1 ### Box 1 Recommendations for the management of hypervolaemic hyponatraemia in patients awaiting liver transplantation 1. Fluid restriction to 1000–1500 ml/day. 2. If fluid restriction is not effective, oral tolvaptan may be used*. Intravenous conivaptan is an option but there is very limited data on its use in cirrhosis†. 3. If tolvaptan is considered, it should be started in the hospital at a dose of 15 mg/day. This dose should be given for the first few days and then the dose should be titrated to 30 and 60 mg/day until normal values of serum sodium are reached. 4. Serum sodium concentration should be monitored closely particularly during the first days of treatment and whenever the dose of the drug is increased or there are changes in the clinical status of the patient. 5. Rapid increases in serum sodium concentration (of greater than 8 mmol/day) should be avoided to prevent the potential occurrence of osmotic demyelination syndrome. 6. Patients may be discharged after serum sodium levels are stable and no further increase in the dose of the drug is required. 7. Treatment with drugs that are either potent inhibitors or inducers of the CYP3A should be avoided. 8. The duration of treatment with tolvaptan is not known as its efficacy and safety has only been established in short-term studies (1 month). *Tolvaptan is approved in the USA for patients with cirrhosis with hyponatraemia (serum sodium ≤125 meq/l) as well as for other conditions with hypervolaemic hyponatraemia. The cost of tolvaptan in the USA ranges between 200 and 300 US$ per day. In Europe, tolvaptan is only approved for the syndrome of inappropriate antidiuretic hormone secretion.

†Conivaptan is only available in the USA.

## Hepatorenal syndrome

HRS is a functional renal failure without any identifiable kidney pathology that occurs in patients with advanced cirrhosis.46 Due to the lack of specific diagnostic markers, the diagnosis of HRS is currently made using criteria to exclude other causes of renal failure that can occur in cirrhosis (box 2). HRS is commonly seen in patients awaiting OLT and remains one of the most challenging complications of cirrhosis to manage. Type 1 HRS is an acute and rapidly progressive form of renal failure with a rise of serum creatinine >2.5 mg/dl that may occur in temporal relationship with a precipitating factor (ie, SBP or alcoholic hepatitis) or spontaneously. The expected survival of type 1 HRS is of only 2 weeks if not treated or transplanted.47 In type 2 HRS, renal failure is usually less severe (serum creatinine 1.5–2.5 mg/dl). HRS is triggered by SBP or other bacterial infections in approximately 30% of cases.48 Therefore, objective signs of infection (blood work and cultures, ascitic fluid analysis and culture, urine analysis and culture, chest x-ray) should be investigated in all patients with cirrhosis and renal failure and antibiotics should be given promptly if there is any suspicion of infection. Prevention of HRS is of key importance in providing care for patients listed for OLT. HRS can be prevented in patients with SBP.49 50 As discussed later, the administration of albumin at the time of diagnosis of SBP is effective in the prevention of HRS that frequently develops after this infection.30 Additionally, the use of norfloxacin in patients with advanced cirrhosis also prevents the development of HRS (see below).51 Finally, a recent study showed that the administration of pentoxifylline reduces the frequency of renal failure in patients with advanced cirrhosis (Child class C), but these results require confirmation in future studies.52

Box 2

### Box 2 Diagnostic criteria of hepatorenal syndrome in cirrhosis*

1. Cirrhosis with ascites.

2. Serum creatinine >1.5 mg/dl (133 μmol/l).

3. No improvement of serum creatinine (decrease to a level lower than 1.5 mg/dl (133 μmol/l) (after at least 2 days off diuretics and volume expansion with albumin (1 g/kg body weight up to a maximum of 100 g/day).

4. Absence of shock.

5. No current or recent treatment with nephrotoxic drugs.

6. Absence of signs of parenchymal renal disease, as suggested by proteinuria (>500 mg/day) or haematuria (>50 red blood cells per high power field), and/or abnormal renal ultrasound.

*Salerno et al. Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis. A consensus workshop of the international ascites club. Gut 2007;56:1310–18.

