Management of Pre-Liver Transplantation Patient
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CAQ CORNER
Management of Pre – Liver Transplantation Patient—
Part 2
Pratima Sharma1 and Jorge Rakela2
Liver transplantation (LT) has grown dramatically over blockade averages less than 50% and the maximum
last 2 decades and the hepatologist has had to assume a benefit is seen in patients with Child-Turcotte-Pugh A
larger role in managing the potential candidate awaiting and B cirrhosis. More than 30% of patients have no
surgery. In part 1 of this review, we described the decrease in portal pressure despite adequate  block-
pre-LT evaluation process, contraindications of LT, ade.10 The addition of long-acting nitrates to nonselec-
general care, and treatment of various etiologies of liver tive -blockers has been shown to enhance their hemo-
disease prior to LT. In this part, we review the manage- dynamic effect and reduce the risk of bleeding from
ment of liver-specific complications that are responsible esophageal varices and therefore should be considered
for significant morbidity and waitlist mortality of LT in patients who do not respond ideally to -blockers.11
candidates. Poorer results compared with pharmacotherapy have
led to the discontinuation of endoscopic variceal scle-
rotherapy as primary prophylaxis for variceal bleed-
Liver-Specific Complications ing.12 – 14 Sarin et al.15 showed that endoscopic variceal
Portal Hypertension band ligation is safer and more effective than propran-
olol for the primary prevention of variceal bleeding.
Portal hypertension is the main complication of liver
However, in a recent randomized controlled multi-
cirrhosis. This syndrome develops in the majority of
center trial that evaluated primary prophylaxis of
patients with cirrhosis and is responsible for most life-
variceal bleeding, variceal band ligation and proprano-
threatening complications of cirrhosis, including gas-
trointestinal bleeding from ruptured gastroesophageal lol were similarly effective.16 Despite effectiveness in
varices, hepatorenal syndrome, and hepatic encepha- the arrest of bleeding, TIPS cannot be recommended as
lopathy. a 1st-line approach to manage variceal bleeding or for
primary prophylaxis because of increase incidence of
Prophylaxis of Esophageal Variceal Bleeding hepatic encephalopathy and expense related to the
The average lifetime risk of variceal bleeding in patients management of TIPS malfunction.17,18
with cirrhosis who have had no previous bleeding is Gastric Variceal Bleeding
30%.1 Each bleeding episode bears a mortality risk of
30 to 50%.2 In prospective studies, advanced Child- No specific measures are available to prevent 1st bleed-
Turcotte-Pugh stage, large esophageal varices, and red ing from gastric varices. Most of the current regimens to
wale markings are independent risk factors for 1st treat gastric varices are derived from anecdotal evidence
variceal bleed.3 – 5 The modalities available for primary
prophylaxis are nonselective -blockers, endoscopic
Abbreviations: LT, liver transplantation; HRS, hepatorenal syn-
therapy, and transjugular intrahepatic portosystemic drome; HPS, hepatopulmonary syndrome; HE, hepatic encephalop-
shunt (TIPS). Nonselective -blockers decrease portal athy; PPH, portopulmonary hypertension; SBP, spontaneous bacte-
pressure and collateral flow through a combination rial peritonitis; PAP, pulmonary artery pressure; TIPS, transjugular
of decreased cardiac output and unopposed alpha- intrahepatic portosystemic shunt.
From the 1Department of Medicine, Emory University Hospital,
mediated splanchnic vasoconstriction, resulting in
Atlanta, GA, and the 2Department of Internal Medicine, Mayo Clinic,
decreased effective splanchnic blood flow, thereby Scottsdale, AZ.
reducing the risk of initial variceal bleeding and a trend Address reprint requests to Pratima Sharma, MD, Assistant Profes-
toward decreased mortality.6 – 8 -blockers should be sor, Emory University Hospital, 1364, Clifton Road, Box 7, Atlanta, GA
considered in all patients with large varices and red 30322. Telephone: 404 712 5454; FAX: 404 712 4621; E-mail:
pratima_sharma@emoryhealthcare.org
markings.7 Propranolol or nadolol can be used and the
Copyright © 2005 by the American Association for the Study of
dose should be titrated weekly to decrease the resting Liver Diseases
heart rate by 25% and the systolic blood pressure to no Published online in Wiley InterScience (www.interscience.wiley.com).
lower than 90 mm of Hg.9 The risk reduction with  DOI 10.1002/lt.20379
Liver Transplantation, Vol 11, No 3 (March), 2005: pp 249 – 260 249250 Sharma and Rakela
or are extrapolated from trials of esophageal varices.14,19 terlipressin for controlling bleeding. The side effects
TIPS is very effective with a success rate of 90% for were less frequent and less severe with octreotide than
initial hemostasis. The rate of early rebleeding after with either vasopressin or terlipressin. However, the
TIPS procedure is 20% and often the source of such efficacy of octreotide as a single therapy is controversial.
