Jaundice and cholestasis post liver transplantation

1. Post LT Cholestasis
Ayman Alsebaey, MD,
Lecturer of Hepatology,
National Liver Institute.
1
Tutorial

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The History says
 Origin of used words:
►Jaundice originates from Latin word "galbinus"
that means yellow-green color.
►Icterus originates from Greek word "ikteros" that
means both yellow bird and jaundice as yellow
birds were used as a “cure” for jaundice.

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Bilirubin metabolism

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Cholestasis and hepatobiliary injury.

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8. Introduction
 Normally after LT operation there is mild elevation of the liver function tests that
normalizes soon with the immunosuppressive drugs.
 Severe intrahepatic cholestasis [SIC]:
 increase of serum bilirubin to more than 100 μmol/L [5.8 mg/dL] and/or
 an increase of alkaline phosphatase (ALP) three times above the normal range (during the first
month after liver transplantation) that is sustained for at least 1 week
 in the absence of biliary complications.
 Fusai et al., 2006:
 SIC prevalence is 25%.
 15% both elevated bilirubin and ALP.
 65% only elevated bilirubin
 20% only ALP elevation.
8Fusai G et al, 2006. Incidence and risk factors for the development of prolonged and severe intrahepatic cholestasis after liver transplantation. Liver Transpl 12(11):1626-33.

9. Fusai et al., 2006
 SIC predictors:
 Pre-operative; non-identical blood group, inpatient status before transplant ‘‘being so
ill’’
 Intra-operative; use of cryoprecipitate and platelet transfusion intraoperatively,
suboptimal graft appearance
 Post-operative: bacteremia.
 SIC absence predictors:
 Pre-operative; older recipient age, higher sodium & potassium preoperatively, acute
liver failure (despite the inpatient status).
 SIC mortality:
 44 % versus 20% in the non-SIC group of patients.
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11. How to
think?
-----------------
The causes
skeleton
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12. Donor
related
Recipient
Related
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13. Donor
Age
Old graft to
young recipient
Sex
Female graft to
male recipient
Relation
Related familial
diseases
Unrelated
Matching
Blood groups HLA mismatch
Diseases
Domino LT
Positive HCV A
or HBc Ab
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Recipient
Pre-
operative
Post-
operative
Intra-
operative

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Pre-operative
Disease
type
Cholestatic
e.g. PBC
Viral status
-ve or +ve
PCR
Acute or not
e.g. FHF
MELD score
High or low
Disease
association
Malignancy
Old cured Ca
breast, colon
infections
Old treated
TB
autoimmune
sarcoidosis

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Intra-operative
Graft
Type
LD or DD LT
Size
Small or
large
Quality
Good or
poor
Preservatio
n
Time
Blood
transfusion
High or low
Surgical
Events
Bleeding Trauma Maneuvers
Time

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Post-operative
Graft
Cell
Functional
cholestasis
1ry graft
dysfunction
Blood
vessel
HAT, PVT
Bile ducts
Stricture or
leak
Biloma,
abscess
Immune
cells
Graft related
infections
Immune
status
High or
low
ACR, CCR
Sepsis and
infections
Viral e.g. CMV
Bacterial
Fungal
Parasitic
DILI
Recurrent
diseases
PBC, AIH
Fibrosing
C, B
Malignancies
Recurrent
HCC
De novo,
PTLD
Events
Bleeding
Trauma
Maneuvers
Time

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• Early [<6mo]
• Late [>6mo]
Time of
complication

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EARLY CAUSES LATE CAUSES
Ischemia-reperfusion injury Chronic rejection
Initial graft dysfunction Hepatic artery thrombosis
Infections Biliary complications
• bacterial • biliary leaks
• fungal • biliary strictures
• viral
Small-for-size graft ABO incompatibility
Drugs Recurrence of disease
• immunosuppressant agents
• cholestatic disease (primary biliary cirrhosis,
primary sclerosing cholangitis)
• sulphonamides • viral disease
• antifungal agents
Acute cellular rejection Malignancies
• posttransplant lymphoproliferative disorder
• Kaposi's sarcoma
Lists of causes of early and late cholestasis after liver transplanttion

20. Perioperative Factors That May Affect Cholestasis 3 Months after LT
 The health of the recipient before
transplantation
 Allograft factors
 Small-for-size syndrome
 ABO blood group–incompatible donor
 Older donor age
 Allograft with greater than 30% steatosis
 Surgical procedure
 Prolonged cold and warm ischemia before
 reperfusion of the allograft:
preservation/reperfusion injury
 Roux-en-Y biliary anastomosis
 Blood product requirement
 Factors after transplantation
 Allograft rejection
 Biliary complications
 HAT
 Medications
 Sepsis/infection
 Recurrent disease
 Malignancy
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Cholestasis
Intracellular
Biliary
obstruction.

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Early cholestasis after liver transplantation
diagnosis flowchart. Fibrosing cholestatic
hepatitis, FCH; liver transplantation, LT; primary
biliary cirrhosis, PBC; primary sclerosing
cholangitis, PSC; ultrasound, US.

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Late cholestasis after liver
transplantation diagnosis flowchart.
Fibrosing cholestatic hepatitis, FCH;
liver transplantation, LT; primary biliary
cirrhosis, PBC; primary sclerosing
cholangitis, PSC; ultrasound, US

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25. Early
Causes
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26. Ischemia-reperfusion injury
 Cold ischemia: ischemia during hypothermic storage
 Warm ischemia: during implantation and restoration of blood flow in the recipient.
 Cholestasis is always associated with prolonged warm ischemia > cold ischemia
time.
 Detachment of biliary epithelium from the basement membrane.
 steatosis, cholestasis, and ballooning degeneration of hepatocytes.
 Biliary strictures is common with prolonged cold ischemia time [>10-12h].
 There is rapid normalization of the ATs but cholestasis may be prolonged to months.
 If multi-strictures occurs, re-transplantation is needed.
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EARLY CAUSES

27. