Liver Transplantation - part 4 pps

Prognostic criteria for predicting requirement of liver transplantation in patients with fulminant hepatic failure Acetaminophen Toxicity: pH 50 seconds and serum creatinine >3.4 mg/dL 3

Criteria for determining the prognosis of fulminant hepatic failure are shown below (Table 7)

Table 7 Prognostic criteria for predicting requirement of liver transplantation in patients with fulminant hepatic failure

Acetaminophen Toxicity:

pH <7.3 (irrespective of grade of encephalopathy)

or

Prothrombin time >50 seconds and serum creatinine >3.4 mg/dL (300 µmol/L) in Patients with grade III or IV encephalopathy:

Arterial blood lactate >3.5 mmol/l is associated with a high mortality

All Other Causes:

Prothrombin time >50 seconds (irrespective of grade encephalopathy)

or

Any three of the following variables (irrespective of grade of encephalopathy): Age <10 years or >40 years

Liver failure due to halothane or other drug idiosyncrasy or idiopathic hepatitis

Duration of jaundice prior to encephalopathy >7 d

Prothrombin time >25 seconds

Serum bilirubin >17.5 mg/dL (300 µmol/L)

Adapted from O’Grady et al Gastroenterology 1989; 97:439 The prothrombin time thresholds have been reduced for application in the US due to differences in laboratory methods to assay prothrombin time between Europe and US In Europe, prothrombin times should be multiplied by 2

These criteria separate acetaminophen-induced FHF from all other causes Drug-induced hepatic failure, other than that caused by acetaminophen, has a poor prognosis Examples include hepatic failure due to phenytoin or halothane HBV-and HAV-induced hepatic failure have a better outcome than idiopathic (presumed viral) fulminant hepatic failure.Patients younger than 2 years or older than 40 years have a poor prognosis Renal failure is also a poor prognostic factor Some have recommended serum factor V levels as an indicator of when to proceed to transplant

A factor V level of less than 20% is a poor prognostic indicator Acidosis is a valuable prognostic factor, particularly in acetaminophen- induced fulminant hepatic failure Whilst listed and awaiting a suitable donor organ, the patient may deteriorate (sepsis, cardiovascular or pulmonary failure, or cerebral edema) which may make transplantation impossible For this reason, human heterotopic auxiliary transplants, live donor segmental liver transplantation, extracorporeal perfusion through human

or pig livers or artificial hepatocyte perfusion devices, and xenografts have been attempted to sustain the patient until spontaneous recovery develops or a suitable organ is found

33 Assessment for Liver Transplantation

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Chronic Hepatitis C

The problem of chronic hepatitis C relates to the recurrence after transplantation Strategies to reduce HCV RNA are currently being evaluated This is discussed in Chapter 8

Hepatitis B Infection

HBV: Markers for active viral replication such as HBeAg and HBV DNA used

to be considered relative contraindications to liver transplantation The advent of anti-viral agents including lamivudine and postoperative management protocols using HBIg has allowed successful transplantation in high-risk patients Patients who have circulating HBV DNA should receive treatment with lamivudine while awaiting transplantation Antibodies to hepatitis D should be measured in HBsAg positive patients Co-infection by hepatitis D ameliorates the severity of post-transplant hepatitis B infection Management of HBV after transplantation is discussed in Chapter 8

Hemochromatosis

Patients with hemochromatosis have a worse outcome after liver transplantation than patients with other diagnoses Some of this effect is due to failure to recognize hemochromatosis during the pre-transplant evaluation All candidates should have serum iron, transferrin and transferrin saturation, and ferritin estimated We recom-mend the measurement of the hemochromatosis gene test (HFE) in anyone with iron saturation in excess of 45% or in anyone with a suggestive history for hemochromatosis (personal or family history of diabetes, cirrhosis, and arthritis) HFE is positive as a homozygous test for the major allele (C282Y) or heterozygous for both the major and minor allele (H62D) in 80% or more of affected persons depending on the ethnic diversity of the population in question Diabetic candidates for liver transplantation need particularly careful cardiac assessment

