The document provides information on pediatric liver transplantation. It discusses the history and development of liver transplantation, including key pioneers like Dr. Thomas Starzl. It outlines the indications for liver transplantation in pediatric patients, including conditions like biliary atresia, Wilson's disease, acute liver failure, and hepatic tumors. The document discusses the evaluation process for pediatric liver transplant candidates. It also reviews contraindications and the pretransplant assessment process. Overall, the document serves as a comprehensive overview of pediatric liver transplantation, covering historical context, indications, evaluation, and pretransplant considerations.

1. LIVER TRANSPLANTATION
Dr T Sasidhar
Moderator: Dr KVS Narayana

2. Introduction
• Liver transplantation has been very successful in treating
children with end-stage liver disease, and offers the
opportunity for a long healthy life.
• Organ scarcity is the main limitation to the full exploitation
of transplantation- Split-liver and living-donor
transplantation have contributed to reversing a situation
• During early periods the 1st year survival is used to be
lessthan 25% which is improved to near 90% with the
present surgical expertise and the available
immunosupressive drugs and better understanding of
different disease processes.
• Combined organ transplantations is recent improvement
and still future improvements are awaiting.

3. Thomas E. Starzl
HISTORY
Initial liver transplant techniques were developed in in
the 50’s & ‘60’s with the pivotal baseline work of Dr
Thomas Starzl in Chicago and Boston
1st human liver transplant 1963- University of Colorado
1970s - immunosuppressive regimen based on steroids,
azathioprine and horse ALG (anti-lymphocyte globulin)
1976 – discovery of immunosupressive activity of
cyclosporine A by – Borel and colleagues
1980s
1980 – Starzl moved the transplant program to Pittsburgh
1981- introduction of cyclosporine A into clinical practice by Sir Calve
1983 – Cyclosporine approved for use by FDA
1983 – National Institutes of Health Consensus Conference
• LT accepted as definitive therapy for end-stage liver disease (ESLD)
1986 – OKT3 (muromonab-CD3) advanced treatment of rejection
1987 – University of Wisconsin solution (UW) improved organ quality

4. • Current American Association for the Study of Liver
Diseases (AASLD) liver transplant evaluation guidelines
include both adult and pediatric patients.
• pediatric liver transplants account for 7.8% of all liver
transplants in the United States.
• To more fully characterize the available evidence
supporting the recommendations, the AASLD Practice
Guidelines Committee has adopted the classification used
by the Grading of Recommendation Assessment,
Development, and Evaluation (GRADE) workgroup with
minor modifications

5. The classifications and recommendations are based on three categories:
•the source of evidence in levels I through III;
•The quality of evidence designated by high (A), moderate (B), or low quality (C); and
•the strength of recommendations classified as strong or weak.

6. Potential Members of the Pediatric Liver Transplant Team

7. Components of the Pediatric Liver Transplantation Evaluation
1. Secure all prior records to identify relevant diagnostic, management and clinical
information
2. Establish appropriate indications for referral
3. Construct a patient and disease specific appointment itinerary
4. Confirm or affirm the diagnosis, associated systemic manifestations, and
management plan
5. Assess disease severity and urgency for liver transplantation
6. Identify opportunities to maximize current medical therapy
7. Determine if non-transplant surgical options are available
8. Identify contraindications for liver transplantation
9. Consider appropriateness of a live donor option
10. Confirm immunization status; if incomplete, establish a strategy to complete
immunizations
11. Establish a trusting relationship among the child, family and transplant team
12. Ensure finances are available
13. Anticipate potential complications following transplant
14. Develop a management and communication plan with the local managing
physician
15. Clarify logistics when a potential donor liver is available

8. INDICATIONS FOR LIVER
TRANSPLANTATION
• Chronic liver failure
– Neonatal liver disease
• Biliary atresia
• Idiopathic neonatal hepatitis
– Cholestatic liver disease
• Alagille’s syndrome
• Familial intrahepatic cholestasis (FIC)
• Non-syndromic biliary hypoplasia
– Inherited metabolic liver disease
• a1-Antitrypsin deficiency
• Cystic fibrosis
• Glycogen storage type IV
• Tyrosinaemia type I
• Wilson’s disease
– Chronic hepatitis
• Autoimmune
• Idiopathic
• Postviral (hepatitis B, C, other)
– Other
• Cryptogenic cirrhosis
• Fibropolycystic liver disease +/– Caroli syndrome

9. • Acute liver failure
– Fulminant hepatitis
– Autoimmune
– Halothane exposure
– Paracetamol poisoning
– Viral hepatitis (A, B, C, E, or NA-G)
• Metabolic liver disease
– Fatty acid oxidation defects
– Neonatal haemochromatosis
– Tyrosinaemia type I
– Wilson’s disease
• Inborn errors of metabolism
– Crigler–Najjar type I
– Familial hypercholesterolaemia
– Primary oxalosis
– Organic acidaemia
– Urea cycle defects
• Liver tumours
– Benign tumours
– Unresectable malignant tumours

10. Etiology of Liver Disease

11. Biliary atresia
• single most common cause of liver disease leading to LT in children
• Diagnosis of BA and performance of a hepatoportoenterostomy
(HPE; Kasai Procedure) by 8 to 10 weeks of age is optimal for
transplant-free survival beyond early childhood.
• Infants with BA with vitamin K nonresponsive coagulopathy,
hypoalbuminemia, histologically advanced cirrhosis, ascites, portal
hypertension, and poor nutritional status prior to HPE have poor
outcomes.
• Following HPE, up to 70% of BA patients may have prolonged
transplant-free survival if the total serum bilirubin falls below 2
mg/dL within 3 months following the HPE.
• Children with biliary atresia splenic malformation (BASM) may have
less favorable rates of transplant-free survival as reported in some
studies.