bleeding is nonvariceal, i.e., ulcer secondary to banding Results from a recent meta-analysis suggest that oct-
or sclerosis.18 reotide may improve the results of endoscopic therapy
but has no or little effect if used alone.19
Treatment of Acute Variceal Bleeding Endoscopic sclerotherapy controls active hemor-
Patients suspected of acute variceal bleeding should be rhage in 80 to 90% of patients. However, a skilled
managed in the intensive care setting. General princi- endoscopist must be readily available, and the proce-
ples of resuscitation should be followed, which include dure is associated with serious complications in 10 to
protection of airway, insertion of 2 large-bore intrave- 20% of patients, with an overall mortality of 2%.19 The
nous cannulas, blood volume resuscitation with packed combination of sclerotherapy with somatostatin, oct-
erythrocytes, correction of coagulopathy with fresh fro- reotide, and vapreotide has been reported to be superior
zen plasma, and platelet transfusion if they are below to sclerotherapy alone in terms of control of bleeding
30,000/mm3. Care must be taken not to overexpand and reduction of treatment failures within 5 days.23,24
plasma volume, which may increase portal pressure and The 6-week survival of the combination of sclerother-
result in exacerbation of variceal bleeding and ascites. apy and drugs was similar to sclerotherapy alone.
Antibiotics should be administered prophylactically, Variceal band ligation was shown to be better than
especially in patients with ascites, to prevent spontane- endoscopic sclerotherapy in controlling the acute bleed
and mortality.25 The banding may be more challenging
ous bacterial peritonitis.20,21 Emergency endoscopy of
during active bleeding due to reduction in the field of
the upper gastrointestinal tract can then be performed
vision by as much as 30% with the addition of banding
and the most appropriate treatment modality should be
device to the endoscope. The choice of procedure
chosen at that point. The drug classes that have been
depends on the available expertise in the center manag-
extensively studied in acute variceal bleeding are vaso-
ing the patient; variceal banding has become the proce-
pressin and somatostatin and their analogs. Both soma-
dure of choice in the management of variceal bleeding.
tostatin and vasopressin arrest variceal bleeding by caus-
Balloon tamponade is a useful temporary measure to
ing splanchnic vasoconstriction and thereby decreasing
control acute variceal bleeding and to stabilize the
the portal pressure, but this has no effect on mortality.19
patient while more definitive procedures are being
There is an increased association between myocardial accomplished. Control of bleeding is successful in as
infarction and arrhythmias and the use of vasopressin. many as 80 to 90% of cases, but rebleeding occurs in up
Furthermore, bowel ischemia, cerebrovascular isch- to 50% when the balloon(s) are deflated. Furthermore,
emia, and peripheral tissue necrosis have been reported. significant perforation risk is present that may lead to
The severity of complications such as myocardial isch- high mortality if the balloons are inflated for prolonged
emia has led to discontinuation of the use of vasopres- periods of time.7
sin.14 Rebleeding is a very common and usually occurs
Terlipressin is a longer acting analog of vasopressin within 6 weeks of the index episode. The recurrence
and can be given as bolus-infusion every 4 hours. Its reported as high as 70% in patients who have had at
efficacy is similar to vasopressin in controlling the acute least 1 prior bleeding episode.21 The use of -blockers
variceal bleeding and is associated with fewer side (with and without variceal band ligation) is the most
effects.22 The ease of administration has allowed for accepted approach to manage these patients. There is
paramedic administration in the field with arrest of still debate about the cost-effectiveness of this pharma-
bleeding prior to arrival at the hospital. Terlipressin is cological approach combined with endoscopy.
not yet approved for use in the United States. In approximately 10% of patients in whom rebleed-
Somatostatin is superior to vasopressin for immedi- ing cannot be controlled with 2 endoscopic therapeutic
ate control of bleeding and has less severe side effects sessions within 24 hours, either surgery or TIPS should
than vasopressin, although survival improvement has be planned. At the most recent American Association
not been seen with somatostatin.19 for the Study of Liver Diseases meeting, Henderson et
Octreotide is a synthetic analog of somatostatin. al.26 presented the 1st analysis of the multicenter study
When compared with other vasoactive drugs, oct- of distal splenorenal shunt vs. TIPS for refractory
reotide was better than vasopressin and equivalent to variceal bleeding. This study found that both modali-Pre – LT Patient Management—Part 2 251
ties were equally effective in preventing rebleeding, and maximum of 400 mg/day / 160mg/day, if weight loss
encephalopathy and survival were similar. TIPS can be and natriuresis are inadequate on lower doses. In gen-
used in patients with Child-Turcotte-Pugh class B or C eral, this ratio maintains normokalemia. Furosemide
cirrhosis as a salvage therapy and preferably as a bridge can be temporarily withheld in patients presenting with
to transplant.18 Worsening of hepatic encephalopathy hypokalemia. Single morning dosing tends to increase
after TIPS procedure may impair the outcome com- compliance and is recommended. The antiandrogenic
pared to Child-Turcotte-Pugh A patients. effects of spironolactone, such as decreased libido,
impotence, and gynecomastia in men may require dose
Ascites reduction or discontinuation of the medicine. Amilo-
Ascites is the most common major complication of ride can be substituted for spironolactone, but it is more
portal hypertension. The initial evaluation of a patient expensive and has been shown to be less effective in a
with ascites should include a history, physical evalua- randomized control trial.