Primary Sclerosing Cholangitis

Colitis and Colon Cancer

Those with PSC and inflammatory bowel disease (IBD) have a greater risk of both cholangiocarcinoma and colon cancer than patients with IBD alone Since the colon cancer is likely to develop in the right colon, all patients should have a colonoscopy to assess the presence and degree of colitis as well as exclude colon cancer Colectomy at the time of transplantation does not seem to add to the risks of the procedure

Cholangiocarcinoma

Because the tumor spreads early along the lymphatics and nerves, the detection

of cholangiocarcinoma is a contraindication for transplantation Exclusion of cholangiocarcinoma is difficult as the tumors are often not visualized on imaging, whether by ultrasound, CT, MR or PET scanning Bile cytology, while specific, is not sensitive and ERCP is associated with a risk of inducing severe cholangitis and/

or pancreatitis Serum markers, such as CEA and CA19-9 may help but have not the specificity nor sensitivity required

Non-Alcoholic Fatty Liver

Non-alcoholic steatohepatitis (NASH) and it’s variant non-alcoholic fatty liver disorder (NAFLD) are terms used to describe an idiopathic clinico-pathological spectrum of disorders characterized by macrovesicular and microvesicular deposition within hepatocytes NASH is associated with histologic appearances of inflammation

in the hepatic lobule often with Mallory’s hyaline, in the absence of alcohol consumption NASH occurs in conjunction with insulin resistance, obesity, and hyperlipidemia, although not all patients exhibit all of these elements of the syndrome NASH may progress to fibrosis within the liver and is thought to be an important cause of cryptogenic cirrhosis Some patients with cryptogenic cirrhosis thought to

be due to NASH progress to liver failure and are candidates for liver transplantation

Celiac Sprue

Because of the association between celiac sprue and autoimmune disorders such

as autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis, all caucasian candidates for orthotopic liver transplantation should be screened for celiac disease by measurement of serum anti-endomysial antibodies When positive,

a duodenal biopsy is mandatory

Retransplantation

Early Retransplantation

Early retransplantation (usually defined as within the first 30 days) is required for primary allograft non-function, hepatic artery thrombosis and massive hemorrhagic necrosis Such patients behave like those with fulminant hepatic failure, and require emergency placement on the waiting list

Late Retransplantation

Late retransplantation is required for management of graft failure due to recurrent disease, vascular or biliary problems, or chronic ductopenic rejection Survival is less than that observed for primary graft recipients Retransplantation on account of recurrent viral hepatitis has a poor outcome due to aggressive recurrence of the underlying disorder Further attempts at rescue with second, third or fourth grafts are associated with progressively poorer outcomes in mortality and morbidity

Suggested Reading

1 Krowka MJ Hepatopulmonary syndromes Gut 2000; 46:1-4

2 Lee WM Management of acute liver failure Seminars in Liver Disease 1996; 16:369-378

3 Cardenas A, Uriz J, Gines P, Arroyo V Hepatorenal syndrome Liver Trans 2000; 6:S63-571

4 Neuberger J, Schulz KH, Day C, Fleig W, Berlakovich GA, Berenguer M et al Transplantation for alcoholic liver disease J Hepatol 2002; 36:130-137

35 Assessment for Liver Transplantation

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5 Trotter J F, Wachs M, Everson GT, Kam I Adult-to-Adult transplantation of the right hepatic lobe from a living donor N Engl J Med 2002; 346:1074-1082

6 Markmann JF, Markowitz JS, Yersiz H, Morrisey M, Farmer DG, Farmer DA et al Long-term survival after retransplantation of the liver Ann Surg 1997; 226:408-418; Discussion 418-420

Liver Transplantation, edited by Michael R Lucey, James Neuberger and Abraham Shaked.

