Management of pre–liver transplantation patient—Part 2

CAQ CORNER

Management of Pre–Liver Transplantation Patient—Part 2

Pratima Sharma1 and Jorge Rakela2

Liver transplantation (LT) has grown dramatically overlast 2 decades and the hepatologist has had to assume alarger role in managing the potential candidate awaitingsurgery. In part 1 of this review, we described thepre-LT evaluation process, contraindications of LT,general care, and treatment of various etiologies of liverdisease prior to LT. In this part, we review the manage-ment of liver-specific complications that are responsiblefor significant morbidity and waitlist mortality of LTcandidates.

Liver-Specific Complications

Portal Hypertension

Portal hypertension is the main complication of livercirrhosis. This syndrome develops in the majority ofpatients with cirrhosis and is responsible for most life-threatening complications of cirrhosis, including gas-trointestinal bleeding from ruptured gastroesophagealvarices, hepatorenal syndrome, and hepatic encepha-lopathy.

Prophylaxis of Esophageal Variceal Bleeding

The average lifetime risk of variceal bleeding in patientswith cirrhosis who have had no previous bleeding is30%.1 Each bleeding episode bears a mortality risk of30 to 50%.2 In prospective studies, advanced Child-Turcotte-Pugh stage, large esophageal varices, and redwale markings are independent risk factors for 1stvariceal bleed.3–5 The modalities available for primaryprophylaxis are nonselective �-blockers, endoscopictherapy, and transjugular intrahepatic portosystemicshunt (TIPS). Nonselective �-blockers decrease portalpressure and collateral flow through a combinationof decreased cardiac output and unopposed alpha-mediated splanchnic vasoconstriction, resulting indecreased effective splanchnic blood flow, therebyreducing the risk of initial variceal bleeding and a trendtoward decreased mortality.6–8 �-blockers should beconsidered in all patients with large varices and redmarkings.7 Propranolol or nadolol can be used and thedose should be titrated weekly to decrease the restingheart rate by 25% and the systolic blood pressure to nolower than 90 mm of Hg.9 The risk reduction with �

blockade averages less than 50% and the maximumbenefit is seen in patients with Child-Turcotte-Pugh Aand B cirrhosis. More than 30% of patients have nodecrease in portal pressure despite adequate � block-ade.10 The addition of long-acting nitrates to nonselec-tive �-blockers has been shown to enhance their hemo-dynamic effect and reduce the risk of bleeding fromesophageal varices and therefore should be consideredin patients who do not respond ideally to �-blockers.11

Poorer results compared with pharmacotherapy haveled to the discontinuation of endoscopic variceal scle-rotherapy as primary prophylaxis for variceal bleed-ing.12–14 Sarin et al.15 showed that endoscopic varicealband ligation is safer and more effective than propran-olol for the primary prevention of variceal bleeding.However, in a recent randomized controlled multi-center trial that evaluated primary prophylaxis ofvariceal bleeding, variceal band ligation and proprano-lol were similarly effective.16 Despite effectiveness inthe arrest of bleeding, TIPS cannot be recommended asa 1st-line approach to manage variceal bleeding or forprimary prophylaxis because of increase incidence ofhepatic encephalopathy and expense related to themanagement of TIPS malfunction.17,18

Gastric Variceal Bleeding

No specific measures are available to prevent 1st bleed-ing from gastric varices. Most of the current regimens totreat gastric varices are derived from anecdotal evidence

Abbreviations: LT, liver transplantation; HRS, hepatorenal syn-drome; HPS, hepatopulmonary syndrome; HE, hepatic encephalop-athy; PPH, portopulmonary hypertension; SBP, spontaneous bacte-rial peritonitis; PAP, pulmonary artery pressure; TIPS, transjugularintrahepatic portosystemic shunt.

From the 1Department of Medicine, Emory University Hospital,Atlanta, GA, and the 2Department of Internal Medicine, Mayo Clinic,Scottsdale, AZ.

