Selection of patient for liver transplant

Apollo Medicine 2012 MarchReview Article

Volume 9, Number 1; pp. 3–8

© 2012, Indraprastha Medical Corporation Ltd

Selection of patient for liver transplant

Nisha Dhar Kapoor*, Mahesh Kumar Goenka***Consultant Gastroenterologist, Columbia Asia Hospital, Gurgaon,**Director and Head, Institute of Gastrosciences, Apollo Gleneagles Hospitals, 58, Canal Circular Road, Kolkata – 700054, India.

ABSTRACT

Liver transplant (LT) is becoming the need of the hour and often the last ray of hope for many of our cirrhotic patients. The dearth of deceased donors, acceptance of living-related donors, better operative skills, and post transplant outcomes have played an important role is making LT accessable to more and more needy people. However, for best outcome it is important to stick to the established criteria laid down for listing a patient for LT for both best outcomes and better distribution of donor livers.

Keywords: Cirrhosis, criteria, liver transplant

Correspondence: Dr. Mahesh Kumar Goenka, E-mail: mkgkolkata@gmail.com doi: 10.1016/S0976-0016(12)60113-6

Liver transplant (LT) has come a long way since the first human transplant by Starzl in 1963 and acceptance of LT by National Institutes of Health Consensus Development Conference in 1983 as an effective therapy. With better oper-ative techniques and postoperative care, the survival rate of LT recipients has improved considerably. The United Network for Organ Sharing (UNOS) database had shown that of the 24,900 patients who underwent LT from 1987 to 1998, the survival rates were 85%, 76%, and 61% at the end of 1 year, 4 years, and 10 years, respectively. Adhering to evidence-based indications, contraindications, and correct selection of transplant recipient have contributed largely to improved survival after LT. While most of the LTs being done in USA and UK are deceased donor liver transplants (DDLT), most of the transplants being done in Asian nations as of now are living donor-related liver transplants due to various cultural beliefs. Given the obvious shortage of donor organ, the selection criteria for the recipients are also impor-tant for better distribution of the available organs.

GENERAL SELECTION CRITERIA FOR LIVER

TRANSPLANT

Liver transplant is offered to patients of chronic liver disease where the expected survival without the transplant is < 90% at the end of 1 year. The most common indications for LT at most of the centers are advanced chronic liver disease due to hepatitis C, alcohol, and acute liver failure (ALF) (Table 1).

Originally, the organ allocation under UNOS was done as per the need of the patient, i.e., the sickest patient who had waited the longest getting liver first. Disease severity was initially defined by the Child-Turcotte-Pugh score (CTP) wherein patients with cirrhosis of liver with CTP score of 7 or more were listed for LT (CTP B/C). However, subse-quently, it was realized that the CTP score has its limita-tions. It gave equal importance to all five parameters; same score was awarded to the parameters beyond a certain level and no importance was given to creatinine which is an inde-pendent predictor of survival in cirrhotics.

To overcome these issues, model for end-stage liver dis-ease (MELD) system was adopted by UNOS from 2002 to decide on the disease severity for organ allocation priority. Model for end-stage liver disease scoring system is a mathe-matical score which utilizes three parameters: serum creati-nine, bilirubin, and international normalized ratio (INR). An individual’s MELD score is updated regularly. Studies have clearly shown that LT reduces the life expectancy for patients who have MELD scores of <15. Initial single center studies showed that addition of a hyponatremia variable improved the MELD score’s ability to predict liver-related mortality. However, these improvements were minimal and of little overall clinical benefit.1,2 Subsequent meta-analysis also showed that the addition of serum sodium to MELD did not add greatly to mortality prediction; however, there was a linear increase in the risk of death as sodium (Na) decreased between 135 mEq/L and 120 mEq/L.3

The ALF remains a separate entity with the highest priority for organ allocation.

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Other than the disease status, important factors to remember when referring a patient for LT are absence of contraindications for LT, the patient’s willingness and abil-ity to accept LT, compliance with follow-up and ability to cover the costs of the surgery and post transplant care.

CHRONIC LIVER DISEASE

This is the commonest indication for LT attributing to approximately 80% of the total transplants done. The ideal situation would be to take up patient when he is bad enough to be included in the transplant list but biochemi-cally still good enough to have a favorable outcome postliver transplant (Table 2).

Hepatic Encephalopathy

Mild hepatic encephalopathy by itself is not an indication for LT as it can be easily controlled with medications. If there is a precipitating cause of hepatic encephalopathy, treatment of the same resolves encephalopathy. However, recurrent or

severe hepatic encephalopathy does warrant referral to a transplant center. Once there is evidence of sustained raised intracranial hypertension (ICT) with cerebral edema, patient LT is no more an option for him. Clinical evidences of raised ICT are hyperventilation, opisthotonus, hyperpronation–adduction of the arms, cardiac arrhythmias, myoclonus, sei-zures, and poorly reactive pupils.