### Management

Although OLT is undoubtedly the best treatment for HRS, successful pharmacological therapy prior to OLT is as important in assuring an optimal outcome similar to that of patients without HRS. Systemic vasoconstrictors with plasma expansion are the therapy of choice for HRS. These include vasopressin analogues (terlipressin) and alpha-adrenergic agonists (midodrine and noradrenaline).53 Albumin (20–40 g/day) is concomitantly used with vasoconstrictors in order to help improve effective arterial blood volume. Randomised and non-randomised studies of terlipressin indicate that it reverses type 1 HRS in approximately 50% of patients.54–60 There are limited data on the role of terlipressin or other vasoconstrictors in type 2 HRS. The recommended doses are 1 mg/4–6 h iv bolus, with a dose increased up to a maximum of 2 mg/4–6 h after 2–3 days if there is no response to therapy as defined by a reduction of serum creatinine >25% of pre-treatment values. Complete response to therapy is considered when serum creatinine levels decrease below 1.5 mg/dl. Treatment response usually occurs within the first 7–10 days and is associated with a marked reduction in serum creatinine, increase in urine volume, increase in arterial pressure, and improvement of hyponatraemia. The incidence of ischaemic side effects during terlipressin therapy that are usually reversible after discontinuation of treatment is approximately 10%.58 59 The use of midodrine, octreotide and albumin as well as noradrenaline with albumin, may also improve renal function in patients with HRS.61–63 Unfortunately, there is limited information and there are no placebo-controlled studies in order to establish their efficacy in HRS. Current guidelines recommend the administration of terlipressin in combination with albumin as the first-line therapeutic agent for type 1 HRS.30

TIPS may improve renal function in HRS, but its applicability in patients with type 1 HRS and advanced liver disease is limited.64 Due to the lack of data, more studies are needed which evaluate the use of TIPS in patients with HRS. Renal replacement therapy is not considered a standard therapy of HRS, but it may serve as a temporary option in patients with no response to vasoconstrictors or in those that develop severe volume overload, metabolic acidosis or refractory hyperkalaemia. The use of the molecular readsorbent recirculating system (MARS), an alternative of dialysis that clears albumin-bound substances, including vasodilators, is currently being investigated and more data are needed in order to consider it as a therapeutic tool for HRS.65 The results of a recent study using another extracorporeal liver support system, Prometheus, suggests that this system may improve survival in patients with type 1 HRS;66 however, these results require confirmation in larger studies.

OLT is the optimal treatment for suitable candidates with HRS. However, patients with type-1 HRS have a high mortality while on the waiting list. Thus these patients should be given a high priority on the list. Although there are limited data, pharmacological treatment of HRS before transplantation may improve outcome after transplantation. In patients who respond to therapy with a fall in serum creatinine values, the subsequent decrease in the MELD score should not change the decision to perform liver transplantation since the prognosis after recovering from type-1 HRS is still poor. Since treatment with cyclosporine and tacrolimus may contribute to renal impairment postoperatively, these drugs should be held for a few days before their introduction until renal function is within normal limits. Steroids, mycophenolate mofetil and interleukin-2 (IL-2) receptor antibodies (ie, basilximab, daclizumab) should preferably be used until diuresis and improvement of renal function is observed, usually 5–7 days after transplantation.

Simultaneous liver kidney transplantation (SLK) has been advocated for patients with HRS, but current criteria for SLK include established end-stage renal disease under dialysis, GFR <30 ml/min and proteinuria >3 g/day with a 24 h urine protein/creatinine ratio >3, and/or acute kidney injury and a requirement for dialysis at least twice a week for more than 6 weeks.67 By definition, patients with HRS do not meet these criteria. Centres that have performed SLK for patients with HRS do not report a better outcome than that of patients with HRS treated with liver transplantation alone.67 Therefore since this approach may divert kidneys from patients with chronic kidney disease that are listed for kidney transplantation and renal function in HRS patients usually recovers after liver transplantation alone, SLK is not routinely recommended as a management strategy for patients with HRS. The only exception may be that of patients with HRS who have been on dialysis for more than 6 weeks.