tion, and abdominal paracentesis with ascitic fluid anal- The etiology of nocturnal muscle cramps is not well
ysis. Bleeding is sufficiently uncommon so as to obviate understood and may respond to magnesium supple-
the routine requirement for fresh frozen plasma or mentation or the oral administration of quinine sulfate
platelets prior to a diagnostic paracentesis.27 The initial at a dose of 325 mg in the evening. Serum sodium less
ascitic fluid analysis should include a cell count and than 120 mmol/day despite fluid restriction and serum
differential and serum-ascites albumin gradient. The creatinine ⬎2.0 mg/dL should result in the cessation of
culture yield increases to 80% when ascitic fluid with a diuretic therapy, reassessment of the situation and con-
polymorphonuclear count ⬎250 cells/mm3 is inocu- sideration of 2nd-line options. These patients should be
monitored for daily weight, orthostatic symptoms, and
lated directly into blood culture bottles at the bed-
periodic serum electrolytes, blood urea nitrogen, and
side.5,28,29
creatinine. Random urine sodium concentration is
The mainstay of treatment of patients with ascites
measured if the weight loss is not adequate. The fre-
includes education regarding dietary sodium restriction
quency of follow-up is determined by response to treat-
(2,000 mg/day or 88 mmol/day) and oral diuretic ther-
ment and by patient stability.
apy30 that has been shown to be effective in 90% of
Refractory ascites is defined as ascites that is not
patients.31 Chronic hyponatremia is commonly seen in
responsive to sodium-restricted diet and high-dose
cirrhotic patients and is seldom morbid, although
diuretic treatment in the absence of prostaglandin
recent data has shown that hyponatremia is an indepen-
inhibitors such as nonsteroidal antiinflammatory
dent risk factor for death while awaiting LT.32 Rapid drugs.30,36 Serial therapeutic paracentesis are effective
attempts to correct hyponatremia can lead to more in controlling ascites. Serial therapeutic paracentesis
complications, such as central pontine myelinolysis, should be performed as needed, approximately every 2
than hyponatremia itself, although severe hyponatre- weeks. The postparacentesis albumin infusion is expen-
mia will increase the risk of posttransplant neurological sive and unproven to be necessary for paracentesis of
complications.33 Severe hyponatremia (serum sodium ⬍5 L. For larger volume paracentesis, an albumin infu-
⬍120 mmol/L) requires fluid restriction in cirrhotic sion of 5 – 8 g/L of ascitic fluid removed can be consid-
patients with ascites. Cirrhotic patients do not usually ered.30
have symptoms from hyponatremia until their sodium LeVeen or Denver shunts were popularized in the
levels fall below 110 mmol/L, or unless the decline in 1970s as a physiologic treatment of ascites. Shunt place-
sodium is very rapid. Recently, Gerbes et al.,34 showed ment has been shown in controlled trials to decrease the
that VPA-985, an orally active vasopressin 2 receptor duration of hospitalization, the number of hospitaliza-
antagonist, can correct severe hyponatremia in patients tions and the dose of diuretics.37,38 However, their poor
with cirrhosis and ascites,34 its clinical utility remains to long-term patency, significant complication profile,
be determined and lack of survival advantage compared with medical
The usual diuretic therapy consists of single morn- therapy in controlled trials have led to near abandon-
ing doses of oral spironolactone and furosemide, begin- ment of these devices.38 Shunt-related fibrous adhe-
ning with 100 and 40 mg, respectively.30 Single-agent sions can make subsequent LT difficult.39
furosemide has been shown to be less efficacious than TIPS is physiologically equivalent to a side-to-side
spironolactone in a randomized controlled trial.35 The portocaval shunt that is placed by an interventional
dose of both oral diuretics can be increased simulta- radiologist.40 Five randomized trials41 – 45 comparing
neously, maintaining the 100 mg / 40 mg ratio, with a TIPS and large volume paracentesis have demonstrated252 Sharma and Rakela
that TIPS is effective in minimizing ascites and in symptoms of infection should also receive empiric anti-
reducing the need for paracentesis. However, whether biotic therapy.30,46
the TIPS procedure improved survival of the patients Oral ofloxacin has been reported in a randomized
with cirrhosis and refractory ascites is still debated; the controlled trial to be as effective as parenteral cefo-