Address reprint requests to Pratima Sharma, MD, Assistant Profes-sor, Emory University Hospital, 1364, Clifton Road, Box 7, Atlanta, GA30322. Telephone: 404 712 5454; FAX: 404 712 4621; E-mail:[email protected]

Copyright © 2005 by the American Association for the Study ofLiver Diseases

Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/lt.20379

249Liver Transplantation, Vol 11, No 3 (March), 2005: pp 249–260

or are extrapolated from trials of esophageal varices.14,19

TIPS is very effective with a success rate of 90% forinitial hemostasis. The rate of early rebleeding afterTIPS procedure is 20% and often the source of suchbleeding is nonvariceal, i.e., ulcer secondary to bandingor sclerosis.18

Treatment of Acute Variceal Bleeding

Patients suspected of acute variceal bleeding should bemanaged in the intensive care setting. General princi-ples of resuscitation should be followed, which includeprotection of airway, insertion of 2 large-bore intrave-nous cannulas, blood volume resuscitation with packederythrocytes, correction of coagulopathy with fresh fro-zen plasma, and platelet transfusion if they are below30,000/mm3. Care must be taken not to overexpandplasma volume, which may increase portal pressure andresult in exacerbation of variceal bleeding and ascites.Antibiotics should be administered prophylactically,especially in patients with ascites, to prevent spontane-ous bacterial peritonitis.20,21 Emergency endoscopy ofthe upper gastrointestinal tract can then be performedand the most appropriate treatment modality should bechosen at that point. The drug classes that have beenextensively studied in acute variceal bleeding are vaso-pressin and somatostatin and their analogs. Both soma-tostatin and vasopressin arrest variceal bleeding by caus-ing splanchnic vasoconstriction and thereby decreasingthe portal pressure, but this has no effect on mortality.19

There is an increased association between myocardialinfarction and arrhythmias and the use of vasopressin.Furthermore, bowel ischemia, cerebrovascular isch-emia, and peripheral tissue necrosis have been reported.The severity of complications such as myocardial isch-emia has led to discontinuation of the use of vasopres-sin.14

Terlipressin is a longer acting analog of vasopressinand can be given as bolus-infusion every 4 hours. Itsefficacy is similar to vasopressin in controlling the acutevariceal bleeding and is associated with fewer sideeffects.22 The ease of administration has allowed forparamedic administration in the field with arrest ofbleeding prior to arrival at the hospital. Terlipressin isnot yet approved for use in the United States.

Somatostatin is superior to vasopressin for immedi-ate control of bleeding and has less severe side effectsthan vasopressin, although survival improvement hasnot been seen with somatostatin.19

Octreotide is a synthetic analog of somatostatin.When compared with other vasoactive drugs, oct-reotide was better than vasopressin and equivalent to

terlipressin for controlling bleeding. The side effectswere less frequent and less severe with octreotide thanwith either vasopressin or terlipressin. However, theefficacy of octreotide as a single therapy is controversial.Results from a recent meta-analysis suggest that oct-reotide may improve the results of endoscopic therapybut has no or little effect if used alone.19

Endoscopic sclerotherapy controls active hemor-rhage in 80 to 90% of patients. However, a skilledendoscopist must be readily available, and the proce-dure is associated with serious complications in 10 to20% of patients, with an overall mortality of 2%.19 Thecombination of sclerotherapy with somatostatin, oct-reotide, and vapreotide has been reported to be superiorto sclerotherapy alone in terms of control of bleedingand reduction of treatment failures within 5 days.23,24

The 6-week survival of the combination of sclerother-apy and drugs was similar to sclerotherapy alone.Variceal band ligation was shown to be better thanendoscopic sclerotherapy in controlling the acute bleedand mortality.25 The banding may be more challengingduring active bleeding due to reduction in the field ofvision by as much as 30% with the addition of bandingdevice to the endoscope. The choice of proceduredepends on the available expertise in the center manag-ing the patient; variceal banding has become the proce-dure of choice in the management of variceal bleeding.

Balloon tamponade is a useful temporary measure tocontrol acute variceal bleeding and to stabilize thepatient while more definitive procedures are beingaccomplished. Control of bleeding is successful in asmany as 80 to 90% of cases, but rebleeding occurs in upto 50% when the balloon(s) are deflated. Furthermore,significant perforation risk is present that may lead tohigh mortality if the balloons are inflated for prolongedperiods of time.7

Rebleeding is a very common and usually occurswithin 6 weeks of the index episode. The recurrencereported as high as 70% in patients who have had atleast 1 prior bleeding episode.21 The use of �-blockers(with and without variceal band ligation) is the mostaccepted approach to manage these patients. There isstill debate about the cost-effectiveness of this pharma-cological approach combined with endoscopy.