## Bacterial infections and spontaneous bacterial peritonitis

Active bacterial infection is considered a relative contraindication for OLT, thus the prompt identification and therapy of any suspected infectious disease will ensure that patients will not progress to a severe infection and only require temporary withdrawal from the list. Bacterial infections in patients with cirrhosis occur at admission or during hospitalisation in 20–60% of patients.48 68–70 Of these, most are secondary to SBP (30%), other common causes are urinary tract infection, pneumonia and bacteraemia secondary to invasive procedures.48 68 When considering all types of infections in patients with cirrhosis 54% will have positive cultures and, of these, 44% are community acquired and 72% are nosocomial. Among all these patients nearly 50% are due to Gram-negative bacteria and 48% due to aerobic Gram-positive bacteria.69

The prevalence of SBP in hospitalised cirrhotic patients is approximately 10–30%.48 68 70 The 1-year survival probability after an episode is only 40%. Thus patients should be evaluated for OLT once they are cured. The clinical spectrum of SBP is variable and ranges from no symptoms to fever, chills, abdominal pain, HE, severe peritonitis, shock, worsening liver failure and/or the development of type 1 HRS. The diagnosis of SBP relies on the examination of peritoneal fluid. The diagnosis is made when the PMN count is greater than 250/mm3.27–30 70 Due to the high prevalence of SBP in patients with ascites, diagnostic paracentesis should be performed routinely in all cirrhotic patients admitted to the hospital with ascites including those on the waiting list for OLT and in hospitalised patients with systemic or local signs suggestive of SBP (ie, fever, leucocytosis, shock, abdominal pain, rebound tenderness, ileus), HE or renal failure.

### Management of spontaneous bacterial peritonitis

Once the diagnosis is secured, empiric antibiotic therapy is started with an intravenous third-generation cephalosporin (cefotaxime 2 g every 8–12 h; ceftriaxone 1 g/24 h) for at least 5–7 days.27–30 70 It is recommended patients have a repeat tap 2 days after to ensure a decrease in neutrophil count by at least 25% of the pre-treatment value. If it fails to decrease, antibiotic resistance should be suspected and modification in therapy be implemented.30 Antibiotics are changed depending on results from cultures. Response to therapy should be monitored by clinical signs, white blood count and PMN count in the ascitic fluid. Therapy can be stopped when clinical signs of infection have disappeared and the PMN count in the ascitic fluid has normalised. Given the high prevalence of nosocomial infections in patients with cirrhosis (including those on the waiting list), the current empirical therapeutic approach may need to be altered in such patients. For instance, response to empirical therapy with third generation cephalosporins in community acquired SBP is 76% whereas it is only 26% for those with noscomial SBP.69 The main reason for these findings is the emergence of multiresistant bacteria mainly extended spectrum β-lactamase bacteria, Pseudomona aeruginiosa, and methicillin resistant Staphylococcus aureus. Thus in patients with nosocomial infections and according to every hospital's data on resistant bacteria, empirical therapy should include antibiotics that cover such microorganisms.

The most important predictor of survival in patients with SBP is the development of renal failure during the infection.49 71 Administration of albumin at a dose of 1.5 g/kg at the diagnosis and 1 g/kg 48 h later prevents HRS and reduces mortality from 30% to 10%.49 Since recurrence of SBP occurs in 70% of cases and constitutes a major cause of death in these patients, prophylaxis is recommended, particularly for listed patients.30 70 Because many cases are caused by Gram-negative bacteria from the intestinal flora, quinolones such as norfloxacin (400 mg/day) or ciprofloxacin (750 g/week) have been used with good results.72 73 That said, patients while on the list may develop resistant Gram-negative bacteria to quinolones and develop SBP. In such cases quinolone prophylaxis should probably be discontinued, but there are no data to support this.

There are two conditions associated with an increased risk of the first episode of SBP where primary prophylaxis is recommended. The first is in patients with gastrointestinal haemorrhage. Multiple studies have shown that short-term (7 days) administration of oral norfloxacin 400 mg twice a day or intravenous ceftriaxone 1 g/day reduces the incidence of SBP, bacteraemia and re-bleeding.74–76 The second is in patients with advanced cirrhosis (serum creatinine >1.2 mg/dl, a Child–Pugh score >9, and/or serum sodium <130 meq/l and ascitic fluid protein levels <15 g/l). These patients benefit from norfloxacin (400 mg/day) as it not only reduces the probability of developing SBP but also reduces the risk of developing HRS and improves survival.51 Recommendations for the management of SBP are outlined in box 3.

Box 3

### Box 3 Recommendations for the management of spontaneous bacterial peritonitis in patients awaiting liver transplantation

1. After diagnosis start with third-generation cephalosporins (ie, cefotaxime 2 g/8–12 h intravenously or ceftriaxone 1 g/24 h intravenously). In nosocomial spontaneous bacterial peritonitis, consider the addition of an antibiotic active against Gram-positive cocci and/or multiresistant bacteria.