©2003 Landes Bioscience

CHAPTER 4

Management on the Liver Transplant

Waiting List

James Neuberger

Introduction

Whilst awaiting liver transplantation, the patient should be closely monitored for several reasons:

• To ensure that the patient is receiving prophylaxis for complications of the liver disease

• To detect any new problems which may affect the success of the transplant

• To ensure the patient is as fit as possible for the procedure

Prevention of Complications of End-Stage Liver Disease

The patient awaiting liver transplantation, like any other patient with end-stage cirrhosis, is at risk of complications which may affect survival or the successful outcome after transplantation (Table 1)

Variceal Hemorrhage

In portal hypertension due to cirrhosis, the threshold of portal hypertension necessary for variceal hemorrhage is a transinusoidal gradient (portal pressure less inferior vena caval pressure) of 12 mm Hg The likelihood of a variceal hemorrhage

is predicted by:

• The degree of portal hypertension

• Severity of liver disease

• Endoscopic appearances: size of varices, presence of red spots

• History of previous variceal hemorrhage

The probability of bleeding or re-bleeding from esophageal varices can be reduced

by pharmacological or physical means Prophylaxis is indicated in those patients with cirrhosis who:

• have had a previous variceal bleed

• are at high risk (varices in a patient who is Child’s class B or C or has large varices)

The initial choice is with a non-cardioselective beta-receptor antagonist such as propranolol or nadalol This effect of beta-blockade may be assessed either by:

• pulse, either a reduction of resting pulse by 25% or to 60 bpm These are indirect measures of changes in portal pressure gradient and may

37 Management on the Liver Transplant Waiting List

4

overestimate the decline in pressure

• reduction in measured portal pressure to either less than 12 mm Hg or 25-50% below the initial portal pressure

About 30% of patients are unable to tolerate beta blockade in sufficient doses so mechanical methods should be considered

Long acting nitrates given in conjunction with non-selective beta receptor an-tagonists may have some additional efficacy

• Prophylactic sclerotherapy

• Prophylactic band ligation

• Transjugular intrahepatic porto-systemic shunt (TIPS)

Band ligation is preferable to sclerotherapy, as the latter is more likely to cause esophageal ulceration or peri-esophageal abscess in the post-opera-tive period TIPS is effecpost-opera-tive in reducing portal pressure and preventing variceal hemorrhage However, there are potential problems:

• The presence of the stent may complicate transplant surgery

• Stent thrombosis and narrowing may occur The benefits of long- term anticoagulation as a means of preventing stent

• TIPS is associated with deterioration in hepatic function when

attempted in patients with severely compromised hepatic function (elevated serum bilirubin, renal failure or marked coagulopathy)

Spontaneous Bacterial Peritonitis

Patients with ascites, which results from portal hypertension, are at risk of spon-taneous bacterial peritonitis (SBP) The predictive factors for SBP are:

• a previous episode of SBP

• ascitic protein < 1 mg/dl

Antimicrobial therapy has been shown to be effective in reducing the probability

of developing SBP from Gram negative organisms but has no impact on the rarer instances of SBP from Gram positive organisms Furthermore, prophylaxis has not been shown to affect mortality among patients with a history of SBP or who have

Table 1 Potential complications in patients with cirrhosis awaiting liver

transplantation

-Variceal hemorrhage

-Development of hepatocellular carcinoma

-Development of portal vein thrombosis

-Renal failure and electrolyte disturbance

-Spontaneous bacterial peritonitis

-Encephalopathy

-Malnutrition

-Sepsis

-Osteopenia

‘high-risk’ indicators for a first episode There are many regimens for prophylaxis against SBP:

• Norfloxacin 400mg/day

• Ciprofloxacin 250mg/day or 500 mg once per week

• Co-amoxyclav one tablet/day

• Trimethoprim/cotrimoxazole one tablet/day

Renal Function and Electrolyte Balance

Patients with end-stage liver failure are at risk of renal failure, occurring spontaneously (hepatorenal failure) or due to iatrogenic intervention Patients with ascites are at greatest risk, because the factors leading to ascites development (portal hypertension, splanchnic vasodilation, and peripheral vasodilatation) are also the factors promoting renal impairment through the development of intrarenal vasoconstriction and renal sodium retention