12. • Post-HPE complications include ongoing cholestasis, cholangitis, portal
hypertension with or without variceal hemorrhage, poor weight gain, fat
soluble vitamin deficiencies, hepatopulmonary syndrome,
portopulmonary hypertension, and rarely hepatocellular carcinoma.
• Post-HPE regimens to promote bile flow (i.e., ursodeoxycholic acid) in BA
patients are not standardized.
• Prophylactic antibiotic regimens with either trimethoprim /
sufamethaxazole or neomycin reduce recurrent rates of cholangitis and
improve survival.
• High-dose corticosteroid therapy initiated within 72 hours of HPE was not
shown to improve bile drainage at 6 months, nor did it enhance
transplant-free survival.
• Aggressive nutritional support to ensure adequate growth and prevention
of fat soluble vitamin deficiency can improve neurodevelopmental and
transplant outcome.

13. • Management of portal hypertension remains poorly
studied in children and use of betablocker therapy for
primary prophylaxis of variceal hemorrhage is
controversial in childhood.
• Variceal hemorrhage may be the sentinel event that
prompts LT evaluation.
• Cases of hepatocellular carcinoma (HCC) in BA patients
have been reported, including patients less than 1 year
of age, but the risk of HCC in BA is low.

14. • LT is recommended for BA patients’ post-HPE
with complications of chronic liver disease.
Recurrent cholangitis with or without
associated decompensation of liver function
can be an indication for LT in BA.

16. Wilsons disease
• WD may be clinically indistinguishable from
autoimmune hepatitis, nonalcoholic fatty liver
disease, or cryptogenic cirrhosis.
• The most dramatic presentation is fulminant WD,
particularly when encephalopathy is present.
• A child over 5 years of age with ALF accompanied
by a Coombs-negative hemolytic anemia and low
or normal serum alkaline phosphatase should
heighten the suspicion for WD.
• WD presenting with an acute hemolytic crisis
carries a poor prognosis

17. Acute liver failure
Recommendations
• Pediatric acute liver failure (PALF) patients should
receive early contact with and/or referral to a
pediatric liver transplant center for
multidisciplinary care. (1-B)
• Establish an etiology of PALF in order to identify
conditions that are treatable without LT or
contraindicated for LT. (1-B)

18. Hepatic Tumors
Hepatoblastoma
Recommendations:
• Children with nonmetastatic and otherwise unresectable
hepatoblastoma should be referred for LT evaluation at the
time of diagnosis or no later than after 2 rounds of
chemotherapy. (1-B)
• Patients with HB and pulmonary metastases can be
considered for LT if, following chemotherapy, a chest CT is
clear of metastases or, if a tumor is identified, the
pulmonary wedge resection reveal themargins are free of
the tumor. (1-B)

19. Hepatocellular Carcinoma
Recommendations:
• Prompt referral to a liver transplant center should
occur for children with or suspected to have
hepatocellular carcinoma. (2-B)
• As the Milan criteria may not be applicable to children,
transplantation for hepatocellular carcinoma must be
individualized and should be considered in the absence
of radiological evidence of extrahepatic disease or
gross vascular invasion, irrespective of size of the lesion
or number of lesions. (2-B)

20. • Absolute contraindications to transplant include
radiological evidence of extrahepatic disease (1-B);
relative contraindications to transplant include major
venous invasion, or rapid disease progression despite
chemotherapy. (2-B)
• Hepatocellular carcinoma (HCC) is uncommon among
children and there are no current data to support
general screening for HCC in children; children with bile
salt excretory pump disease and tyrosinemia are at
higher risk for developing HCC and should undergo
periodic screening. (2-B)

21. Cystic Fibrosis-Associated Liver Disease
Recommendation:
• The indications for liver transplantation are
guided by
– the degree of hepatic synthetic failure and
– the presence of otherwise unmanageable
complications of portal hypertension.
• Optimal timing for isolated liver transplantation
involves careful assessment of pulmonary and
cardiac function and nutritional status in CF
patients. (2-B)

22. Urea Cycle Defects
Recommendation:
• Urgent referral for LT should be considered
when patients present in the first year of life
with severe UCDs in order to prevent or
minimize irreversible neurological damage
(1A); living related liver transplantation may
be an option for some patients. (1-B)