2. Give albumin 1.5 g/kg intravenously at the time of diagnosis of the infection and 1 g/kg 48 h later.

3. A repeat diagnostic tap 2 days after the start of treatment may help guide the antibiotic therapy.

4. Maintain antibiotic therapy until disappearance of signs of infection and reduction of polymorphonuclear cells in ascitic fluid below 250 mm3.

5. After resolution of infection, start long-term oral norfloxacin 400 mg/day.

## Hepatic encephalopathy

Hepatic encephalopathy is a complex neuropsychiatric syndrome that frequently occurs in patients with advanced cirrhosis. The diagnosis is clinical and confirmed after excluding other causes of changes in mental status. Patients with cirrhosis may exhibit episodic, persistent or minimal features of HE.77 Episodic HE is defined as a disturbance of consciousness and a change in cognition in non-demented patients. Episodic HE is sub-divided into precipitated and spontaneous episodes.77 Precipitating factors include: gastrointestinal haemorrhage, uraemia, use of psychoactive medication or of diuretics increasing renal ammonia release, infection, excessive dietary protein consumption, constipation, dehydration, hypo- or hyperkalaemia, and hyponatraemia. Persistent HE includes cognitive deficits that impact negatively on social and occupational functioning. Minimal HE (MHE) occurs when patients do not have any recognisable clinical symptoms of brain dysfunction; however, it is currently considered that securing the diagnosis of MHE requires specialised testing.78 The diagnosis of HE is usually based on clinical findings. Brain imaging (magnetic resonance, computed tomography, positron emission tomography) is not required for establishing the diagnosis, yet in selected cases it may be helpful in excluding other conditions.78 79

### Management

The mainstay of therapy is based on supportive care, identification and removal of precipitating factors, reduction of nitrogenous load from the gut and assessment of long-term therapy. Patients with overt hepatic encephalopathy need to be admitted to the hospital; the majority can be transferred to a regular ward, but those who are comatose need to be admitted to a monitored unit and airway protection should be performed. Common precipitating factors (see above) should be sought and corrected if possible. Protein restriction is not recommended. A normal protein diet is safe and, in fact, nutritionally better for patients with HE.80 Synthetic disaccharides (lactulose and lactitol) are currently the mainstay of therapy of hepatic encephalopathy. For acute encephalopathy if patients are awake, oral lactulose or lactitol are the first-line pharmacological treatment.78 81 82 The recommended dose is 15–45 ml orally every 6–8 h adjusted to achieve two to three soft bowel movements; diarrhoea must be avoided. Lactulose or lactitol enemas (colonic cleansing) are very useful in patients who cannot tolerate the oral route. Antibiotics are considered for those who cannot tolerate or are resistant to disaccharides. Several oral antibiotics have been used, such as neomycin, metronidazol and vancomycin; nonetheless, there is lack of strong evidence indicating their effectiveness for the treatment of HE.81 83 Rifaximin is a luminal antibiotic with activity against Gram-negative, Gram-positive and anaerobic organisms.84 85 Since it can modulate gut flora, rifaximin is an attractive treatment for the prevention of HE. In a recent large randomised controlled trial, patients with cirrhosis with a MELD score < 25 who had recovered from an acute episode of HE and were on lactulose received rifaximin or placebo for 6 months.86 Compared to placebo, rifaximin (1100 mg/day) reduced the time to the first episode of HE and also the time to the first HE-related hospitalisation. The medication was well tolerated and the incidences of adverse events were similar in the rifaximin group and the placebo group.86 The available data on rifaximin indicate that it has a protective effect against recurrent episodes of HE and thus should always be considered in patients with previous episodes of HE on the liver transplantation list. There are no data on the use of rifaximin in patients receiving norfloxacin as prophylaxis for SBP.