In approximately 10% of patients in whom rebleed-ing cannot be controlled with 2 endoscopic therapeuticsessions within 24 hours, either surgery or TIPS shouldbe planned. At the most recent American Associationfor the Study of Liver Diseases meeting, Henderson etal.26 presented the 1st analysis of the multicenter studyof distal splenorenal shunt vs. TIPS for refractoryvariceal bleeding. This study found that both modali-

250 Sharma and Rakela

ties were equally effective in preventing rebleeding, andencephalopathy and survival were similar. TIPS can beused in patients with Child-Turcotte-Pugh class B or Ccirrhosis as a salvage therapy and preferably as a bridgeto transplant.18 Worsening of hepatic encephalopathyafter TIPS procedure may impair the outcome com-pared to Child-Turcotte-Pugh A patients.

Ascites

Ascites is the most common major complication ofportal hypertension. The initial evaluation of a patientwith ascites should include a history, physical evalua-tion, and abdominal paracentesis with ascitic fluid anal-ysis. Bleeding is sufficiently uncommon so as to obviatethe routine requirement for fresh frozen plasma orplatelets prior to a diagnostic paracentesis.27 The initialascitic fluid analysis should include a cell count anddifferential and serum-ascites albumin gradient. Theculture yield increases to 80% when ascitic fluid with apolymorphonuclear count �250 cells/mm3 is inocu-lated directly into blood culture bottles at the bed-side.5,28,29

The mainstay of treatment of patients with ascitesincludes education regarding dietary sodium restriction(2,000 mg/day or 88 mmol/day) and oral diuretic ther-apy30 that has been shown to be effective in 90% ofpatients.31 Chronic hyponatremia is commonly seen incirrhotic patients and is seldom morbid, althoughrecent data has shown that hyponatremia is an indepen-dent risk factor for death while awaiting LT.32 Rapidattempts to correct hyponatremia can lead to morecomplications, such as central pontine myelinolysis,than hyponatremia itself, although severe hyponatre-mia will increase the risk of posttransplant neurologicalcomplications.33 Severe hyponatremia (serum sodium�120 mmol/L) requires fluid restriction in cirrhoticpatients with ascites. Cirrhotic patients do not usuallyhave symptoms from hyponatremia until their sodiumlevels fall below 110 mmol/L, or unless the decline insodium is very rapid. Recently, Gerbes et al.,34 showedthat VPA-985, an orally active vasopressin 2 receptorantagonist, can correct severe hyponatremia in patientswith cirrhosis and ascites,34 its clinical utility remains tobe determined

The usual diuretic therapy consists of single morn-ing doses of oral spironolactone and furosemide, begin-ning with 100 and 40 mg, respectively.30 Single-agentfurosemide has been shown to be less efficacious thanspironolactone in a randomized controlled trial.35 Thedose of both oral diuretics can be increased simulta-neously, maintaining the 100 mg / 40 mg ratio, with a

maximum of 400 mg/day / 160mg/day, if weight lossand natriuresis are inadequate on lower doses. In gen-eral, this ratio maintains normokalemia. Furosemidecan be temporarily withheld in patients presenting withhypokalemia. Single morning dosing tends to increasecompliance and is recommended. The antiandrogeniceffects of spironolactone, such as decreased libido,impotence, and gynecomastia in men may require dosereduction or discontinuation of the medicine. Amilo-ride can be substituted for spironolactone, but it is moreexpensive and has been shown to be less effective in arandomized control trial.

The etiology of nocturnal muscle cramps is not wellunderstood and may respond to magnesium supple-mentation or the oral administration of quinine sulfateat a dose of 325 mg in the evening. Serum sodium lessthan 120 mmol/day despite fluid restriction and serumcreatinine �2.0 mg/dL should result in the cessation ofdiuretic therapy, reassessment of the situation and con-sideration of 2nd-line options. These patients should bemonitored for daily weight, orthostatic symptoms, andperiodic serum electrolytes, blood urea nitrogen, andcreatinine. Random urine sodium concentration ismeasured if the weight loss is not adequate. The fre-quency of follow-up is determined by response to treat-ment and by patient stability.