23. Crigler-Najjar Type I
Recommendation:
• Referral for LT evaluation should be
considered for CNI patients before the
development of brain damage, ideally at the
time of diagnosis when the option of LT can be
discussed. (1A)

24. Immune-Mediated Liver Disease
Autoimmune Hepatitis
Recommendations:
• LT is considered in patients with autoimmune hepatitis
(AIH) who present with acute liver failure associated with
encephalopathy and those who develop complications of
endstage liver disease not salvageable with medical
therapy (2-B).
• Children with AIH and families being evaluated for LT
should be informed they may require more
immunosuppression than children transplanted for other
indications and remain at risk for recurrence of AIH. (2-B)

25. Primary Sclerosing Cholangitis
Recommendations:
• Surveillance for inflammatory bowel disease with a full
colonoscopy with biopsy both before and after LT in
patients with features of primary sclerosing cholangitis
is recommended. (2-B)
• LT evaluation should be considered for patients with
decompensated liver disease, recurrent cholangitis,
unmanageable bile duct strictures, and/or concerns for
the risk of cholangiocarcinoma. (2-B)

26. Hereditary Tyrosinemia Type 1
Recommendations:
• Initial treatment of hereditary tyrosinemia type 1 is
with NTBC when the diagnosis is established. (1-A)
• Referral for LT evaluation should occur promptly if the
child has progressive liver disease despite an adequate
dose of and compliance with NTBC, rising AFP while on
NTBC, a change in liver imaging with a single nodule
exceeding 10 mm or an increase in the number or size
of hepatic nodules, or if management with NTBC and
diet cannot be adequately maintained. (1-B)

27. Glycogen Storage Disease
Recommendations:
• LT evaluation should be considered for patients
with:
• GSD I with poor metabolic control,
• multiple hepatic adenomas, and/or
• concern for HCC(1-B);
• GSD III and IV with poor metabolic control,
complications of cirrhosis, progressive hepatic
failure, and/or suspected liver malignancy. (1-B)

28. Fatty Acid Oxidation Defects
Recommendations:
• Management of FAOD with diet and intravenous
glucose should be the first line of therapy. (2-B)
• Patients with FAOD should be considered for LT
evaluation if they experience recurrent episodes
of PALF or have failed medical therapy. (2-B)

29. Contraindications for liver transplantation
Absolute
• Hepatocellular carcinoma with extrahepatic disease and rapid progression
• Generalized extrahepatic malignancy
• Exception: Hepatoblastoma with isolated pulmonary metastases
• Uncontrolled systemic infection
• Severe multisystem mitochondrial disease
• Valproate induced liver failure
• Niemann-Pick Disease Type C
• Severe portopulmonary hypertension not responsive to medical therapy
Relative
1. Hepatocellular carcinoma with Venous invasion/ Rapid progression despite
chemotherapy
2. High certainty of nonadherence despite multidisciplinary interventions and
support
3. Hemophagocytic lymphohistiocytosis
4. Critical circumstances not amenable to psychosocial intervention

30. PRETRANSPLANT ASSESSMENT

31. PREPARATION FOR TRANSPLANTATION
Immunization
• Live vaccines are usually contraindicated in
the immunosuppressed child, and so it is
important to ensure that routine
immunizations are complete.

32. Management of hepatic complications
• Variceal bleeding should be managedwith oesophageal
banding or sclerotherapy, vasopressin or octreotide
infusion.
• Oesophageal banding is preferred to injection
sclerotherapy for children on the active liver transplant list.
• In children with uncontrolled variceal bleeding, the
insertion of TIPSS (transjugular intrahepatic porto systemic
stent-shunt) has proved an effective management strategy
in older children

33. • Sepsis, particularly ascending cholangitis and
spontaneous bacterial peritonitis, requires effective
treatment with appropriate broad-spectrum
antibiotics.
• Salt and water retention leading to ascites and cardiac
failure should be effectively managed with diuretics
and salt and water restriction.
• It is essential to consider intervention with
haemodialysis and/or haemofiltration if acute renal
failure or hepatorenal failure develop.

34. Donor Organs – Legal Obstacles
1968 – Ad Hoc Committee of the Harvard Medical School
examined the Definition of Brain Death
1981 – Uniform Determination of Death Act
• irreversible cessation of circulatory and respiratory
functions, or
• irreversible cessation of all functions of the entire brain,
including the brain stem
1984 – National Organ Transplant Act
• Created a nationally regulated system of organ allocation
• authorized the DHHS to establish Organ Procurement
Organizations
• established the formation UNOS

35. United Network for Organ Sharing (UNOS)
• Established as a non-profit organ sharing
system
• Policies and procedures set up to determine
how to distribute organs
• Initially priority given to local OPO and those
with the greatest waiting time

36. Liver Transplant – Unequal Access
• MELD (Model for End-Stage Liver Disease) scoring system – 2002
– Sickest patients should get transplanted first
– Model predicts risk of death from ESLD for adults
Bilirubin, Coagulation (INR), Creatinine
• MELD = 3.78[Ln bili (mg/dL)] + 11.2[Ln INR] + 9.57[Ln creat
(mg/dL)] + 6.43
• MELD predicted 3 month mortality
– 40 or more — 71.3% mortality
– 30–39 — 52.6% mortality
– 20–29 — 19.6% mortality
– 10–19 — 6.0% mortality
– <9 — 1.9% mortality