Ascites

While ascites easily controlled on drugs is not an indication for LT, if there is increasing diuretic requirement, side effects due to diuretics as hypokalemia, hyponatremia, or the need for large volume paracentesis, LT should be advised. Patients of refractory ascites may require transhepatic intrahepatic portosystemic shunt (TIPS) placement while waiting for trans-plant. A single episode of spontaneous bacterial peritonitis (SBP) confers a mortality risk of 50% and hence these patients are taken up for LT. Transplantation is usually deferred for minimum of 48 hours after antibiotics are instituted for SBP.

Portal Hypertensive Bleeding

A single episode of variceal bleed in a stable cirrhotic meets minimal listing criteria for LT as mortality risk for each episode of bleed is up to 50%. During active variceal bleeding, the patient is given vasoactive drugs (octreotide, somatosta-tin, terlipressin) and endoscopy is done. Endoscopic variceal banding/sclerotherapy is done for esophageal varices and glue injection is done for gastric varices. In case of uncontrolled or recurrent variceal bleed, TIPS maybe required. Other therapies for control of acute variceal bleed are balloon tamponade and surgical porto-systemic shunts. For secondary

Table 1 Indications for liver transplant.

1. Acute liver failure Acute viral hepatitis Drug/toxin hepatotoxicity2. Decompensated/advanced cirrhosis from chronic liver diseases

Chronic hepatitis B or CAlcoholic liver diseaseAutoimmune hepatitisCryptogenic liver diseaseCholestatic liver disease

3. Metabolic disordersAlfa-1 antitrypsin deficiencyWilson’s diseaseHereditary hemochromatosisGlycogen-storage disordersType 1 hyperoxaluriaFamilial homozygous hypercholesterolemia

4. MalignancyPrimary hepatic cancer: hepatocellular carcinoma and

cholangiocarcinomaMetastatic: carcinoid tumors and islet cell tumors

5. MiscellaneousPolycystic liver diseaseBudd-Chiari syndromeCaroli’s disease

Table 2 Indications for transplant in chronic liver disease.

1. Child-Turcotte-Pugh stage B/C2. Model for end-stage liver disease score >153. Recurrent or severe hepatic encephalopathy4. Refractory ascites5. Spontaneous bacterial peritonitis6. Recurrent portal hypertensive bleeding7. Hepatorenal syndrome8. Hepatocellular carcinoma within Milan Criteria9. Other indications:

a. Persistent hypoalbuminemia (<3 g/L)b. Persistently raised prothrombin time (>3 s above control)c. Severe malnutritiond. Severe chronic fatigue and weakness

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Selection of patient for liver transplant Review Article 5

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prophylaxis of variceal bleed, beta blockers (propanolol, nadolol), endoscopic banding/sclerotherapy, TIPS are used.

Severe Chronic Fatigue and Weakness

This symptom maybe severe enough to interfere with activ-ities of daily living and LT is recommended for a better quality of life.

Malnutrition

Progressive malnutrition is usually associated with advanced liver disease and hence as such may fulfill the criteria for LT. However, every attempt must be made to improve the nutrition status of the patient with good proteins, low fat frequent meals, and a good exercise regimen.

Hepatorenal Syndrome

Liver transplant reverses hepatorenal syndrome (HRS) and given its high mortality especially with HRS type I, patients who develop HRS should be referred for LT. The patient may require hemodialysis, molecular absorbent recirculating sys-tem (MARS) dialysis as a bridge to LT.

ALCOHOLIC LIVER DIEASE

Patients with alcohol liver disease should undergo assess-ment by a psychiatrist to evaluate for addiction status and risk of recidivism. These patients are accepted for LT after 6 months of abstinence as during this period liver functions may improve to the extent to get them off the list. This then also weeds out patients who are unlikely to remain abstinent postliver transplant. However, if it is presumed that they may not survive up to this period of abstinence, they may be taken up earlier as well. Pretransplant abstinence does not affect the post transplant survival.

HEPATITIS C

There is 100% recurrence of viremia postliver transplant. Post transplant treatment for hepatitis C is offered only if there is significant disease on liver biopsy. High pretransplant viral load, advanced donor/recipient age, hyperbilirubinemia,

elevated prothrombin time, and pretransplant cytomegalo-virus status have an adverse effect on patient survival.4 Retransplantation in hepatitis C cases has a worse off out-come as compared with the primary transplant.

