Liver Transplantation - part 10 pps

The pediatric advantages were granted in re-sponse to concern that the small number of children waiting for liver transplant would be overwhelmed by the huge number of adults with equiva

advantages for pediatric recipients The pediatric advantages were granted in re-sponse to concern that the small number of children waiting for liver transplant would be overwhelmed by the huge number of adults with equivalent higher scores, causing increases in deaths and lengthy waiting times Lengthy waiting time has a disproportionate negative effect on young infants and children due to the impact of chronic liver disease on physical, cognitive and social development For these reasons, pediatric donors (donors under 18 years of age) are offered to pediatric recipients at

an equivalent status or score before potential adult recipients Furthermore, standard UNOS exceptions exist for specific metabolic diseases, and additional exceptions may be granted by the regional review boards of UNOS on request

Pre-Operative Management

• Medical therapy to correct metabolic abnormalities, coagulopathy, ascites, vitamin Deficiencies and malnutrition as much as is possible is a critical part of the management of any child with liver disease

• Malnutrition requires special attention as optimization of nutrition protects brain development prior to transplant and also improves outcome after surgery Nutritional support can start with institution of a high-density caloric diet, but often infants and young children require supplemental tube feedings The choice of formula is important, a partially hydrolyzed protein formula with increased medium-chain triglycerides is generally selected to optimize absorption in the face of cholestasis

• Meticulous attention to the delivery of normal “well-child” care is crucial

• Vaccination: children awaiting liver transplantation should receive all standard immunizations (Polio, DPT, HIB, HBV, MMR, Varicella) with particular attention given to live virus vaccines (which are generally not administered to immunosuppressed individuals) Furthermore, additional vaccinations (pneumococcus, influenza, etc.) are generally indicated Serologic evaluation for prior virus infections (particularly varicella, CMV and EBV) are also of great importance and have considerable impact on post-transplant management and monitoring

Surgical Issues and Options

• In the early era of liver transplantation the severe shortage of size-matched donors for infants and young children limited the application of transplantation to pediatric patients Although the death rate on the waiting list remains significant for children, the risk of dying whilst waiting for a liver allograft has considerably improved for pediatric patients as shown

in data in Table 2

• Innovative surgical techniques including reduced-size liver grafts, split and living related grafts has resulted in dramatic improvements in organ procurement for even very small infants and waiting times and deaths have been proportionately reduced The surgical aspects of these forms of transplant operation are discussed in Chapter 5

• Biliary atresia

- Biliary atresia is the result of an inflammatory/obliterative process of the extrahepatic bile ducts of unknown etiology Left untreated, this process results in obstructive cholestasis, biliary cirrhosis and death in 100% of children by age 2 years Management with the Kasai procedure can re-store bile flow in up to 80% of cases with the anastamosis of a bowel limb

to the hepatic capsule Despite the improvement in survival following the Kasai procedure, many of these children will develop complications of portal hypertension in late childhood or adolescence (variceal hemorrhage, ascites) and require transplantation at that time

- Biliary atresia is the most frequent underlying diagnosis in pediatric liver transplant recipients (See Table 1)

- Since almost all of candidates undergoing liver transplantation for bil-iary atresia will have had a prior portoenterostomy, the bilbil-iary anastamosis

is made to the existing or newly revised intestinal “Roux-en-Y” limb rather than to the native common duct (by definition absent in biliary atresia)

• Even children with intact extrahepatic biliary structures may require im-plantation of the bile duct into a Roux limb due to size limitations or multiple donor ducts in a partial graft Use of a Roux limb is an impor-tant feature, as future biliary problems can not be approached by ERCP Direct visualization of the biliary system can only be achieved by percuta-neous transhepatic cholangiogram in these patients

• Children may require vascular grafts or microsurgical techniques for the vascular anastamoses and the risks of thrombosis (particularly of the he-patic artery) are greatly increased for small infants Vascular bypass is gen-erally not required for children or infants and is rarely performed (then only in larger teenagers)

Early Post-Operative Management

The immediate post-operative management of pediatric liver graft recipients is directed toward continued support of liver function, critical care issues and detec-tion of early surgical complicadetec-tions

• Vascular problems: small children and infants are particularly at risk for vascular thromboses so the routine includes frequent Doppler ultrasound

to evaluate flow Pediatric recipients are routinely treated with intrave-nous Dextran to prevent thromboses in the peri-operative period and