37. PELD (Pediatric End-Stage Liver Disease)
Predicts risk of death from ESLD for children (<11y)
• Bilirubin, INR, Albumin, Age <1 and Growth Failure.
• PELD = 4.80[Ln bili (mg/dL)] + 18.57[Ln INR] - 6.87[Ln
albumin (g/dL)] + 4.36(<1 year old) + 6.67(growth)
• Review of the PELD system showed that in the majority
of pediatric patients (53%), the actual calculated PELD
score was not utilized to determine liver allocation
• An exception to the PELD score was utilized in 24%

38. exceptions
• When the PELD score is believed not to reflect the
• severity of liver disease or its consequences the PELD score
can be adjusted higher.
• These conditions include
• failure to thrive,
• intractable ascites,
• pathologic bone fractures,
• refractory pruritus, and
• hemorrhage due to complications associated with portal
hypertension.
• A pediatric liver transplant candidate with a urea cycle
disorder or organic acidemia shall be assigned a PELD (less
than 12 years old) or MELD (12-17 years old) score of 30.

39. • If the candidate does not receive a transplant
within 30 days of being listed with a
MELD/PELD of 30, then the candidate may be
listed as a Status 1B. Candidates meeting
these criteria will be listed as a MELD/PELD of
30 and subsequent Status 1B without reviews.
• A similar policy exists for hepatoblastoma

40. Organ procurement - Donor selection
Hepatocellular Mass
• How do you determine the appropriate
parenchymal mass for adequate function?
Estimated liver volume
LV (mL) = 706.2 × BSA (m2) + 2.4
or
LV (mL) = 2.223 × BW (kg)0.426 × height (cm)0.682
Graft to Recipient Weight Ratio (GRWR)
• 1-3% is optimum
• < 0.7% survival will suffer-insufficient liver mass

41. Practical Application
• Whole organ – Donor weight 1/3 above or
below that of recipient is appropriate
• L Lat Segment = donor/recipient wt ~10:1
• L lobe = donor/recipient wt ~5:1
• R Lobe = donor/recipient wt ~1:1

42. LIVER SEGMENTS-Couinaud

43. Organ Preservation
• Based on principles of hypothermia and prevention of cell swelling
Collins (EuroCollins) solution – 1969
Hypothermia minimizes cellular metabolism
High K to mimic intracellular fluid
High glucose (or mannitol) to reduce cell swelling
UW (Viaspan) solution – 1987
Lactobionate, raffinose, HES (oncotics, prevention of edema)
Supplementation with precursors of ATP (adenosine)
Antioxidants (allopurinol, glutathione)
HTK (Custidiol) solution – 1999
Histidine (strong buffer), Tryptophan & Ketoglutarate (amino acids
with low permeability), mannitol (osmotic barrier), low Na/K/Mg
Much lower viscosity, better for DCD donors

44. Liver grafts
Cadaveric
– Whole
– Reduced size
– Split size
Living related
Auxillary LT
Domino LT

45. Whole liver transplant
• Performed exactly as in adults- described by Starzl et al
• Performed with two different techniques: the classic technique with
inferior vena cava replacement, and the piggyback technique with
preservation of the native inferior vena cavaormed exactly as in
adults.
• Veno-venous bypass is generally not used in pediatric liver
transplantation
• In cases in which the liver is encased in adhesions, as it is in biliary
atresia- surgeons first approach the hepatic hilum from the right
posterolateral aspect, identifying the Roux-en-Y jejunal limb, which
is transected with a linear stapler or between ligatures. This allows
better exposure and dissection of the hilum.
• If the portal vein is small and sclerotic, it has to be dissected
proximally to the confluence of the splenic and superior mesenteric
vein, dividing the coronary vein of the stomach

46. Hepatectomy
Incision: Subcostal or hockey stick
• Division of hepatic ligaments
• Hilar dissection*
Common bile duct or Roux-en-Y
Hepatic Artery
Portal Vein
• Caval dissection
Remove and replace
or
Leave IVC in place (Piggyback)
*Often complicated by prior surgery (e.g.,
Kasai)

47. Veno-venous bypass – largely abandoned

48. After Recipient Hepatectomy

50. • Portal vein anastomosis will then be performed by means of a
donor interposition vein graft. In difficult dissections, the vena cava
can be clamped above and below the liver before completing the
mobilization of the liver itself.
• arterial reconstruction- preference to anastomose the small arterial
vessels encountered in pediatric whole liver transplantation in an
end-to-end manner.
• in the case of aberrant arterial anatomy, the supraceliac aorta is the
inflow vessel of choice. The use of arterial conduits anastomosed to
the infrarenal aorta is avoided if possible.
• biliary tract continuity can be restored through direct anastomosis/
hepaticojejunostomy.
• abdominal-wall closure may be impossible because of the large size
of the transplanted liver. This may be remedied by creating a silo on
the abdominal wall