HEPATITIS B

Recurrence postliver transplant has been reduced consider-ably with use of antivirals with hepatitis B immunoglobulin (HBIG) post transplant. Those with HBeAg positivity and high hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) load (>106 copies/mL) had a high rate of recurrence. The duration of use of HBIG postliver transplant still remains controversial though most programs use HBIG for minimum of 1 year and lifelong antivirals. Levels of HBIG >500 IU/mL are associated with low rate of recurrence.

CHOLESTATIC LIVER DISEASE

Cholestatic liver diseases (primary biliary cirrhosis [PBC] and primary sclerosing cholangitis [PSC]) have the best sur-vival rates postliver transplant. Table 3 gives the indications for LT in cholestatic liver disease. Mayo models for PSC and PBC are frequently used for assessing the disease severity. Patients with a Mayo model Risk Score of >10% mortality at 1 year are listed for transplant. Model for end-stage liver disease also has been shown to be equally helpful in predict-ing survival in cholestatic liver diseases and hence maybe used for listing patients for LT.

MALIGNANT DISEASE OF LIVER

Cholangiocarcinoma

While earlier cholangiocarcinomas were rejected in view of poor outcome and high recurrence rates postliver transplant, it is now realized that localized hilar cholangiocarcinomas

Table 3 Indications for transplant in cholestatic liver disease.

1. Bilirubin >10 mg/dL2. Progressive bone disease3. Recurrent bacterial cholangitis4. Poor quality of life: xanthomatous neuropathy, intractable

pruritis

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with no nodal involvement who have received neoadjuvant chemotherapy will do well postliver transplant.

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is given extra MELD points depending on its staging and waiting time on the list. While the T1 lesion gets no extra benefit, T2 lesion gets an initial MELD score of 24. Patients with HCC receive 10% mortality bonus every 3 months while continuing on the waiting list. Liver transplant is indicated in stage I and stage II HCC (T1 or T2, N0, M0) with no extrahepatic spread or invasion of vascular structures. Recurrence is more frequent with high alfa-fetoprotein (AFP) value (usually >1000–2000) probably due to more extensive spread than apparent on imag-ing. Along with the AFP levels, the tumor size, presence of vascular or capsular invasion, bilobular location, poorly dif-ferentiated histology, and number of nodules indicate poor prognosis post liver transplant.5 Most of the patients are still taken up for LT if they satisfy the Milan criteria, i.e., solitary tumor of size <5 cm or up to three nodules each not >3 cm. Since, the patients with HCC cannot wait for long, LDLT (living donor liver transplant) is promoted for HCC. This has given better post transplant outcome as the donors are usu-ally young. Recent data show that neoadjuvant locoregional therapy, i.e., ethanol injection/embolization, TACE, or RFA for HCC, improves outcome post transplant. The extended Milan Criteria/the University of California, San Francisco (UCSF) criteria accept patients with single tumors ≤6.5 cm in diameter or three or less tumors with the largest being 4.5 cm or less in diameter but overall of 8.0 cm or less.6

Other Liver Malignancies

Patients who have hemangiosarcoma and metastatic lesions to the liver, except neuroendocrine tumors, have poor out-come after transplantation. Fibrolamellar cancer is a less aggressive rare variant of HCC with better survival postliver transplant than HCC.

ACUTE LIVER FAILURE

Acute liver failure forms one of the most important indica-tions for LT which gets highest priority. Given the deficiency of donor organ availability, LDLT is encouraged for ALF. Criteria laid down by King’s College and Paris group at

Villejuif are the ones most followed for selection of patients for LT. Early referral to transplant center is important for good outcome. Once grade 4 encephalopathy or cerebral edema sets in, it heralds poor patient outcome. Along with the workup for transplant, these patients require aggressive management for prevention and management of complications like bleed-ing, infection, renal failure, and respiratory failure. Hepatic support devices as MARS can be used as a bridge to LT.

CRITERIA FOR LIVER TRANSPLANTATION IN

FULMINANT HEPATIC FAILURE

A. Criteria of King’s College, London Acetaminophen patients

pH <7.3, orINR >6.5 and serum creatinine level >3.4 mg/dL

Nonacetaminophen patientsINR >6.5 or

Any three of the following variables7: 1. Age <10 years or >40 years 2. Etiology: non-A, non-B hepatitis; halothane hepa-

titis; idiosyncratic drug reaction 3. Duration of jaundice before encephalopathy >7 days 4. INR >3.5 5. Serum bilirubin level >17.5 mg/dL.