trials have reported the discordant results of the effect of taxime in the treatment of SBP in patients who are not
TIPS on survival. Rossle et al.42 and Salerno et al.43 vomiting and are not in shock.49 Repeat paracentesis
showed that TIPS was independently associated sur- should be performed to document cultures sterility and
vival without LT. Salerno et al.43 observed the relative decrease in polymorphonuclear cell count in patients
risk of dying was 2.95 times greater in patients assigned with SBP; this step is particularly important in cases in
to the paracentesis group, according to the multivariate which clinical improvement is not apparent after the 1st
analysis. The results from the North American Study 3 days of antibiotic therapy.50
for the Treatment of Refractory Ascites41 and a ran- Short-term inpatient quinolone should be consid-
domized trial from the University of Barcelona, Spain44 ered in the prevention of bacterial infections in patients
showed that TIPS is substantially superior to conven- with low protein (⬍1 gm/dL) ascites, variceal hemor-
tional medical therapy but does not improve the sur- rhage, and prior SBP. Long-term outpatient antibiotic
vival or quality of life. The reasons why randomized use can probably be reserved for patients who have
trials have not demonstrated a survival benefit are survived an SBP infection.30,50
unclear. However, the Child-Turcotte-Pugh class or its Hepatic Encephalopathy
component was similar among the trials. Factors asso-
ciated with increased mortality after TIPS include Hepatic encephalopathy (HE) is a complex neuropsy-
Child-Turcotte-Pugh class C, renal insufficiency, chiatric syndrome that may complicate acute or chronic
liver failure. It is characterized by changes in mental
hyperbilirubinemia, marked coagulopathy, and
state, including a wide range of neuropsychiatric symp-
advanced age.45 Before recommending TIPS to LT can-
toms ranging from minor signs of altered brain function
didates, the risks and benefits should be carefully
to deep coma.
assessed to avoid a potentially catastrophic outcome.
Most theories explaining the pathogenesis of HE
Spontaneous Bacterial Peritonitis accept that nitrogenous substances derived from the gut
adversely affect brain function. These compounds gain
Spontaneous bacterial peritonitis (SBP) is a particularly
access to the systemic circulation as a result of decreased
important complication because the presence of infec-
hepatic function or portosystemic shunts and may pro-
tion usually removes a patient from consideration of
duce alterations of neurotransmission that affect con-
transplantation until the infection is cleared. A diagnos- sciousness and behavior.51 Abnormalities in glutamin-
tic abdominal paracentesis must be performed and the ergic, serotoninergic and gamma-aminobutyric
ascitic fluid must be analyzed for cell count and bacte- acidergic, and catecholamine pathways, among others,
rial culture before a confident diagnosis of ascitic fluid have been described in experimental HE.51 A large body
infection is made. The diagnosis of SBP is made when of work points towards ammonia as a key factor in the
there are ⬎250 polymorphonuclear cells per milliliter pathogenesis of HE.52
and / or positive ascitic fluid bacterial culture without The approach to HE has not changed significantly
an evident intraabdominal or surgically correctable in recent years. HE is a diagnosis of exclusion and is
source.46 These patients should receive empiric treat- mainly clinical. The suspicion of HE in patients with
ment with broad-spectrum antibiotics. Delaying treat- chronic liver disease should prompt the search for the
ment until the ascitic fluid culture grows bacteria may precipitating factors that include gastrointestinal bleed-
result in the patients’ death from overwhelming infec- ing, electrolyte abnormalities, renal failure, infection,
tion. Cefotaxime, a 3rd generation cephalosporin, has recent placement of TIPS shunt,53 use of sedatives /
been shown to be superior to ampicillin in combination hypnotics, development of hepatocellular carcinoma,
with tobramycin in a controlled trial.47 In a randomized and constipation. However, the other causes of change
controlled trial involving 100 patients, it has been in mental status such as intracranial bleed or masses,
reported that 5 days of treatment is as efficacious as 10 hypoglycemia, and a postictal state should be ruled out.