Table 2 Deaths awaiting OLT in 1990, 1995 and 1999

Age of candidate: < 1 year 1-5 years 6-10 years 11-17 years

Data are shown as Patients listed/Deaths/Death rate per 1000 patient years at risk (Adapted from the UNOS web-site: www.unos.org)

then receive oral aspirin for 1 year after transplantation

• Bile leaks: Reduced size, living related or split liver grafts have increased risk of bile leak and/or bleeding from the cut surface

• Nutrition: Feeding can be difficult in small children and infants with midline liver placement and short term trans-pyloric tube feeding may be needed

similar to that in adults, although the arguments for restricting corticosteroids is even greater Drug dosages need be considered for the child’s weight

Subsequent Management

This is similar to that of adult recipients in terms of monitoring for and management of changes in liver function, rejection, late biliary complications and infections, but there are a few important exceptions

• Nutrition is again of utmost importance in recovery and rehabilitation, though a standard formula can generally replace the specialized feedings used pre-transplant Very young children and infants who received tube feedings pre-transplant often have delayed oral-motor development and may require feeding therapy in order to accept oral feedings

• Occupational or physical therapy may be necessary for children and infants with a lifetime history of chronic liver disease Older children generally recover very quickly and are eager to return to school and normal activities, often much faster than their adult counterparts return to work

• Infections: Prophylaxis and surveillance for viral infections, particularly

in those young children who did not have primary infections with EBV and CMV pre-transplant, is an ongoing issue

- EBV nạve children undergoing liver transplant are at high risk of devel-oping chronic EBV infection and post transplant lymphoproliferative dis-ease if the primary EBV infection occurs on immunosuppression The use of new quantitative PCR analysis for EBV has improved the monitor-ing for EBV activity PTLD is discussed in Chapter 7 In addition to the standard reduction or elimination of immune suppression and addition

of ganciclovir or acyclovir antiviral therapy

- CMV negative children will often receive CMV positive grafts (espe-cially if they receive a partial graft from an adult donor) and are at risk of CMV infection

- Exposure to other childhood viral illnesses is an ongoing issue for these children; varicella exposure for example is a frequent occurrence Chil-dren should be vaccinated for varicella prior to transplant, however the vaccine is less effective if given under 1 year of age Varicella antibody negative children should receive varicella immune globulin within 48 hours of known exposure (ideally within 12-24 hours) and are treated with intravenous acyclovir if clinical chicken pox develops Even after an episode of clinical infection most of these children will not develop

bodies and they are therefore at risk for repeated infection with subse-quent exposures

- Live vaccine administration to immunosuppressed transplant recipients

is controversial, with standard recommendations against immunization Even in those centers where MMR and/or varicella immunizations are given post transplant, reduced response to vaccination is observed

• Compliance: Compliance with medical therapy is a major issue with teen-age liver graft recipients especially those transplanted in infancy or early childhood Many of these teenagers do not remember their transplant experience and are entering a time of personality turbulence, testing of limits, and have acquired a general sense of invulnerability that extends from the usual adolescent risk taking (experimentation with drugs of abuse, exploration of sexuality) to failure to take medications The response to this behavior must be tailored to the individual child and family and must take into account the social and cultural background Parents, social workers, school guidance counselors and other resources are important partners in the effort to sustain delivery of medical care through adolescence

The adolescent patient: Children entering adolescence experience a variety of endocrinologic, physical and psychosocial changes In most cases these young adults will be best served at a pediatric center but care should be transitioned to an adult transplant center when medically and psychosocially appropriate

Suggested Reading

1 Kogan-Liberman D, EMRe S, Shneider BL Recent advances in pediatric liver transplantation Current Gastro Reports 2002; 4(1):84-97

2 Emre S Living-donor liver transplantation in children Pediatric Transplantation 2002; 6(1):43-46

3 Bucuvalas JC, Ryckman FC Long-term outcome after liver transplantation in chil-dren Pediatric Transplantation 2002; 6(1):30-36

4 Shneider BL Pediatric liver transplantation in metabolic disease: Clinical decision making Pediatric Transplantation 2002; 6(1):25-29

5 McDiarmid SV Management of the pediatric liver transplant patient Liver Trans-plantation 2001; 7(11suppl 1):S77-S86

6 Emond JC, Whitington PF, Thistlewaite JR et al Transplantation of two patients with one liver: analysis of a preliminary experience with “split-liver” grafting An-nals of Surgery 1990; 212(1):14-22