## Variceal bleeding

When cirrhosis is diagnosed, varices are present in about 30–40% of compensated patients and in 80% of those with decompensated cirrhosis;87 88 these figures are similar to what is seen in cirrhotic patients on the waiting list.89 Patients awaiting OLT must have an upper endoscopy performed to rule out varices. Mortality rates have decreased in the last three decades but are still around 15–20% 6 weeks after the index bleed.90 Poor prognostic factors are active bleeding at the time of endoscopy, bacterial infection, portal vein thrombosis, and a hepatic venous pressure gradient (HVPG) greater than 20 mm Hg early after admission.91–95 Re-bleeding within the first 6 weeks ranges from 30% to 40%, with nearly half of these occurring within the first week of the index bleed.87

### Management

#### Primary prophylaxis

If small varices are present in patients with a high risk of bleeding (ie, Child B or C cirrhosis or the presence of red wale marks) patients should receive ongoing therapy with non-selective beta-blockers (ie, propranolol or nadolol). These drugs decrease portal pressure by blocking β1 receptors with a reduction in cardiac output and β2 receptors causing constriction of the splanchnic vascular bed. Patients with medium- or large-sized varices should be initially treated with non-selective beta-blockers if there are no contraindications or endoscopic variceal ligation. The choice of beta-blockers or endoscopic therapy should be made depending on the local resources, availability of experienced endoscopists, patient preference, side effects and contraindications.96–98 Propranolol is typically started at 20 mg bid and nadolol at 40 mg qd.88 96 These drugs are given in a stepwise fashion, increasing the dose until it is maximally tolerated or the resting heart rate is between 50 and 60 beats/min. Variceal ligation is performed every 3–4 weeks until eradication which typically occurs after two to four sessions. The limited data in the group of patients awaiting liver transplantation indicate that both methods are effective.99 Meta-analyses of randomised controlled trials of beta-blockers versus band ligation indicate that ligation is associated with a lower incidence of first variceal haemorrhage without differences in mortality.98 100 Nonetheless, endoscopic ligation requires several sessions and may be associated with important side effects such as bleeding from post-ligation ulcers. Thus a reasonable approach is to begin with beta-blockers if there are no contraindications because they are inexpensive, easy to use and relatively safe.88 Those patients who develop side effects or have contraindications to beta-blockers should be offered endoscopic variceal band ligation. The recommendations for primary prophylaxis of variceal bleeding are outlined in box 4.

Box 4

### Box 4 Recommendations for primary and secondary prophylaxis of variceal bleeding in patients with cirrhosis awaiting liver transplantation

Primary prophylaxis

• Screen all patients on the waiting list with upper endoscopy.

• No varices: No therapy indicated. But if the patients remain on the list, a repeat endoscopy should be performed in 1 year.

• Small varices: Consider non-selective beta-blockers (propranolol or nadolol) in patients with Child B/C cirrhosis.

• Medium/large varices: Beta-blockers or endoscopic band ligation may be used.

Secondary prophylaxis

• Non-selective beta-blockers plus endoscopic band ligation should be used for prevention of recurrent bleeding.

• Endoscopic band ligation should be done every 3–4 weeks until obliteration (approx. three to four sessions). Surveillance endoscopy should be done 3 months after obliteration.

• If previously on beta-blockers for primary prophylaxis, band ligation should be added to drug treatment. Those previously treated with band ligation and with no contraindication to beta-blockers should receive them.

• TIPS is indicated in Child A or B patients who re-bleed despite combination therapy.

#### Active bleeding

Active bleeding from varices is a medical emergency and its management should be performed in an intensive care setting by a team of experienced hepatologists/gastroenterologists, endoscopists, critical-care specialists and nurses. Initial therapy is aimed at resuscitating the patient. In addition, other primary goals include obtaining haemostasis and preventing infection which increases the risk of re-bleeding. The airway needs to be assessed and the decision of protecting the airway by means of intubation should be made in patients with severe HE or those actively vomiting blood. Volume resuscitation should be instituted in order to keep haemodynamic stability.97 Avoidance of shock prevents renal failure which is associated with an increased risk of death.101 On the other hand, over-transfusion should be avoided since it may induce rebound increases in portal pressure and re-bleeding. Blood transfusions should aim for a haemoglobin level of 7–8 g/l.97 Bacterial infections in variceal bleeding are associated with a poor prognosis. Early administration of prophylactic antibiotics after admission is recommended and this measure has been shown to improve survival.74 75 Norfloxacin 400 mg p.o. twice daily for 7 days should be given in patients without shock and with moderately advanced cirrhosis; however, patients with ascites, malnutrition, encephalopathy or bilirubin >3 mg/dl should receive intravenous ceftriaxone (1 g/day) as it is more effective than oral norfloxacin.76 Since most patients on the waiting list have poor liver function, intravenous cephalosporins appear to be the best choice for antibiotic prophylaxis in this group.