53. Arterial Anastomosis
Incidence of anomalies* = 40%
*Gruttadauria et al, The hepatic artery in liver transplantation and surgery:
Vascular anomalies in 701 cases. Clinical Transplantation 2001; 15: 359-363
Three techniques
•End to End
•Complex reconstruction
•Aortic graft

55. Liver Transplant 4 main connections

56. Reduced-size liver transplantation
• first described by Bismuth et al
• consists in the procurement of the whole liver from an adult cadaver
donor, which is reduced in its size on the back-table- the left lobe
(Couinaud liver segments 1 to 4), including the vena cava, was
transplanted in a child.
• The graft is transplanted retaining the recipient’s vena cava, anastomosing
the graft left hepatic vein to the recipient’s vena cava.
• shows outcomes in line, if not superior, to whole-liver transplantation, and
has become an essential part of the technical expertise of pediatric
transplant centers
• main limitation is that it withdraws organs from the larger adult recipient
pool.
• For this reason, after the development of living-related and split-liver
transplantation, reduced-size live transplantation is used increasingly less,
and should not be considered an option anymore.

57. Living-related liver transplantation
• first description segments 2 and 3 -procured from a living
donor (the mother)-1988
• involves performing a left lobectomy during which
segments 2 and 3 are separated and dissecting the
parenchyma along a section running to the right of the
round ligament.
• Then the left branch of the portal vein, the hepatic artery,
and the left suprahepatic vein are quickly clamped and
dissected, and the left lobe perfused on the back-table.
• The recipient’s procedure is similar to the one described for
the transplant of segments 2 and 3 from a cadaver donor,
except for the fact that the arterial anastomosis can be
performed only in the left branch of the hepatic artery

58. • Widely debated with regard to the ethics of
performing major surgery on a healthy person
• a donor mortality and morbidity of
approximately 0.2% and 10%, respectively.
• Morbidity relates mainly to biliary fistulas,
incisional hernias, and bleeding.

59. Split-liver transplantation
• described originally by Pichlmayr
• procuring a whole liver from a cadaver donor and
dividing it into two sections along the round ligament,
leaving the vascular structures for the two portions of
hepatic parenchyma intact.
• This procedure involves a much longer ischemia time,
which, at the beginning of its adoption, led to
unsatisfactory results, with a high incidence of primary
dysfunction and technical complications.
• Rogiers described a technical variation in the split liver
technique, derived from the living-related transplant
experience that consisted in dividing the liver in situ

60. A section of the liver is made along the falciform ligament and
divides the left lateral segment from the extended right liver. The left graft,
composed of segments 2 and 3, and representing 20%-25% of the total liver volume,
includes the left hepatic vein, the left branch of the portal vein, and the left branch
of the hepatic artery, along with the common hepatic artery and the celiac tripod.
The right graft composed of segments 1 and 4-8, and representing 75%-80% of the
total liver volume, includes the vena cava, the right branch of the hepatic artery, and
the portal vein.
Spit liver allows for the procurement of two
separate grafts of different sizes

62. Donor selection
• Commonly accepted donor selection criteria
for split liver procurement are:
 age 15-50 years;
 weight > 40 kg;
 no past history of liver dysfunction/damage;
 liver function tests within 2-5-fold of normal
values;
 normal macroscopic appearance of the graft; and
 hemodynamic stability

63. • Data from multicenter registries have shown
that pediatric patients receiving livers from
pediatric-age donors have significantly better
graft survival compared to those receiving
livers from donors aged > 18 years

64. Living-donor selection
• usually a parent or first-degree relative
• Donors should be 18-55 years of age, and
• have an ABO-compatible blood type

65. Postoperative management of liver transplantation

67. EARLY POSTOPERATIVE PERIOD
• consists of managing problems related to
technical complications and to the prevention,
diagnosis, and treatment of acute rejection
and infection episodes.
• usually present with a combination of
cholestasis, rising hepatocellular enzyme
levels, and variable fever, lethargy and
anorexia

68. Primary non-function
• can be seen in the first hours following transplantation, with
– high lactate levels,
– increased prothrombin time and partial thromboplastin time, and
– failure of the patient to wake despite sedation suspension.
• Extremely serious complication - must be treated aggressively and
immediately by
– infusing prostaglandin E1,
– adopting the necessary measures to prevent a brain edema (mannitol
infusion, hyperventilation), and
– addressing the effects of the liver failure by infusing plasma and
glucose.
• If persist for more than a few hours, the patient needs a new
transplant as soon as possible.

69. • The status of the donor liver contributes
significantly to the potential for primary non-
function because of ischemic injury secondary
to anemia, hypotension, hypoxia, or direct
tissue injury.
• A possible cause of primary nonfunction is
hyperacute rejection.