Refractory ascites is defined as ascites that is notresponsive to sodium-restricted diet and high-dosediuretic treatment in the absence of prostaglandininhibitors such as nonsteroidal antiinflammatorydrugs.30,36 Serial therapeutic paracentesis are effectivein controlling ascites. Serial therapeutic paracentesisshould be performed as needed, approximately every 2weeks. The postparacentesis albumin infusion is expen-sive and unproven to be necessary for paracentesis of�5 L. For larger volume paracentesis, an albumin infu-sion of 5–8 g/L of ascitic fluid removed can be consid-ered.30

LeVeen or Denver shunts were popularized in the1970s as a physiologic treatment of ascites. Shunt place-ment has been shown in controlled trials to decrease theduration of hospitalization, the number of hospitaliza-tions and the dose of diuretics.37,38 However, their poorlong-term patency, significant complication profile,and lack of survival advantage compared with medicaltherapy in controlled trials have led to near abandon-ment of these devices.38 Shunt-related fibrous adhe-sions can make subsequent LT difficult.39

TIPS is physiologically equivalent to a side-to-sideportocaval shunt that is placed by an interventionalradiologist.40 Five randomized trials41–45 comparingTIPS and large volume paracentesis have demonstrated

251Pre–LT Patient Management—Part 2

that TIPS is effective in minimizing ascites and inreducing the need for paracentesis. However, whetherthe TIPS procedure improved survival of the patientswith cirrhosis and refractory ascites is still debated; thetrials have reported the discordant results of the effect ofTIPS on survival. Rossle et al.42 and Salerno et al.43

showed that TIPS was independently associated sur-vival without LT. Salerno et al.43 observed the relativerisk of dying was 2.95 times greater in patients assignedto the paracentesis group, according to the multivariateanalysis. The results from the North American Studyfor the Treatment of Refractory Ascites41 and a ran-domized trial from the University of Barcelona, Spain44

showed that TIPS is substantially superior to conven-tional medical therapy but does not improve the sur-vival or quality of life. The reasons why randomizedtrials have not demonstrated a survival benefit areunclear. However, the Child-Turcotte-Pugh class or itscomponent was similar among the trials. Factors asso-ciated with increased mortality after TIPS includeChild-Turcotte-Pugh class C, renal insufficiency,hyperbilirubinemia, marked coagulopathy, andadvanced age.45 Before recommending TIPS to LT can-didates, the risks and benefits should be carefullyassessed to avoid a potentially catastrophic outcome.

Spontaneous Bacterial Peritonitis

Spontaneous bacterial peritonitis (SBP) is a particularlyimportant complication because the presence of infec-tion usually removes a patient from consideration oftransplantation until the infection is cleared. A diagnos-tic abdominal paracentesis must be performed and theascitic fluid must be analyzed for cell count and bacte-rial culture before a confident diagnosis of ascitic fluidinfection is made. The diagnosis of SBP is made whenthere are �250 polymorphonuclear cells per milliliterand / or positive ascitic fluid bacterial culture withoutan evident intraabdominal or surgically correctablesource.46 These patients should receive empiric treat-ment with broad-spectrum antibiotics. Delaying treat-ment until the ascitic fluid culture grows bacteria mayresult in the patients’ death from overwhelming infec-tion. Cefotaxime, a 3rd generation cephalosporin, hasbeen shown to be superior to ampicillin in combinationwith tobramycin in a controlled trial.47 In a randomizedcontrolled trial involving 100 patients, it has beenreported that 5 days of treatment is as efficacious as 10days of treatment in the treatment of carefully charac-terized patients with SBP.48 Patients with less than 250polymorphonuclear cells in ascitic fluid and signs or

symptoms of infection should also receive empiric anti-biotic therapy.30,46

Oral ofloxacin has been reported in a randomizedcontrolled trial to be as effective as parenteral cefo-taxime in the treatment of SBP in patients who are notvomiting and are not in shock.49 Repeat paracentesisshould be performed to document cultures sterility anddecrease in polymorphonuclear cell count in patientswith SBP; this step is particularly important in cases inwhich clinical improvement is not apparent after the 1st3 days of antibiotic therapy.50

Short-term inpatient quinolone should be consid-ered in the prevention of bacterial infections in patientswith low protein (�1 gm/dL) ascites, variceal hemor-rhage, and prior SBP. Long-term outpatient antibioticuse can probably be reserved for patients who havesurvived an SBP infection.30,50

Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a complex neuropsy-chiatric syndrome that may complicate acute or chronicliver failure. It is characterized by changes in mentalstate, including a wide range of neuropsychiatric symp-toms ranging from minor signs of altered brain functionto deep coma.