7 McDiarmid SV, Gornbein JA, Desilva PJ et al Factors affecting growth after pedi-atric liver transplantation Transplantation 1999; 67(3):404-411

8 Gloss JA, Shackleton CR, McDiarmid SV et al Long-term results of pediatric liver transplantation: An analysis of 569 patients Annals of Surgery 1998; 228(3):411-420

A

Acetaminophen 30-33

Acne 67, 102

Acute cellular rejection (ACR) 5, 8,

11, 12, 14, 16, 47, 60, 71, 74-77,

86, 104

Acyclovir 63, 79, 81, 101, 112

Addiction 28, 29, 41, 92, 103

Alcoholism 27, 29, 41, 92, 99

Alloimmune response 5, 7, 9

Alpha feto protein (AFP) 25, 39

Alpha-1-antitrypsin deficiency 108,

109

Amyloidosis 90, 91

Anergy 12-15

Angina pectoris 22

Angiotensin converting enzyme (ACE)

63, 96

Angiotensin II 96

Antibody dependent cellular

cytotoxic-ity (ADCC) 13

Antigen presenting cells 5, 15

Apoptosis 11, 14, 15, 64

Argon beam coagulatorargon beam

coagulator 54

Autoimmune hepatitis 28, 34, 64, 78,

89, 93, 98

Azathioprine (AZA) 12, 13, 61, 63,

68, 72, 79, 90

B

B-cells 5-8, 11, 12, 14

Basiliximab 12, 71

Biliary atresia 4, 109, 110, 111

Biliary cast syndrome 83, 84

Biliary leaks 74, 83, 84

Bone densitometry 27

Breast feeding 72, 104

Burkholderia cepacia 23

C

Calcineurin 12, 63, 64, 66, 68, 69, 72,

86, 95-98, 102, 103

Calcium 27, 64, 96, 97, 99, 103

CBD 44, 45, 50, 53

CD antigen 14

CD28 9, 15

CD3 8, 9, 12, 14, 68 Celiac sprue 28, 34 Central pontine myelinolysis 38, 103 Cerebral edema 29, 32

Cervical cancer 100 Cervical carcinoma 101 Chemoembolization 39 Chemokine 10, 15 Child-Pugh classification 17, 18 Cholangiocarcinoma 20, 26, 33, 39, 92

Cholangiogram 57, 59, 111 Cholestipol 20

Cholestyramine 20, 27, 63 Chronic ductopenic rejection (COPD)

11, 12, 15, 22, 34, 71, 74, 76-79, 84

Chronic obstructive pulmonary disease 22

Ciprofloxacin 38 Cirrhosis 3, 4, 18, 19, 27, 30, 33, 34,

36, 39, 41, 79, 86-88, 90, 93, 98, 107-109, 111

Co-amoxyclav 38 Co-stimulation 7 Coagulopathy 19, 29, 37, 74, 103, 110

Colon cancer 26, 33, 39, 101 Common bile duct 44, 50, 53, 57 Complement 11, 13

Cotrimoxazole 38 Creatinine 18, 24, 33, 38, 57, 67, 98 Crigler-Najjar syndrome 90, 107, 109 Cryoglobulinemia 98

Cryotherapy 39 Cryptogenic cirrhosis 34, 93, 109 CSA 13

CTLA-4 15, 63 Cutaneous warts 102 Cyclosporin 12, 13, 63-69, 71, 72, 76,

97, 99, 101-103 Cyclosporine 69 Cystic duct 49, 53, 57 Cystic fibrosis 23, 90, 107-109 Cytokine 7, 9-12, 15, 64, 66, 68 Cytomegalovirus (CMV) 27, 30, 40,

68, 72, 74, 76, 78, 79, 82, 86,

101, 110, 112 Cytotoxic T lymphocyte CTL) 14, 15

D

Daclizumab 12, 71

Deletion 12, 13

DEXA scan 99

Diabetes insipidus 42

Diabetes mellitus 25, 65, 67, 72, 95,

97, 98, 104

Diltiazem 66, 96

Direct antigen recognition 8

Diuretics 23, 24, 38, 97

E

Ebstein-Barr virus 27

EBV 27, 40, 73, 74, 79, 80, 81, 100,

101, 110, 112

Etidronate 27

Extended criteria donors 46

Extended use organs 2

Extracorporeal perfusion 32

F

Factor V 32

FAH 109

Fas 11

Fibrosing cholestatic hepatitis 86

FK506 13

FK506 binding protein 13

FKBP 13, 66

Foscarnet 79

Fulminant hepatic failure 20, 29-33,

34, 79, 109

Fumarylacetoacetate hydrolase 109

G

Gadolinium angiography 28

Gallbladder 44, 53, 54, 57, 59

Ganciclovir 79, 81, 112

Gentamicin 38, 66, 72

Glomerulonephritis 72, 98

Glucocorticoids 12, 63, 64

Glypressin 23

Graft versus host disease (GVHD) 15

Granzymes 11

Gum hypertrophy 64, 102

H

Halothane 30, 32, 33 Headache 64-68, 103 Hemochromatosis 33, 90, 91 Hemochromatosis gene test 33 Hemorrhagic necrosis 34, 74 Heparin 44, 46

Hepatic artery stenosis 83 Hepatic artery thrombosis (HAT) 34,

69, 74, 79, 81-83 Hepatic osteodystrophy 20 Hepatitis A virus (HAV) 32, 41, 88 Hepatitis B immunoglobulin (HBIg)

33, 88 Hepatitis B virus (HBV)

32, 33, 41, 72, 74, 87, 88, 110

Hepatitis C virus (HCV) 2, 23, 30,

33, 39, 41, 72, 74, 86, 87, 89,

93, 97, 98, 102 Hepatitis D virus (HDV) 33, 78, 88, 93

Hepatoblastomas 26 Hepatocellular cancer 20, 21, 109 Hepatopulmonary syndrome 19, 23, 34

Herpes simplex virus 27 Heterotopic auxiliary transplants 32 HFE 33

HHV-8 100 Hirsutism 64, 102 HMG CoA-reductase inhibitors 97 HPV 100, 101

HPV-6 101 HSV 27, 41, 74 Human herpes virus-8 100 Human immunodeficiency virus (HIV)

20, 26, 42, 57, 100 Human papilloma virus 100 Hydrocortisone 46, 62 Hyperacute rejection 2, 11 Hyperhomocysteinemia 95 Hyperkalemia 64, 97 Hyperlipidemia 34, 67, 69, 95, 97 Hypertension 18, 20, 22, 23, 36-38,

41, 42, 63-65, 67, 68, 83, 95-98,

103, 104, 107, 111 Hypoalbuminemia 24 Hypomagnesemia 97, 103

Hyponatremia 38

I

IBD 33

Immunoglobulin superfamily 11

Impotence 25

Inflammatory bowel disease 33

Innate immunity 16

Insomnia 63, 102

Insulin resistance 25, 34, 97

Integrins 11

Interferon 87

Interleukin-2 (IL-2) 7, 9, 12, 64, 66,

67, 71, 79

Interleukin-4 (IL-4) 7, 9, 66

Interleukin-6 (IL-6) 7, 9

Ischemic hepatitis 30

Isoniazid 26, 30, 72, 101

K

Kasai procedure 111

Kidney transplantation 24

L

Lamivudine 33, 88, 93

Lassitude 102

Lethargy 19

Live donor right lobe recipient

operation 59

Live liver donation 20, 21

Living donation 2, 57

Lymphoma 30, 73, 80, 81

M

Macrophages 5-7, 10, 11, 14

Magnetic resonance (MR) 25, 28, 33,

39, 41, 57, 82, 83, 89, 93, 103,

110, 113

Major histocompatibility complex

(MHC) 5-9, 11, 13-16, 86

Malabsorption 27, 28

Mammography 26, 39

Marginal donors 2

MELD score 17, 18

Menstruation 25

Midodrine 23

Molecular mimicry 8

Musculoskeletal pain 102, 103 Mycophenolate 12, 13, 68, 72, 97 Mycophenolate mofetil 12, 13, 97 Myocardial infarction 22

N

Nadalol 36 Naltrexone 20 NASH 34, 74, 93 Nephrotic syndrome 24 Neuroendocrine tumors 26, 93 Niemann-Pick disease 90 Nifedipine 96

NK cells 11 Non-alcoholic fatty liver disorder (NAFLD) 34, 93 Non-alcoholic steatohepatitis 34 Non-heart beating donors 2, 42, 84 Non-heart-beating donors 46 Non-steroidal anti-inflammatory agents 38