70. Vascular complications
Hepatic artery thrombosis
• hepatic artery anastomosis carries the highest
risk of thrombosis (5%-18%) and leads to massive
graft necrosis in cases of early onset
• 3-4 times >adults and occurs most often within
the first 30 d after transplantation and in small
babies transplanted with whole livers.
• If identified early, reconstruction can be
attempted to avoid allograft necrosis
• When allograft failure develops, urgent
retransplantation is the only option

71. • Late thromboses can manifest with biliary
complications (stenosis or dehiscence of the
biliary anastomosis, intrahepatic bilomas) or
sepsis.
• Clinical manifestations include cholestasis or graft
failure caused by diminution in hepatic blood
flow.
• diagnosis relies on Doppler ultrasound-
Treatment modalities include revision of the
anastomosis or balloon angioplasty.

72. portal vein thrombosis
• 5%-10%
• more frequent in children transplanted for biliary atresia,
because of pre-existing portal vein hypoplasia
• Early thrombosis -detected by ultrasound screening,
requires immediate anastomotic revision and
thrombectomy.
• Later thrombosis is usually detected by decreased platelet
counts and increasing spleen size or gastrointestinal
bleeding.
• Interventional radiographic stent placement or balloon
dilation has been successful in patients who have portal
anastomotic stenosis.

73. Hepatic vein stenosis
• typical complication of a left lateral segment
graft
• between the left hepatic vein of the graft and
the native vena cava, which in the worst cases
can lead to acute Budd-Chiari syndrome.
• since the introduction of the triangulation
technique, this complication has become quite
rare.

74. Anastomosis between the left hepatic vein of the graft and the
inferior vena cava of the recipient, performed with the triangulation technique.
A: The bridge between the ostia of the right, middle, and left hepatic
veins is cut to obtain a single opening;
B: The opening is further enlarged by cutting the anterior face of the vena cava to
obtain a wide triangular orifice;
C: Three 5/0 vascular monofilament sutures are placed, taking the three corners of
the graft and recipient orifices

75. Biliary complications
• 10%-30%
• In the early postoperative period, the presence of bile-like fluid in
the abdominal drainage is strongly suggestive of a bile leak.
• Ultrasound evidence of intrahepatic biliary ducts dilatation,
elevated alkaline phosphatase and γ-glutamyl transferase (GT),
and/or recurrent cholangitis suggest anastomotic or intrahepatic
biliary stricture or small bowel obstruction at or distal to the Roux-
en-Y anastomosis.
• Complications after duct-to-duct biliary reconstruction can be
treated by dilation and internal stenting. With recur rent stenosis or
persistent postoperative leak, Roux-en-Y choledochojejunostomy is
the preferred treatment.
• In small children and in all patients transplanted for biliary atresia
or with a partial graft, Roux-en-Y choledochojejunostomy is the
reconstruction method of choice.

76. Reoperation and re-transplantation
• Early second-look reoperation is commonly used
in several centers for the best diagnosis and
treatment of bile leakage, hemorrhage, bowel
injury secondary to multiple intra-abdominal
adhesions, and sepsis.
• Infants and small children who have had only
initial skin closure require secondary laparotomy
for musculofascial closure in 5-7 d.
• overall incidence of re-transplantation ranges
from 8% to 29%.

77. • incidence of re-transplantation is similar for
whole-organ allografts and partial allografts.
• The majority of re-transplantations result from
acute allograft damage caused by either hepatic
artery thrombosis or primary non-function;
chronic rejection and biliary complication.
• When undertaken in a timely manner, patient
survival exceeds 80%. If delayed - <50%

78. Acute rejection
• 20%-50% of patients in the first weeks
• Clinical features- fever, irritability, malaise,
leucocytosis, often with eosinophilia, and
increased γ-GT, bilirubin, and transaminases.
• A liver biopsy is required to confirm rejection
• characterized by the histological triad of
– endothelialitis,
– portal triad lymphocyte infiltration with bile duct
injury, and
– Hepatic parenchymal cell damage

79. Acute cellular rejection: histopathological findings and grading.
A: Mild acute cellular rejection, portal tracts are mildly expanded because of a
predominantly mononuclear, but mixed portal inflammation. Rejection infiltrate is
composed of blastic and small lymphocytes, eosinophils, macrophages, and occasional
plasma cells. Lymphocytes are also present inside the basement membrane of the
small bile ducts and in the subendothelial space of small portal vein branches.
B: Moderate acute cellular rejection, all the portal tracts are markedly expanded by a
predominantly mononuclear, but mixed inflammation. Centrilobular inflammation and
hepatocyte necrosis and dropout are absent.
C:severe acute cellular rejection, severe expansion of the portal tracts because of
inflammation with focal portal-to-portal bridging; perivenular inflammation with
hepatocyte necrosis and dropout; inflammation and damage to small bile ducts.

80. • Severity of acute rejection is scored according
to the Banff scheme
• a semi-quantitative rejection activity index
(RAI) scoring on a scale from 0 to 3.

82. • The primary treatment of rejection is a short course of
high-dose steroids.
• Bolus doses administered over a 3-6-day period with a
rapid taper to baseline therapy are successful in the
majority of cases.
• When refractory or recurrent rejection occurs,
conversion from cyclosporine to tacrolimus, or
antilymphocyte therapy using the monoclonal
antibody, ornithine-ketoacid transaminase orthoclone,
have been successfully used.