Most theories explaining the pathogenesis of HEaccept that nitrogenous substances derived from the gutadversely affect brain function. These compounds gainaccess to the systemic circulation as a result of decreasedhepatic function or portosystemic shunts and may pro-duce alterations of neurotransmission that affect con-sciousness and behavior.51 Abnormalities in glutamin-ergic, serotoninergic and gamma-aminobutyricacidergic, and catecholamine pathways, among others,have been described in experimental HE.51 A large bodyof work points towards ammonia as a key factor in thepathogenesis of HE.52

The approach to HE has not changed significantlyin recent years. HE is a diagnosis of exclusion and ismainly clinical. The suspicion of HE in patients withchronic liver disease should prompt the search for theprecipitating factors that include gastrointestinal bleed-ing, electrolyte abnormalities, renal failure, infection,recent placement of TIPS shunt,53 use of sedatives /hypnotics, development of hepatocellular carcinoma,and constipation. However, the other causes of changein mental status such as intracranial bleed or masses,hypoglycemia, and a postictal state should be ruled out.Although hyperammonemia is associated with HE,ammonia levels do not correlate with the level ofencephalopathy.54


The treatment goals for HE are provision of sup-portive care, identification and removal of precipitatingfactors, and reducing the production and absorption ofnitrogenous load from the gut. Ultimately, assessmentof the need for long-term therapy is very important.

There is no good clinical evidence supporting pro-tein restriction in patients with acute hepatic encepha-lopathy. The only randomized trial, reported only inabstract form, found no difference between moderate(.8 gm/kg per day) and more aggressive protein restric-tion.51 Zinc, a cofactor of urea cycle enzymes, may bedeficient in cirrhotic patients, especially if associatedwith malnutrition. Zinc supplementation improves theactivity of the urea cycle in experimental models ofcirrhosis.55 One trial has evaluated the effects of zincover a short period (up to a week), without majorimprovement. Another nonrandomized study reportedpositive results with administration of zinc for 3months.56,57 However, this anecdotal report has notbeen confirmed in larger studies.

Nonabsorbable disaccharides such as lactulose areroutinely used to decrease ammonia production in thegut. Lactulose increases fecal nitrogen excretion byfacilitation of the incorporation of ammonia into bac-teria as well as by its cathartic effect.51 Lactulose admin-istered orally reaches the cecum, where it is metabolizedby the enteric bacteria, causing a fall in pH. This drop inpH leads to metabolic shift in bacteria favoring uptakeof ammonia.58 The dose is adjusted to produce 2 or 3soft bowel movements daily.51 A systematic reviewfound that lactulose or lactitol were more effective thanplacebo in improving hepatic encephalopathy but hadno significant benefit on mortality.59 However, thebenefit on encephalopathy no longer reached statisticalsignificance when the analysis was confined to studieswith the highest methodologic quality. The authorsalso found that antibiotics appeared to be relativelymore effective.

Antibiotics such as neomycin, low dose metronida-zole, vancomycin, and rifaximin are also useful for low-ering blood ammonia, mainly by an effect on ammoniaproduction by intestinal bacteria. However, antibiotictherapy may be associated with significant toxic sideeffects (e.g., renal failure, ototoxicity, and peripheralneuropathy).

An alternate strategy for lowering of blood ammoniais the stimulation of ammonia fixation. Under normalphysiological conditions, ammonia is removed by theformation of urea in periportal hepatocytes and by glu-tamine synthesis in perivenous hepatocytes, skeletalmuscle, and brain. In cirrhosis, both urea cycle enzymesand glutamine synthetase activity are decreased in the

liver. Strategies to stimulate residual urea cycle activitiesand / or glutamine synthesis have been tried over thelast 20 years. One of the most successful agents to beused so far is L-ornithine L-aspartate. Randomized con-trolled clinical trials with L-ornithine L-aspartate dem-onstrate significant ammonia lowering and concomi-tant improvement in psychometric testing.60

Benzoate is also effective in reducing blood ammo-nia both in patients with inherited urea cycle disordersand in cirrhotic patients. In a randomized controlledclinical trial with sodium benzoate vs. lactulose,improvement in neuropsychiatric performance wasfound to be comparable.61

Several controlled clinical trials have been per-formed to assess the efficacy of the benzodiazepinereceptor antagonist flumazenil in cirrhotic patients withvarious degree of severity of HE.62 Spectacularimprovements in neuropsychiatric status were recordedin a subset of patients receiving flumazenil. However,the possible confounding effects of prior exposure tobenzodiazepines, possibility of seizures, and lack of cor-relation between the clinical response and blood levelsof diazepines have tempered enthusiasm for the use ofbenzodiazepine receptor agonist in these patients.63