Renal function should be monitored carefully and any episode of renal impairment should be investigated fully

Care must be taken to avoid precipitating renal impairment by:

• Avoidance of nephrotoxic drugs (such as gentamicin)

• Avoidance of non-steroidal anti-inflammatory agents

• Avoidance of intravenous contrast material

• Monitoring the use of diuretics very closely and discontinue if serum urea

>8mmol/l, serum creatinine > 150µmol/l or serum sodium<120mmol/l

• Avoidance of hypovolemia: in particular, reduce diuretics when patient likely to become dehydrated (as in hot weather)

Hyponatremia, due to impaired free water clearance, often exacerbated by diuretics, is common in end-stage liver failure When the serum sodium concentration

is less than 120 mmol/L, there is a high risk of central pontine myelinolysis during

or soon after liver transplantation Treatment of hyponatremia includes withdrawal

of diuretics, restriction of water intake, and in rare cases dialysis Many programs will attempt to restore the serum sodium concentration to greater than 120 mmol/

L before starting the procedure

Cancer Development

Hepatocellular Carcinoma (HCC)

HCC may be the indication for liver transplant or may develop during the waiting period Follow-up of transplant candidates will differ:

Follow-up of Patients with Known HCC

In patients known to have HCC, it is important to monitor the growth of the tumor since during this time transplantation may no longer be indicated Features indicating transplantation may no longer be appropriate include:

• More than three detectable nodules

• Tumor diameter greater than 5 cm

• Spread of tumor outside the liver

• Invasion of the portal vein or hepatic artery by tumor This may be

39 Management on the Liver Transplant Waiting List

4

recognized as clot formation and a presumption drawn that the clot is malignant

The serum alpha feto protein (AFP) level is a poor guide to the size of the cancer but the rate of rise is a reasonable guide to the rate of growth The frequency of repeat imaging of the tumor will depend on the size and location of the tumor: for example, a large tumor close to the margin of the liver will require more frequent monitoring than a small 1 cm tumor in the right lobe As an approximate guide, we suggest the following follow-up schedule:

• Serum AFP every month

• Liver ultrasound or CT every 3 months

• Chest x-ray every 6 months

The role of ablative therapy (radiofrequency ablation, cryotherapy, chemoembolization, alcohol injection) in this situation is uncertain

Follow-Up of Patients Without a Known HCC (the ‘At-Risk’ Group)

The main risk factors for the development of HCC include the presence and duration of cirrhosis, male sex and chronic viral infection There are no established guidelines regarding the best screening protocol for at-risk patients

• Serum AFP measurement: There are many causes of an elevated serum AFP Elevations of serum AFP, often in the range of 100-500 ng/ml are particularly common among patients infected by HCV Sustained, progressively rising serum AFP levels demand a full assessment for HCC

In the absence of rising levels, repeat levels every 3-6 months are appropriate for cirrhotic patients awaiting liver transplantation

• Imaging of the abdomen (sonography or CT scanning) should be done every 6 months whilst awaiting a liver transplant

Cholangiocarcinoma

In general, the known presence of cholangiocarcinoma is a contra-indication for liver transplantation However, such cancers are very difficult to detect using either serological tests (such as CA19-9 or CEA) or imaging techniques (such as ultrasound,

CT or MRI scanning) There is little evidence to suggest that assessment by serological

or imaging is of value although the development of progressively dilated bile ducts may herald the onset of a cholangiocarcinoma

Other Cancers

Patients awaiting liver transplantation are susceptible to the development of extra-hepatic malignancy It remains uncertain whether the presence of cirrhosis or which

of the diseases predisposing to cirrhosis are associated with a greater probability of developing cancer The most common extrahepatic cancers to bear in mind are colon cancer in patients with ulcerative colitis These patients should have full colonoscopy every year while awaiting liver transplantation