days of treatment in the treatment of carefully charac- Although hyperammonemia is associated with HE,
terized patients with SBP.48 Patients with less than 250 ammonia levels do not correlate with the level of
polymorphonuclear cells in ascitic fluid and signs or encephalopathy.54Pre – LT Patient Management—Part 2 253
The treatment goals for HE are provision of sup- liver. Strategies to stimulate residual urea cycle activities
portive care, identification and removal of precipitating and / or glutamine synthesis have been tried over the
factors, and reducing the production and absorption of last 20 years. One of the most successful agents to be
nitrogenous load from the gut. Ultimately, assessment used so far is L-ornithine L-aspartate. Randomized con-
of the need for long-term therapy is very important. trolled clinical trials with L-ornithine L-aspartate dem-
There is no good clinical evidence supporting pro- onstrate significant ammonia lowering and concomi-
tein restriction in patients with acute hepatic encepha- tant improvement in psychometric testing.60
lopathy. The only randomized trial, reported only in Benzoate is also effective in reducing blood ammo-
abstract form, found no difference between moderate nia both in patients with inherited urea cycle disorders
(.8 gm/kg per day) and more aggressive protein restric- and in cirrhotic patients. In a randomized controlled
tion.51 Zinc, a cofactor of urea cycle enzymes, may be clinical trial with sodium benzoate vs. lactulose,
deficient in cirrhotic patients, especially if associated improvement in neuropsychiatric performance was
with malnutrition. Zinc supplementation improves the found to be comparable.61
activity of the urea cycle in experimental models of Several controlled clinical trials have been per-
cirrhosis.55 One trial has evaluated the effects of zinc formed to assess the efficacy of the benzodiazepine
over a short period (up to a week), without major receptor antagonist flumazenil in cirrhotic patients with
improvement. Another nonrandomized study reported various degree of severity of HE.62 Spectacular
positive results with administration of zinc for 3 improvements in neuropsychiatric status were recorded
months.56,57 However, this anecdotal report has not in a subset of patients receiving flumazenil. However,
been confirmed in larger studies. the possible confounding effects of prior exposure to
Nonabsorbable disaccharides such as lactulose are benzodiazepines, possibility of seizures, and lack of cor-
routinely used to decrease ammonia production in the
relation between the clinical response and blood levels
gut. Lactulose increases fecal nitrogen excretion by
of diazepines have tempered enthusiasm for the use of
facilitation of the incorporation of ammonia into bac-
benzodiazepine receptor agonist in these patients.63
teria as well as by its cathartic effect.51 Lactulose admin-
istered orally reaches the cecum, where it is metabolized Renal Insufficiency and Hepatorenal Syndrome
by the enteric bacteria, causing a fall in pH. This drop in
Acute renal failure is thought to be common in patients
pH leads to metabolic shift in bacteria favoring uptake
with cirrhosis, but its exact incidence is variable.
of ammonia.58 The dose is adjusted to produce 2 or 3
Patients with cirrhosis are predisposed to acute renal
soft bowel movements daily.51 A systematic review
found that lactulose or lactitol were more effective than failure following complications such as variceal bleed-
placebo in improving hepatic encephalopathy but had ing or administration of nephrotoxic drugs such as non-
no significant benefit on mortality.59 However, the steroidal antiinflammatory drugs, antibiotics, dilti-
benefit on encephalopathy no longer reached statistical azem, etc. The cause of renal insufficiency could be
significance when the analysis was confined to studies prerenal, intrarenal, or hepatorenal. The management
with the highest methodologic quality. The authors of renal insufficiency in patients awaiting LT focuses on
also found that antibiotics appeared to be relatively prevention of additional injury and optimization of
more effective. existing renal function. Nonsteroidal antiinflammatory
Antibiotics such as neomycin, low dose metronida- drugs should be used only with close follow-up, because
zole, vancomycin, and rifaximin are also useful for low- the subsequent decrease in renal prostaglandin may pre-
ering blood ammonia, mainly by an effect on ammonia cipitate acute renal failure. Radiographic imaging stud-
production by intestinal bacteria. However, antibiotic ies using intravenous contrast dye also need to be
therapy may be associated with significant toxic side approached with caution because of the known risk of
effects (e.g., renal failure, ototoxicity, and peripheral renal injury. The use of acetylcysteine together with
neuropathy). hydration is the treatment of choice to protect against
An alternate strategy for lowering of blood ammonia radiographic contrast media – induced nephropathy.64
is the stimulation of ammonia fixation. Under normal Large volume paracentesis followed by intravenous
physiological conditions, ammonia is removed by the albumin infusion decreases the risk of acute renal failure
formation of urea in periportal hepatocytes and by glu- after paracentesis.30 The results of albumin use in this
tamine synthesis in perivenous hepatocytes, skeletal clinical setting are better than other volume expanders
muscle, and brain. In cirrhosis, both urea cycle enzymes such as dextran.65,66 In a recent study comparing nor-
and glutamine synthetase activity are decreased in the mal saline and albumin, albumin was more effective254 Sharma and Rakela
than saline in the prevention of paracentesis-induced recirculating system combined with intermittent
circulatory dysfunction.67 Saline is a valid alternative to venovenous hemofiltration vs. intermittent veno-
albumin when less than 5 L of ascitic fluid is evacuated. venous hemofiltration alone, suggests that the molec-
Moreover, patients with cirrhosis may develop a spe- ular adsorbent recirculating system may improve sur-
cific acute renal failure called hepatorenal syndrome vival in HRS.75
(HRS). It is a diagnosis of exclusion. HRS is an omi-
nous complication of end-stage liver disease. Retrospec- Hepatopulmonary Syndrome
tive studies indicate that HRS is present in ⬃17% of Hepatopulmonary syndrome (HPS) is a progressive,
patients admitted to the hospital with ascites and in debilitating complication of end-stage liver disease that
⬎50% of cirrhotic patients who die from liver failure. occurs in 4 to 25% of liver transplant candidates.76 – 78
The hallmarks of HRS are reversible renal constriction The diagnosis of HPS rests on the triad of cirrhosis,
and mild systemic hypotension.68 The kidneys are
hypoxemia, and intrapulmonary vascular dilation. Pul-
structurally normal and at least in the early part of the
monary features include digital clubbing, cyanosis, dys-
syndrome, tubular function is intact, as reflected by
pnea, platypnea, and orthodeoxia.
avid sodium retention and oliguria. The cause of renal
LT candidates with hypoxemia (PaO2 ⬍ 70 mm of
vasoconstriction is unknown, but its pathogenesis may
predominantly involve both increased vasoconstrictor Hg or arteriolar – aveolar gradient ⬎20) in the absence
and decreased vasodilator factors. Two patterns of HRS of any pulmonary dysfunction, should be screened for
are observed in clinical practice: type 1 and type 2. Type HPS since the syndrome appears to resolve after ortho-
1 HRS is an acute form of HRS in severe liver disease topic LT. Further work-up should include an arterial
and is progressive. It is associated with poor prognosis blood gas on 100% oxygen, double contrast echo or
with 80% mortality at 2 weeks. Type 2 HRS occurs in 99mTC macro-aggregated albumin lung perfusion
patients with diuretic-resistant ascites. The course of scan to establish the presence of intrapulmonary vascu-
renal failure is slow. It is also associated with poor prog- lar dilatation. The presence of microbubbles in the left
nosis, although the survival time is longer than that of cardiac chambers between 3 and 6 heartbeats after the
patients with type 1 HRS. The definition of HRS was visualization in the right chambers and a shunt fraction
proposed by the International Ascites Club.36 of more than 6% is considered as a positive test for the
Although the best treatment for HRS is LT, presence of intrapulmonary vascular dilatation and thus
patients with HRS who are transplanted have more confirms the diagnosis.79,80 Figure 1 illustrates the work
complications and a higher in-hospital mortality rate for HPS.
than those without HRS.69 It has been suggested that Patients with HPS awaiting LT get a priority over
systemic vasoconstrictor therapy may improve renal other patients. Complete resolution after orthotopic
function in patients with HRS by increasing the LT even in the setting of severe hypoxemia has been
effective arterial blood volume. A nonrandomized well documented.59,77 However, PaO2 less than 50 mm
retrospective study in a large series of patients with of Hg and 99mTC macro-aggregated albumin brain
HRS suggests that the vasopressin analog terlipressin uptake ⬎20% are the pretransplantation risk factors for
is an effective treatment of renal failure.70 Other
increased mortality.
nonrandomized studies suggest that vasoconstrictive
Efforts have to be made to rule out intrapulmonic
therapy with noradrenaline71 or midodrine com-
shunting. Pharmacologic approaches have been disap-
bined with octreotide72 may improve renal function
pointing in providing consistent and reproducible
in these patients. TIPS has previously been shown to
have beneficial effect on renal function in HRS.73 In improvement in hypoxemia.81 The placement of TIPS
a recent study by Wong et al.,74 TIPS was associated to improve hypoxemia due to HPS remains controver-
with further improvement in the renal function as sial and cannot be advised without further prospective
well as circulatory function, with normalization of study.82 Coil embolization to occlude discrete arterio-
effective arterial blood volume in selected type 1 venous communications in patients with severe hypox-
HRS patients (international normalized ratio less emia and HPS has resulted in significant improvement
than 2, bilirubin less than 5 mg/dL, and Child-Tur- in PaO2 in 2 adults.83 Embolotherapy is an accepted
cotte-Pugh lower than 12), following administration approach to the management of severe hypoxemia asso-
of combination therapy with midodrine, octreotide, ciated with discrete arteriovenous malformation,84 but
and albumin.74 A randomized study in a small series is not effective in HPS due to capillary dilation without
of patients, comparing the molecular adsorbent discrete anatomic shunting.Pre – LT Patient Management—Part 2 255
epoprostenol (prostacyclin, or prostaglandin I2) is a
potent vasodilator shown to improve exercise tolerance,
reduce pulmonary vascular resistance, and improve
mortality in patients with primary pulmonary hyper-
tension.87 Similar hemodynamic improvements have
been achieved before LT in patients with PPH.88,89 Kuo
et al.88 treated 4 patients with 10 – 28 ng/kg/minute of
epoprostenol over 6 to 14 months and reported a 29 to
46% decrease in mean PAP, a 22 to 71% decrease in
pulmonary vascular resistance, and a 25 to 75%
increase in cardiac output. Krowka et al.89 treated 10
patients with mean PAP of 35 mm of Hg and higher for
8 days to 30 months. Six patients showing improve-
ments in pulmonary vascular resistance, mean PAP, and
cardiac output after 1 hour had further reduction of
pulmonary vascular resistance when treated with con-
tinuous therapy. Not enough data exist regarding the
long term benefit of epoprostenol therapy or regarding
the lasting effect after the cessation of therapy to make
any recommendations. However, epoprostenol therapy
is most appropriate for the cirrhotic patient who except
for moderate to severe PPH has no other contraindica-
tion for LT.
Figure 1. Work-up for hepatopulmonary syndrome. Hepatic Hydrothorax
Hepatic hydrothorax is defined as the accumulation of
Portopulmonary Hypertension fluid in the pleural space as a consequence of liver dis-
ease. The most common symptom is dyspnea without
Portopulmonary hypertension (PPH) refers to the
chest pain. It can be detected with chest radiographs in
development of pulmonary arterial hypertension in the
as many as 13% of patients with cirrhosis. Right-sided
setting of portal hypertension with or without liver
disease. It is defined as mean pulmonary artery pressure pleural effusion is seen in 66% of the patients with
(PAP) ⬎25, with a normal pulmonary capillary wedge hepatic hydrothorax.90 The management options for
pressure, an elevated pulmonary vascular resistance hepatic hydrothorax include medical management of
⬎125 dynes/second/cm – 5, or increased trans pulmo- ascites, and therapeutic thoracocentesis for the control
nary gradient (mean PAP / pulmonary capillary wedge of shortness of breath. The pleural fluid usually has the
pressure ⬎10 mm of Hg).85 Candidates with PAP characteristics of a transudate. However, an occasional
greater than or equal to 40 mm of Hg on echocardiog- patient with hepatic hydrothorax may develop “spon-
raphy should undergo a right heart catheterization to taneous bacterial pleuritis.” They should be treated as
confirm the diagnosis of PPH. Figure 2 illustrates the for SBP; insertion of chest tube is contraindicated in
work-up for PPH. It has been estimated that in patients these patients. TIPS has been successfully used to man-
who undergo LT with a mean PAP between 35 and 49 age the symptoms of hepatic hydrothorax in the setting
mm of Hg and pulmonary vascular resistance ⬎250 of marked ascites.91 Pleurodesis of the pleural space
dynes/second/cm – 5 or greater, the mortality is 50%. with chemical means such as talc, antibiotics, or che-
Patients with a mean PAP of 50 mm of Hg or greater motherapeutic agents usually fails. Video thoracoscopy
have a cardiopulmonary mortality rate of 100%.86 It is with the repair of presumed diaphragmatic defects has
therefore recommended that moderate to severe PPH been described in the literature.92
and significant right ventricle dysfunction should be
Pruritus
considered contraindications to LT.
However, preoperative therapy to reduce PPH and Pruritus is a common symptom of chronic cholestatic
right ventricular dysfunction may improve clinical sta- liver diseases, particularly primary biliary cirrhosis. The
tus and make LT feasible. Continuous intravenous 1st line of treatment is cholestyramine, an anion256 Sharma and Rakela Figure 2. Work-up for portopulmonary hypertension. PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; PGI2, prostaglandin I2; ECHO, echocardiogram; RHC, right heart catheterization. exchange resin. It should be administered at least 4 ness of opioid receptor antagonists (nalmefene, nalox- hours before or after taking the other medications, as it one, and naltrexone) in the control of pruritus.95,96 The binds many drugs.93 Side effects include bloating, con- major side effects are the symptoms of opioid with- stipation, and sometimes diarrhea. The 2nd line of drawal. The treatment should be started slowly, prefer- medication is rifampin.94 The mechanism of action is ably in a hospital setting. unclear but it is effective in controlling pruritus in 50% of the patients with primary biliary cirrhosis. Dosage is Management of Osteopenia and Osteoporosis 150 mg twice a day and it is effective within 6 weeks of therapy. The drug should be taken regularly for the Osteoporosis and fractures are more common in cir- effectiveness of treatment. These patients should be rhotic patients than in the general population in the monitored closely for the possibility of drug hepatotox- absence of confounding risk factors such as female gen- icity. Several studies have demonstrated the effective- der, cholestasis, and excess alcohol intake.97,98 The role
Pre – LT Patient Management—Part 2 257
of calcium and vitamin D in preventing osteoporosis is esophageal endoscopy. Gastrointest Endosc 1981;27:213 –
unclear. According to recently published guidelines on 218.
4. D’Amico G, Luca A. Natural history. Clinical-haemodynamic
the management of osteoporosis associated with
correlations. Prediction of the risk of bleeding. Baillieres Clin
chronic liver disease, patients with cirrhosis or severe Gastroenterol 1997;11:243 – 256.
cholestasis should have a baseline bone mineral densi- 5. Runyon BA, Canawati HN, Akriviadis EA. Optimization of
tometry.99 If the T score is more than – 1.5 or between ascitic fluid culture technique. Gastroenterology 1988;95:
– 1.5 and – 2.5, no treatment is recommended. These 1351 – 1355.
patients should be followed up with bone mineral den- 6. Riggio O, Ariosto F, Merli M, Caschera M, Zullo A, Balducci
G, et al. Short-term oral zinc supplementation does not
sitometry every 2 years.100 The work-up for the patients improve chronic hepatic encephalopathy. Results of a double-
with bone mineral densitometry less than – 2.5 should blind crossover trial. Dig Dis Sci 1991;36:1204 – 1208.
include thyroid function tests, serum calcium, phos- 7. Vargas HE, Gerber D, Abu-Elmagd K. Management of portal
phate, estradiol, follicle stimulating hormone, luteiniz- hypertension-related bleeding. Surg Clin North Am 1999;79:
ing hormone, testosterone, and sex hormone binding 1 – 22.
8. Feu F, Bordas JM, Luca A, Garcia-Pagan JC, Escorsell A, Bosch
globulin levels. The optimum duration of therapy has
J, Rodes J. Reduction of variceal pressure by propranolol: com-
not been established.100 parison of the effects on portal pressure and azygos blood flow
The current recommendation is that the treatment in patients with cirrhosis. Hepatology 1993;18:1082 – 1089.
should be given for a minimum of 5 years and the bone 9. Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L,
mineral densitometry repeated after 2 years and at the Lebrec D. Beta-adrenergic-antagonist drugs in the prevention
end of treatment.100 In women, hormone replacement of gastrointestinal bleeding in patients with cirrhosis and esoph-
ageal varices. An analysis of data and prognostic factors in 589
therapy with estrogen and progesterone should be
patients from four randomized clinical trials. Franco-Italian
offered to premenopausal females. For men, transder- Multicenter Study Group. N Engl J Med 1991;324:1532 –
mal testosterone can be given to hypogonadal males. 1538.
The treatment recommendation for patients unable 10. Garcia-Tsao G, Grace ND, Groszmann RJ, Conn HO, Ber-
to take hormone replacement therapy / testosterone or mann MM, Patrick MJ, et al. Short-term effects of propranolol
eugonadal is bisphosphonates. Calcitriol or calcitonin on portal venous pressure. Hepatology 1986;6:101 – 106.
11. Garcia-Pagan JC, Feu F, Bosch J, Rodes J. Propranolol com-
should be considered in those patients with osteoporo-
pared with propranolol plus isosorbide-5-mononitrate for por-
sis who are either intolerant of hormone replacement tal hypertension in cirrhosis. A randomized controlled study.
therapy and bisphosphonates or whose bone mineral Ann Intern Med 1991;114:869 – 873.
densitometry worsens despite either the use of bisphos- 12. Fardy JM, Laupacis A. A meta-analysis of prophylactic endo-
phonates or treatment of hypogonadism. scopic sclerotherapy for esophageal varices. Am J Gastroenterol
In the absence of larger studies on the effect of vita- 1994;89:1938 – 1948.
13. Paquet KJ, Kalk JF, Klein CP, Gad HA. Prophylactic sclero-
min D supplementation on bone mineral densitometry, therapy for esophageal varices in high-risk cirrhotic patients
it seems reasonable to recommend correction of vita- selected by endoscopic and hemodynamic criteria: a random-
min D deficiency with an oral daily dose of 800 IU of ized, single-center controlled trial. Endoscopy 1994;26:734 –
vitamin D, and 1 – 2 gm of elemental calcium supple- 740.
mentation. 14. D’Amico G, Pagliaro L, Bosch J. The treatment of portal hyper-
tension: a meta-analytic review. Hepatology 1995;22:332 –
354.
Conclusion 15. Sarin SK, Lamba GS, Kumar M, Misra A, Murthy NS. Com-
parison of endoscopic ligation and propranolol for the primary
The care and monitoring of pre-LT candidates is very prevention of variceal bleeding. N Engl J Med 1999;340:988 –
challenging. Careful management of liver-specific com- 993.
plications can maximize their survival on the waiting 16. Schepke M, Kleber G, Nurnberg D, Willert J, Koch L, Veltzke-
Schlieker W, et al. Ligation versus propranolol for the primary
list. prophylaxis of variceal bleeding in cirrhosis. Hepatology 2004;
40:65 – 72.
17. Burroughs AK, Patch D. Transjugular intrahepatic portosys-
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