Renal Insufficiency and Hepatorenal Syndrome

Acute renal failure is thought to be common in patientswith cirrhosis, but its exact incidence is variable.Patients with cirrhosis are predisposed to acute renalfailure following complications such as variceal bleed-ing or administration of nephrotoxic drugs such as non-steroidal antiinflammatory drugs, antibiotics, dilti-azem, etc. The cause of renal insufficiency could beprerenal, intrarenal, or hepatorenal. The managementof renal insufficiency in patients awaiting LT focuses onprevention of additional injury and optimization ofexisting renal function. Nonsteroidal antiinflammatorydrugs should be used only with close follow-up, becausethe subsequent decrease in renal prostaglandin may pre-cipitate acute renal failure. Radiographic imaging stud-ies using intravenous contrast dye also need to beapproached with caution because of the known risk ofrenal injury. The use of acetylcysteine together withhydration is the treatment of choice to protect againstradiographic contrast media– induced nephropathy.64

Large volume paracentesis followed by intravenousalbumin infusion decreases the risk of acute renal failureafter paracentesis.30 The results of albumin use in thisclinical setting are better than other volume expanderssuch as dextran.65,66 In a recent study comparing nor-mal saline and albumin, albumin was more effective


than saline in the prevention of paracentesis-inducedcirculatory dysfunction.67 Saline is a valid alternative toalbumin when less than 5 L of ascitic fluid is evacuated.

Moreover, patients with cirrhosis may develop a spe-cific acute renal failure called hepatorenal syndrome(HRS). It is a diagnosis of exclusion. HRS is an omi-nous complication of end-stage liver disease. Retrospec-tive studies indicate that HRS is present in �17% ofpatients admitted to the hospital with ascites and in�50% of cirrhotic patients who die from liver failure.The hallmarks of HRS are reversible renal constrictionand mild systemic hypotension.68 The kidneys arestructurally normal and at least in the early part of thesyndrome, tubular function is intact, as reflected byavid sodium retention and oliguria. The cause of renalvasoconstriction is unknown, but its pathogenesis maypredominantly involve both increased vasoconstrictorand decreased vasodilator factors. Two patterns of HRSare observed in clinical practice: type 1 and type 2. Type1 HRS is an acute form of HRS in severe liver diseaseand is progressive. It is associated with poor prognosiswith 80% mortality at 2 weeks. Type 2 HRS occurs inpatients with diuretic-resistant ascites. The course ofrenal failure is slow. It is also associated with poor prog-nosis, although the survival time is longer than that ofpatients with type 1 HRS. The definition of HRS wasproposed by the International Ascites Club.36

Although the best treatment for HRS is LT,patients with HRS who are transplanted have morecomplications and a higher in-hospital mortality ratethan those without HRS.69 It has been suggested thatsystemic vasoconstrictor therapy may improve renalfunction in patients with HRS by increasing theeffective arterial blood volume. A nonrandomizedretrospective study in a large series of patients withHRS suggests that the vasopressin analog terlipressinis an effective treatment of renal failure.70 Othernonrandomized studies suggest that vasoconstrictivetherapy with noradrenaline71 or midodrine com-bined with octreotide72 may improve renal functionin these patients. TIPS has previously been shown tohave beneficial effect on renal function in HRS.73 Ina recent study by Wong et al.,74 TIPS was associatedwith further improvement in the renal function aswell as circulatory function, with normalization ofeffective arterial blood volume in selected type 1HRS patients (international normalized ratio lessthan 2, bilirubin less than 5 mg/dL, and Child-Tur-cotte-Pugh lower than 12), following administrationof combination therapy with midodrine, octreotide,and albumin.74 A randomized study in a small seriesof patients, comparing the molecular adsorbent

recirculating system combined with intermittentvenovenous hemofiltration vs. intermittent veno-venous hemofiltration alone, suggests that the molec-ular adsorbent recirculating system may improve sur-vival in HRS.75

Hepatopulmonary Syndrome

Hepatopulmonary syndrome (HPS) is a progressive,debilitating complication of end-stage liver disease thatoccurs in 4 to 25% of liver transplant candidates.76–78

The diagnosis of HPS rests on the triad of cirrhosis,hypoxemia, and intrapulmonary vascular dilation. Pul-monary features include digital clubbing, cyanosis, dys-pnea, platypnea, and orthodeoxia.