Norfloxacin 38

O

Obesity 34, 95, 97 OKT-3 12 Oral cancer 100 Ornithine transcarbamylase deficiency

107, 109 Orthoclone 14 Osteopenia 36, 99 Osteoporosis 65, 99, 103

P

Palmidronate 27 Pancreatitis 28, 34, 63, 92 Pap smears 39

Parvovirus B19 101 PELD 20, 109 Perforins 11 Peritonitis 19, 36, 37 Phenytoin 20, 32, 66 Plasmapheresis 20 Porcine endogenous retrovirus (PERVs) 2

Portal hypertension 18, 23, 36-38, 83,

107, 111

Portal vein thrombosis 36, 55, 83

Portal venous bypass 50

Porto-pulmonary hypertension 22, 23

Post-transplant lymphoproliferative

disorders (PTLD) 80, 100, 112

PPD 26

Pregnancy 30, 67, 68, 72, 104

Primary biliary cirrhosis 18, 19, 34,

79, 88, 98

Primary graft non-function 2, 74

Primary hyperoxaluria 109

Primary sclerosing cholangitis 19, 33,

34, 79, 89, 109

Propranolol 36

Prostatic specific antigen 26, 40

Protoporphyria 90

PSA 26, 40

Psychological assessment 28

Purified protein derivative 26

R

Radiofrequency ablation 39

Rapamycin 12, 63, 66, 69

Renal function 23, 24, 28, 57, 97, 98

Retransplantation 3, 4, 34, 35, 54, 72,

76, 83, 84, 86

Ribavirin 87

Rifampicin 65, 66, 101

Rifampin 20

Right lobe living donor operation 57

Roux-en-Y hepatico-jejunostomy 55

S

Seizures 68, 103

Selectins 11

Sirolimus 12, 63, 66, 67, 69-72, 97

Skin cancer 20, 80, 97, 100

Somatostatin 23

Split liver grafts 47, 112

Spontaneous bacterial peritonitis (SBP)

19, 36, 37, 38

Statins 66, 97

Steatosis 57

Stent thrombosis 37

Steroid resistant rejection 76

Subacute hepatic necrosis 31

Subfulminant hepatic failure 29, 30

Suppression 3, 12, 16, 20, 60, 61, 63,

66, 68, 70-73, 76, 78, 79, 81, 86,

89, 90, 95, 97, 101, 104, 112

T

T helper 7, 14-16 T-cell receptor 5-9 T-cells 5-8, 11-13 T-tube 53, 83, 84 Tacrolimus 12, 13, 63-67, 71-73, 76,

89, 97, 99, 101-103 Target of rapamycin (TOR) 63, 66 TCR 8, 14, 15, 16

Th lymphocytes 7 Th1 and Th2 paradigm 7 Th2 paradigm 7 Thyroid disease 25 Tobacco products 23 Tolerance 7, 12, 14, 16, 30, 60, 87, 104

Transjugular intrahepatic porto-systemic shunt (TIPS) 23, 37,

56, 57 Tremor 63, 64, 66, 67, 103 Trimethoprim 38

Tuberculosis 26, 72, 101 Tyrosinemia 30, 90, 108, 109

U

Ulcerative colitis 26, 39 UNOS 20, 25, 108-110 Ursodeoxycholic acid 20, 89

V

Vaccinations 40, 101, 103, 110 Vanishing bile duct syndrome 12, 71, 76

Variceal hemorrhage 19, 36, 37, 41, 111

Varicella zoster 101 Verapamil 66, 96 Vertebral fractures 99 Vitamin A 27 Vitamin D 27, 99, 110 Vitamin K 27 VZV 74, 101

X

Xenotransplants 2

V m

Michael R Lucey James Neuberger Abraham Shaked

a d e m e c u

Table of contents

1 Liver Transplantation:

An Overview

2 The Allograft Immune

Response

3 Assessment for Liver

Transplantation

4 Management on the Liver

Transplant Waiting List

5 The Liver Transplant

Operation

6 Immunosuppression after

Liver Transplantation

7 Graft Dysfunction

8 Recurrence of Disease after

Liver Transplantation

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LANDES

B I O S C I E N C E

Liver Transplantation

9 Medical Management of the Liver Transplant Patient

10 Pediatric Liver Transplantation