Annual mammography and cervical screening (‘Pap smears’) should be main-tained in women of 40 years or more who are awaiting transplantation Annual

prostatic specific antigen (PSA) levels should be measured in men over 45 years who are on the waiting list for liver transplantation

Vaccinations

Most candidates for liver transplantation will have been vaccinated against or exposed to many of the viral pathogens which might prove harmful after liver transplantation It is appropriate therefore to assess the immunity to potential viral pathogens as part of the transplant evaluation Serologic markers to CMV, EBV,

Table 2 Immunizations in adults awaiting liver transplantation

Tetanus-diphtheria Toxoid vaccine 3 doses in nạve Persistent immunity

patients at 0, 4 up to 10 years weeks and 6-12

months Poliomyelitis Trivalent Nạve: 3 doses at Booster every

inactivated whole 0, 4 weeks and 10 years virus vaccine (IPV) 6-12 months

Influenza Trivalent split or One dose Annual booster

Hepatitis B Recombinant or 3 doses at 0, 4 Monitor anti-HBs;

plasma-derived weeks and 6 if <10 IU/L repeat subunit vaccine months booster dose Hepatitis A Inactivated whole- 2 doses, at 0 and Persistent immunity

virus vaccine 3-6 months up to 10 years Pneumococcus 23-valent One dose Persistent immunity

vaccine

H influenzae type b Polysaccharide One dose Complete

weeks prior to Tpx Varicella Live-attenuated 2 doses 6 weeks Complete

weeks prior to Tpx Mumps-measles- Live-attenuated One dose Complete rubella

weeks prior to Tpx Adapted from Stark K, Gunther M, Schonfeld, Tullius SG, Bienzle U

Immunizations in solid-organ transplant recipients Lancet 2002; 359: 957-965 Tpx indicates transplantation

41 Management on the Liver Transplant Waiting List

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HSV, varicella, HBV, HCV and HAV are checked as a routine measure Patients without immunity to the viruses listed in Table 2 should be vaccinated if time permits Candidates for liver transplantation should receive annual influenza immunization

Progression of Medical Complaints

Hypertension

Patients with systemic hypertension will need monitoring to ensure that the blood pressure is optimally controlled If there is any cardiac abnormality on screening, then it may be helpful to repeat the ECG and echocardiograph at 6 monthly intervals

Diabetes Mellitus

Patients with established diabetes mellitus will need careful monitoring to ensure that the blood sugar is within acceptable limits; when normoglycemia cannot be maintained by dietary methods or with oral hypoglycemic agents, then insulin should

be instituted

Alcoholism and Other Addictions

Alcohol addicted persons should have their alcohol use monitoring whilst awaiting transplantation This can be achieved by asking the patient and their family about drinking relapses and by random checks of blood and urine screens Smoking cessation: patients are advised to stop smoking, and formal smoking cessation programs are worth attempting

Temporary Suspension from the Waiting List

Patients may be suspended from the waiting list for several reasons and returned

to the active list when the temporary problem is resolved Temporary events leading

to suspension from the list include:

• Intercurrent infections

• Variceal bleeding

• Alcohol use by alcoholics

Suggested Reading

1 Runyon BA Management of adult patients with ascites caused by cirrhosis Hepatology 1998; 27:264-272

2 Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F et al Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis New Eng J Med 1996; 334:693-699

3 Schafer DF, Sorrell MF Hepatocellular carcinoma Lancet 1999; 353:1253-1257

4 Sharara AI, Rockey DC Gastroesophageal variceal hemorrhage New Eng J Med 2001; 345:669-681

5 Stark K, Gunther M, Schonfeld, Tullius SG, Bienzle U Immunizations in solid-organ transplant recipients Lancet 2002; 359:957-959