LT candidates with hypoxemia (PaO2 � 70 mm ofHg or arteriolar–aveolar gradient �20) in the absenceof any pulmonary dysfunction, should be screened forHPS since the syndrome appears to resolve after ortho-topic LT. Further work-up should include an arterialblood gas on 100% oxygen, double contrast echo or99mTC macro-aggregated albumin lung perfusionscan to establish the presence of intrapulmonary vascu-lar dilatation. The presence of microbubbles in the leftcardiac chambers between 3 and 6 heartbeats after thevisualization in the right chambers and a shunt fractionof more than 6% is considered as a positive test for thepresence of intrapulmonary vascular dilatation and thusconfirms the diagnosis.79,80 Figure 1 illustrates the workfor HPS.

Patients with HPS awaiting LT get a priority overother patients. Complete resolution after orthotopicLT even in the setting of severe hypoxemia has beenwell documented.59,77 However, PaO2 less than 50 mmof Hg and 99mTC macro-aggregated albumin brainuptake �20% are the pretransplantation risk factors forincreased mortality.

Efforts have to be made to rule out intrapulmonicshunting. Pharmacologic approaches have been disap-pointing in providing consistent and reproducibleimprovement in hypoxemia.81 The placement of TIPSto improve hypoxemia due to HPS remains controver-sial and cannot be advised without further prospectivestudy.82 Coil embolization to occlude discrete arterio-venous communications in patients with severe hypox-emia and HPS has resulted in significant improvementin PaO2 in 2 adults.83 Embolotherapy is an acceptedapproach to the management of severe hypoxemia asso-ciated with discrete arteriovenous malformation,84 butis not effective in HPS due to capillary dilation withoutdiscrete anatomic shunting.


Portopulmonary Hypertension

Portopulmonary hypertension (PPH) refers to thedevelopment of pulmonary arterial hypertension in thesetting of portal hypertension with or without liverdisease. It is defined as mean pulmonary artery pressure(PAP) �25, with a normal pulmonary capillary wedgepressure, an elevated pulmonary vascular resistance�125 dynes/second/cm–5, or increased trans pulmo-nary gradient (mean PAP / pulmonary capillary wedgepressure �10 mm of Hg).85 Candidates with PAPgreater than or equal to 40 mm of Hg on echocardiog-raphy should undergo a right heart catheterization toconfirm the diagnosis of PPH. Figure 2 illustrates thework-up for PPH. It has been estimated that in patientswho undergo LT with a mean PAP between 35 and 49mm of Hg and pulmonary vascular resistance �250dynes/second/cm–5 or greater, the mortality is 50%.Patients with a mean PAP of 50 mm of Hg or greaterhave a cardiopulmonary mortality rate of 100%.86 It istherefore recommended that moderate to severe PPHand significant right ventricle dysfunction should beconsidered contraindications to LT.

However, preoperative therapy to reduce PPH andright ventricular dysfunction may improve clinical sta-tus and make LT feasible. Continuous intravenous

epoprostenol (prostacyclin, or prostaglandin I2) is apotent vasodilator shown to improve exercise tolerance,reduce pulmonary vascular resistance, and improvemortality in patients with primary pulmonary hyper-tension.87 Similar hemodynamic improvements havebeen achieved before LT in patients with PPH.88,89 Kuoet al.88 treated 4 patients with 10–28 ng/kg/minute ofepoprostenol over 6 to 14 months and reported a 29 to46% decrease in mean PAP, a 22 to 71% decrease inpulmonary vascular resistance, and a 25 to 75%increase in cardiac output. Krowka et al.89 treated 10patients with mean PAP of 35 mm of Hg and higher for8 days to 30 months. Six patients showing improve-ments in pulmonary vascular resistance, mean PAP, andcardiac output after 1 hour had further reduction ofpulmonary vascular resistance when treated with con-tinuous therapy. Not enough data exist regarding thelong term benefit of epoprostenol therapy or regardingthe lasting effect after the cessation of therapy to makeany recommendations. However, epoprostenol therapyis most appropriate for the cirrhotic patient who exceptfor moderate to severe PPH has no other contraindica-tion for LT.