B. Criteria of Hospital Paul-Brousse, Villejuif Hepatic encephalopathy and factor V level: <20% in

patient ≤30 years of age or <30% in patient 30 years of age or more.8

PRETRANSPLANTATION EVALUATION FOR

LIVER TRANSPLANTATION

Any patient who is listed for LT has to undergo a number of tests before he/she can be declared fit for LT. These tests are as follows:• Routine blood tests: Complete blood cell count, liver

function tests (LFT), urea, creatinine, serum electrolytes, calcium, magnesium, phosphate, coagulation profile (prothrombin time, partial thromboplastin time).

• Others: Cytomegalovirus, Epstein–Barr virus, herpes simplex virus, varicella zoster virus, human immunode-ficiency virus (HIV); syphilis; toxoplasmosis.

• Workup for etiology of chronic liver diseases: Antinuclear antibody, antismooth muscle antibody, anti-LKM1 antibody,

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IgA anti-tTG antibody, antimitochondrial antibody, Iron studies, ceruloplasmin, a1 antitrypsin phenotype, IgM anti-HAV, IgM anti-HEV, HBsAg, anti-HCV, HCV-RNA, HBV-DNA (HBeAg, anti-HBe antibody, IgM anti-HBc antibody in HBV patients), serum ceruloplasmin levels, 24 hours urinary copper levels, KF rings.

• Tumor markers: Alfa-fetoprotein, CA 19-9, CEA, CA 125, PSA.

• Other standard tests: Abdominal ultrasound with Doppler, electrocardiogram, chest radiograph posteroanterior (PA) view, pulmonary function tests, arterial blood gas (ABG), endoscopic evaluations, contrast-enhanced computed tom-ography (CECT) abdomen.

• Standard consultations: Dietary, psychological, gyneco-logical for women, anesthetic workup.

• Cardiological workup (ESP >50 years of age): Contrast echo, dobutamine stress test, coronary angiogram if indicated.

CONTRAINDICATIONS TO LIVER

TRANSPLANT

It is important to remember the various contraindications to LT to have good outcomes postsurgery. Some of the contrain-dications are absolute whereas others are relative (Table 4).

RETRANSPLANTATION

Quite a number of diseases like hepatitis B and C, alcoholic liver disease, non-alcoholic steatohepatitis, HCC, and the autoimmune and cholestatic diseases may recur after LT with prevailing deficiency of donor livers, retransplantation is a subject of discussion especially for diseases like hepati-tis C and HCC as retransplantated liver has a poorer outcome.

REFERENCES

1. Ruf AE, Kremers WK, Chavez LL, et al. Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. Liver Transplant 2005;11:336–43.

2. Biggins SW, Rodriguez HJ, Bacchetti P, et al. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology 2005;41:32–9.

3. Biggins SW, Kim WR, Terrault NA, et al. Evidence-based incorporation of serum sodium concentration into MELD. Gastroenterology 2006;130:1652–60.

4. Charlton M, Ruppert K, Belle SH, et al. Predictors of patient and graft survival following liver transplantation for hepatitis C. Hepatology 1998;28:823–30.

5. Klintman GB. Liver transplantation for hepatocellular carci-noma. Ann Surg 1998;228:479–90.

6. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403.

7. O’Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439–45.

8. Bernuau J, Samuel D, Durand F, et al. Criteria for emergency LT in patients with acute viral hepatitis and factor V below 50% of normal: a prospective study [abstract]. Hepatology 1991;14:49A.

FURTHER READING

1. Yu AS, Keeffe EB. Liver transplantation. In: Hepatology: A Textbook of Liver Disease 4th edn. Zakim D, Boyer TD, eds. Philadelphia: USA, Elsevier 2003:1617–56.

Table 4 Contraindications to liver transplantation.

1. Absolute contraindicationsExtrahepatic malignancyActive uncontrolled infectionActive alcoholism and substance abuseAcquired immunodeficiency syndrome (AIDS) not on highly

active anti-retroviral threaphy (HAART)Severe cardiopulmonary diseasePortopulmonary hypertension with mean pulmonary artery

pressure (PAP) of 50 mmHg or higherInability to comply with medical regimenLack of psychosocial supportAnatomic abnormalities precluding liver transplantationBody mass index (BMI) >40 Kg/m2

2. Relative contraindicationsAdvanced ageCholangiocarcinomaPortal vein thrombosisPortopulmonary hypertension with mean PAP between

35 mmHg and 50 mmHg

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2. Maddrey WC, Schiff ER, Sorrell MF. Transplantation of the Liver 3rd edn. Philadelphia: Lippincott Williams & Wilkins 2001.

3. Ahmed A, Keeffe EB. Current indications and contraindica-tions for liver transplantation. Clin Liver Dis 2007;11:227–47.

4. Murray KF, Carithers RL. AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology 2005;41:1407–32.

5. Busuttil RW, Klintmalm GB. Transplantation of the Liver 2nd edn. New York: Elsevier Health Sciences 2002:117.

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