83. INFECTIONS
• Infectious complications now represent the most common
source of morbidity and mortality after transplantation.
• Bacterial infections occur in the immediate
posttransplantation period and are most often caused by
Gram-negative enteric organisms, enterococci, or
staphylococci.
• Fungal infection most often occurs in high-risk patients
requiring multiple operative procedures, re-
transplantation, hemodialysis or continuous hemofiltration,
pre-transplant chemotherapy, and multiple antibiotic
courses - prophylaxis with liposomal amphotericin B.

84. Viral
Early and severe viral infections –
Herpes family
EBV, CMV and
Herpes simplex Herpes virus 6 and 7
Risk of CMV and EBV infections –
pre-operative serological status of recipient and
donor
D+ / R- greatest risk of primary infection

85. CMV infection
-fever, leukopenia, rash
-hepatitis
-pneumonitis
-GIT involvement
-CMV colitis frequently serum PCR negative needs tissue
diagnosis
EBV infection
-mononucleosis-like syndrome
-hepatitis resembling rejection
-post transplant lymphoproliferative disease
Monitor CMV and EBV PCR
all children receive IVI Gancyclovir
conversion to oral Valgancyclovir

86. MANAGING IMMUNOSUPPRESSIVE
THERAPY
Corticosteroids
• first drugs to be used to control rejection
• Act through intracellular receptors expressed in all cells of the body.
• Their immunosuppressive action mechanism, not fully clarified yet,
is linked to the
– suppression of antibody production;
– inhibition of synthesis of cytokines such as (IL-2) and interferon-γ;
– reduction in the proliferation of helper and suppressor T cells,
cytotoxic T cells, and B cells; and
– the migration and activity of neutrophils
• Overimmunosuppression is associated with increased incidence of
bacterial, fungal and viral infections
• Detrimental metabolic effects of steroids are wide ranging and are
of particular concern for the pediatric transplant patient

87. Calcineurin inhibitors
• Cyclosporine and tacrolimus
• they inhibit T-cell responses and bind to
intracellular proteins called immunophilins.
• The immunophilin-drug complex competitively
binds to and inhibits the phosphatase activity of
calcineurin. Calcineurin inhibition indirectly
blocks the transcription of cytokines, particularly
IL-2, which regulate the proliferative T-cell
response

88. 3- Cyclosporine and tacrolimus inhibit antigen stimulated act1vat1on and proliferatiOn
of helper T cells as well as expression of IL-2 and other cytokines by them
1-Glucocorticoids inhibit M H C
expression and IL-1 IL-2. IL-6
product ion so that helper T-cells
are not activated.

89. • side-effect profiles, which include dose-dependent
nephrotoxicity, neurotoxicity, and hypertension
• Most adverse effects are reversible after dose
reduction or discontinuation of the drug.
• Tacrolimus has not been associated with cosmetic
adverse effects such as hypertrichosis and gingival
hyperplasia
• Moreover, tacrolimus is associated with less
hyperlipidemia and a lower adverse cardiovascular risk
Profile but with slightly more de novo diabetes and
gastrointestinal symptoms

90. • Calcineurin inhibitors are mainly absorbed from
the small intestine.
• metabolized in the liver and small intestine by the
cytochrome P4503A enzyme system.
• The majority of their metabolites are excreted in
bile.
• tacrolimus is superior to cyclosporine for the
treatment of rejection episodes that may resolve
when patients are switched from cyclosporine to
tacrolimus therapy.

91. Mycophenolate mofetil
• active metabolite- mycophenolic acid, is a selective inhibitor of the
enzyme inosine monophosphate dehydrogenase, which is essential
for the de novo pathway of purine synthesis.
• Mycophenolate mofetil has been used successfully as an alternative
immunosuppressive agent in patients with chronic rejection,
refractory rejection, or severe calcineurin inhibitor toxicity.
• has also been used in calcineurin-inhibitor and corticosteroid-
sparing immunosuppressive protocols, without increasing the risk
of rejection.
• suggested dose for pediatric liver transplant recipients is 15 mg/kg
twice daily
• adverse effects dose-dependent gastrointestinal symptoms and
bone marrow suppression

92. Sirolimus
• Sirolimus (rapamycin) is a macrolide antibiotic
with potent immunosuppressive properties that
acts by blocking T-cell activation by way of IL-2R
post-receptor signal transduction.
• reduces rate of acute rejection, when used in
combination with calcineurin inhibitors, even at
low doses, or facilitates early steroid withdrawal.
• Sirolimus has also been used as rescue treatment
in chronic rejection and calcineurin inhibitor
toxicity
• Increased incidence of HAT is seen.

