Liver Transplantation - part 4 pps

32 Liver Transplantation 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 3 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/ 34 Liver Transplantation 3 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 3 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. 36 Liver Transplantation 4 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 effective 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 occlusion are uncertain • 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 38 Liver Transplantation 4 ‘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 40 Liver Transplantation 4 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 Vaccine Type of Vaccine Dose Regimen Comment Tetanus-diphtheria Toxoid vaccine 3 doses in naïve Persistent immunity patients at 0, 4 up to 10 years weeks and 6-12 months Poliomyelitis Trivalent Naïve: 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 subunit vaccine prior to ‘flu season’ 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 polysaccharide up to 6 years vaccine H influenzae type b Polysaccharide One dose Complete conjugate vaccine immunization > 6 weeks prior to Tpx Varicella Live-attenuated 2 doses 6 weeks Complete vaccine apart immunization 4 weeks prior to Tpx Mumps-measles- Live-attenuated One dose Complete rubella rubella (MMR) vaccine immunization 4 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 4 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. Te mporary 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. [...]... occurs after cardiac death has been declared -Controlled Support is withdrawn and death is declared -Non-Controlled Cardiac arrest occurs despite continued support Table 3 Pre-operative management of the donor Problem Management Aim Hypotension Transfusion, dopamine, levo-thyroxine, Epinephrine Beta blockers or other anti-hypertensives Diuresis and oxygen delivery Dextrose replacement Maintenance of... case The surgeon determines, based upon the donor and relevant recipient factors, the suitability of the donor for liver procurement Donor suitability can sometimes only be determined intra-operatively or with a liver biopsy Pre-Op Donor Management The patients’ team carries out the pre-operative management of a potential donor Once a donor has been identified and consent obtained, a transplant coordinator... and to the left, passing behind the second and third parts of the duodenum The superior mesenteric artery limits this dissection The infrahepatic IVC is thus exposed and the upper border of the renal veins are defined as they enter it Liver Transplantation, edited by Michael R Lucey, James Neuberger and Abraham Shaked ©2003 Landes Bioscience 43 The Liver Transplant Operation Table 1 Donor information... alcohol history Results of electrolytes and liver function studies Results of relevant pre-operative imaging Table 2 Donor definitions Extended Criteria Livers which are less than perfect due to previous donor history or current condition of donor Brain Dead or Heart-Beating Donors Heart still beating, brain death declared by clinical or investigational findings Non-heart beating donors Fail brain death.. .42 Liver Transplantation CHAPTER 5 The Liver Transplant Operation Michael Crawford and Abraham Shaked Cadaveric Donors 5 Donor Selection The cadaveric liver transplant begins with a donor offer from an Organ Procurement Organization (OPO) coordinator The information in Table... preservation solution into the IMV and aorta is begun Ice is quickly placed over the liver and other intra-abdominal organs Suction catheters are placed in the chest to take the warm blood coming out of the IVC away from the liver Infusion of preservation solution continues until the effluent from the IVC is clear (usually around 4- 5 L total) The IVC is completely transected in the chest and the posterior pericardium... hypertensive injury to donor organ Maintain adequate oxygenation of donor organs Avoid hypernatremia Bicarbonate replacement Avoid end organ acidosis Urgent procurement Minimize time of organ injury 5 44 Liver Transplantation Figure 1 Donor setup 5 The ligament of Treitz is taken down and the inferior mesenteric vein (IMV) is exposed and isolated The aorta is then dissected just above its bifurcation, umbilical . Farmer DG, Farmer DA et al. Long-term survival after retransplantation of the liver. Ann Surg 1997; 226 :40 8 -4 18; Discussion 41 8 -4 20. 36 Liver Transplantation 4 Liver Transplantation, edited by Michael. peritonitis -Encephalopathy -Malnutrition -Sepsis -Osteopenia 38 Liver Transplantation 4 ‘high-risk’ indicators for a first episode. There are many regimens for prophylaxis against SBP: • Norfloxacin 40 0mg/day •. 2000; 46 : 1 -4 . 2. Lee WM. Management of acute liver failure. Seminars in Liver Disease 1996; 16:36 9-3 78. 3. Cardenas A, Uriz J, Gines P, Arroyo V. Hepatorenal syndrome. Liver Trans 2000; 6:S6 3-5 71. 4.