Specific haemostatic treatments for variceal bleeding include vasoactive drugs that decrease portal pressure plus endoscopic band ligation or sclerotherapy, and rescue therapy such as TIPS. Pharmacotherapy must be started as soon as possible and before endoscopy. If available, terlipressin (2 mg/4 h for the first 48 h, then 1 mg/4 h for up to 5 days) should be the first choice, as it is superior to placebo in reducing mortality.102 103 This medication controls variceal bleeding in 75–80% of cases in 2 days and around 70% at 5 days.103 Somatostatin (bolus of 250 mg, followed by an infusion of 250 mg/h for 5 days) or octreotide (50–100 μg bolus followed by 50 μg/h for 5 days) are good options if terlipressin is not available.104 105 Endoscopy is one of the cornerstones of management as it confirms the diagnosis and allows therapy during the same session. The two endoscopic methods available for variceal bleeding are endoscopic sclerotherapy and band ligation; however, the latter method is preferred due to fewer side effects.106 Endoscopic therapy should be instituted as early as possible and within 12 h of the index bleed.88 97 106 The recommended combination treatment for acute variceal bleeding is early administration of a vasoconstrictor (to be continued for up to 5 days) plus therapeutic endoscopy. This approach controls bleeding in 85–90% of cases.88 97 106

If the patient has a recurrent bleeding episode, a single endoscopic re-treatment is reasonable if the patient is stable. That said, a recent study has shown that the early placement of TIPS (within 72 h) for patients with Child B or C cirrhosis (<13 points) with active bleeding is associated with a significant reduction in re-bleeding and mortality and should be considered in such cases,107 however the results of this study need to be confirmed in larger series of patients. If bleeding cannot be controlled by endoscopy or there is severe recurrent bleeding, oesophageal balloon tamponade may temporarily aid in controlling the haemorrhage; however, it has a high incidence of re-bleeding when the balloon is deflated and may cause pressure necrosis of the oesophageal mucosa with prolonged use.108 TIPS after balloon tamponade is effective with control rates around 90–95%, but since these patients are very sick mortality rates remain high.109–111 TIPS is preferred over shunt surgery because it is associated with less operative morbidity and mortality.111 Moreover, in patients awaiting liver transplantation, TIPS appears to be a better option than surgery.112

#### Secondary prophylaxis

After patients have bled, the risk of a repeat episode is around 60% at 1 year and mortality from each re-bleeding episode is near 20%.87 Both beta-blockade plus endoscopic band ligation should be used. A large meta-analysis (1860 patients in 23 trials) that evaluated the role of combination therapy versus either therapy alone in preventing the re-bleeding revealed that combination therapy reduced overall re-bleeding at higher rate than endoscopic therapy or beta-blocker therapy alone without any difference in survival.113 Current guidelines recommend combination therapy with endoscopic variceal ligation plus non-selective beta-blockers for the prevention of recurrent variceal haemorrhage.96 97 Those patients with recurrent bleeding despite the above measures should be offered TIPS.

#### Gastric varices

These varices may be present as a prolongation of oesophageal varices or be isolated in the fundus, body or antrum. They occur in nearly 20% of patients with cirrhosis. Bleeding episodes from gastric varices are usually severe and difficult to control. Endoscopic injection of N-butyl-2-cyanoacrylate glue is one of the cornerstones of therapy as this measure is effective in over 90–95% of patients presenting with acute bleeding from gastric varices.114 Patients that cannot be controlled by this measure require TIPS.

## Summary

The demand for OLT continues to be on the rise with patients spending a long time on the waiting list; this not only increases the risk of developing further decompensation but also mortality. The complications discussed above may not only lead to removal from the waiting list in some cases but also a poorer outcome following transplantation. Therefore the appropriate prevention, recognition and treatment of the above-mentioned complications of cirrhosis will have a positive impact on the outcome before and after liver transplantation.

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## Footnotes

• Funding Part of the research reported in this article was funded by grants EC 07/ 90077 and FIS PI080126 from the Instituto de Salud Carlos III. CIBERHED is funded by the Instituto de Salud Carlos III.

• Competing interests AC is a consultant for Otsuka Pharmaceuticals and has been a consultant for Orphan Therapeutics and GlaxoSmithKline. PG has been a consultant for Otsuka Pharmaceuticals and Orphan Therapeutics.

• Provenance and peer review Commissioned; externally peer reviewed.