93. IL-2 receptor antibodies
• IL-2 receptor antibodies have been used primarily in
children as induction agents in double or triple
immunosuppression protocols
• incidence of acute rejection was lower in the induction
groups
• pediatric patients less than 35 kg in weight should
receive two intravenous 10-mg doses, and those
weighing ≥ 35 kg should receive two 20-mg doses of
basiliximab
• The first dose should be given within 6 h after organ
reperfusion, and the second on day 4 after
transplantation

94. POST-TRANSPLANT LYMPHOPROLIFERATIVE
DISORDERS (PTLDS)
• heterogeneous group of diseases, ranging
from benign lymphatic hyperplasia to
lymphomas.
• most frequent tumor in children following
transplantation, and occurs in the majority of
the cases within the first 2 years after
transplantation.
• Late forms have usually an aggressive clinical
course and severe prognosis

95. • Development is favored by the intensity of the
immunosuppression, its lifetime duration, and the
absence of prior exposure to EBV infection in 60%-80%
of patients.
• Risk factors for PTLD development are:
(1) high total immunosuppression load;
(2) EBV-naive recipients; and
(3) the intensity of active viral Load
• Treatment of PTLD is based on the immunological cell
typing and clinical presentation
• Rx – immediate withdrawl of immunosupression

96. • If a tumor expresses the B-cell marker CD20, the
anti-CD20 monoclonal antibody rituximab has
been successfully used.
• In some studies, the combination of
cyclophosphamide, prednisone and rituximab has
shown a response rate of 100%, with minimal
toxicity
• Recently, autologous EBV-specific cytotoxic T-
lymphocytes have proved effective in enhancing
EBV-specific immune responses and reducing
viral load.

97. LATE LIVER ALLOGRAFT DYSFUNCTION
• several potential causes
• Recurrent infections and immune-based diseases
are the most difficult diagnostic challenges.
• Most late causes of liver allograft dysfunction are
detected because of abnormalities in routinely
monitored liver tests; clinical signs and symptoms
are much less common. When signs or symptoms
do occur, liver biopsy is indicated.

98. Late-onset acute rejection
• show slightly different features than typical
acute rejection episodes
• commonly characterized by:
• (1) predominantly mononuclear portal inflammation;
• (2) venous subendothelial inflammation of portal or
central veins or perivenular inflammation; and
• (3) bile duct inflammation and damage
• Mild cases may resolve spontaneously, but
more severe forms warrant more aggressive
treatment.

99. Chronic rejection
• 5%-10%
• The primary clinical manifestation is progressive
cholestasis
• Two clinical forms have been described
vanishing bile duct syndrome
– The biliary epithelium is primarily injured with changes
ranging from senescence (early stage) to severe
ductopenia in at least 50% of the portal tracts (late stage).
– This form can be successfully treated by conversion from
cyclosporine to tacrolimus immunosuppression protocols.
– Re-transplantation is necessary in non-responding
children.

100. • The second subtype is characterized by the
development of progressive ischemic injury to bile
ducts and hepatocytes, which causes ductopenia and
ischemic necrosis with fibrosis
• the diagnosis is rarely based on histology alone,
because arteries with pathognomonic changes are
rarely present in needle biopsy specimens
• Selective hepatic angiography showing pruning of the
intrahepatic arteries with poor peripheral filling and
segmental narrowing supports a diagnosis of chronic
rejection.
• This form nearly always requires retransplantation

101. Recurrent and new-onset or de novo
autoimmune hepatitis
• Theoretically all forms of autoimmune hepatitis
after transplantation can be classified as rejection
Positive autoantibodies –
ANF, ASA, LKM-1 Ab
Hypergammaglobulinaemia
Histology - Interface hepatitis with portal lympho-plasmocytic
infiltrates
Exclusion of viral or drug-induced hepatitis
• recipients often require the use of second-line
immunosuppressive drugs (azathioprine,
mycophenolate mofetil).

102. Idiopathic post-transplant hepatitis
• Chronic hepatitis that cannot be ascribed to a
particular cause
• Cases presenting with central perivenulitis
probably represent centrilobular-based acute
rejection or autoimmune hepatitis
• Does not usually require treatment with
increased immunosuppression

103. Recurrent Primary sclerosing cholangitis
• nearly identical to that seen in native livers
• An accurate diagnosis of primary sclerosing
cholangitis recurrence requires well-defined
cholangiographic and histological criteria.
• Other disorders that can produce biliary
strictures after transplantation should be
excluded.

104. OUTCOME FOLLOWING TRANSPLANTATION

105. Age
• Survival for infants < 1 year of age or weighing < 10 kg
has been reported to be between 65% and 80% overall
Diagnosis
• Early survival rates are worse for patients who have
acute liver failure and liver tumors, but their long-term
survival rates are similar to those of other recipients.
• Similar decreased survival trends are seen in patients
who have a PELD score > 20, in status 1 recipients, and
in patients whose PELD scores deteriorate significantly
before transplantation.

106. Graft type
• Donor factors influencing patient and graft
survival include a donor age < 6 mo or > 50 years.
• The impact on the outcome of graft type (whole,
reduced, split, or living-donor) is less clear.
• recipients of whole organs had better patient and
graft survival than recipients of reduced, split, or
living-donor allografts.

107. Influence of Graft Type on Survival

108. Thank you.