Hepatic Hydrothorax

Hepatic hydrothorax is defined as the accumulation offluid in the pleural space as a consequence of liver dis-ease. The most common symptom is dyspnea withoutchest pain. It can be detected with chest radiographs inas many as 13% of patients with cirrhosis. Right-sidedpleural effusion is seen in 66% of the patients withhepatic hydrothorax.90 The management options forhepatic hydrothorax include medical management ofascites, and therapeutic thoracocentesis for the controlof shortness of breath. The pleural fluid usually has thecharacteristics of a transudate. However, an occasionalpatient with hepatic hydrothorax may develop “spon-taneous bacterial pleuritis.” They should be treated asfor SBP; insertion of chest tube is contraindicated inthese patients. TIPS has been successfully used to man-age the symptoms of hepatic hydrothorax in the settingof marked ascites.91 Pleurodesis of the pleural spacewith chemical means such as talc, antibiotics, or che-motherapeutic agents usually fails. Video thoracoscopywith the repair of presumed diaphragmatic defects hasbeen described in the literature.92

Pruritus

Pruritus is a common symptom of chronic cholestaticliver diseases, particularly primary biliary cirrhosis. The1st line of treatment is cholestyramine, an anion

Figure 1. Work-up for hepatopulmonary syndrome.


exchange resin. It should be administered at least 4hours before or after taking the other medications, as itbinds many drugs.93 Side effects include bloating, con-stipation, and sometimes diarrhea. The 2nd line ofmedication is rifampin.94 The mechanism of action isunclear but it is effective in controlling pruritus in 50%of the patients with primary biliary cirrhosis. Dosage is150 mg twice a day and it is effective within 6 weeks oftherapy. The drug should be taken regularly for theeffectiveness of treatment. These patients should bemonitored closely for the possibility of drug hepatotox-icity. Several studies have demonstrated the effective-

ness of opioid receptor antagonists (nalmefene, nalox-one, and naltrexone) in the control of pruritus.95,96 Themajor side effects are the symptoms of opioid with-drawal. The treatment should be started slowly, prefer-ably in a hospital setting.

Management of Osteopenia and Osteoporosis

Osteoporosis and fractures are more common in cir-rhotic patients than in the general population in theabsence of confounding risk factors such as female gen-der, cholestasis, and excess alcohol intake.97,98 The role

Figure 2. Work-up for portopulmonary hypertension. PAP, pulmonary artery pressure; PCWP, pulmonary capillarywedge pressure; PVR, pulmonary vascular resistance; PGI2, prostaglandin I2; ECHO, echocardiogram; RHC, right heartcatheterization.


of calcium and vitamin D in preventing osteoporosis isunclear. According to recently published guidelines onthe management of osteoporosis associated withchronic liver disease, patients with cirrhosis or severecholestasis should have a baseline bone mineral densi-tometry.99 If the T score is more than –1.5 or between–1.5 and –2.5, no treatment is recommended. Thesepatients should be followed up with bone mineral den-sitometry every 2 years.100 The work-up for the patientswith bone mineral densitometry less than –2.5 shouldinclude thyroid function tests, serum calcium, phos-phate, estradiol, follicle stimulating hormone, luteiniz-ing hormone, testosterone, and sex hormone bindingglobulin levels. The optimum duration of therapy hasnot been established.100

The current recommendation is that the treatmentshould be given for a minimum of 5 years and the bonemineral densitometry repeated after 2 years and at theend of treatment.100 In women, hormone replacementtherapy with estrogen and progesterone should beoffered to premenopausal females. For men, transder-mal testosterone can be given to hypogonadal males.

The treatment recommendation for patients unableto take hormone replacement therapy / testosterone oreugonadal is bisphosphonates. Calcitriol or calcitoninshould be considered in those patients with osteoporo-sis who are either intolerant of hormone replacementtherapy and bisphosphonates or whose bone mineraldensitometry worsens despite either the use of bisphos-phonates or treatment of hypogonadism.

In the absence of larger studies on the effect of vita-min D supplementation on bone mineral densitometry,it seems reasonable to recommend correction of vita-min D deficiency with an oral daily dose of 800 IU ofvitamin D, and 1–2 gm of elemental calcium supple-mentation.

Conclusion

The care and monitoring of pre-LT candidates is verychallenging. Careful management of liver-specific com-plications can maximize their survival on the waitinglist.

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Management of pre–liver transplantation patient—Part 2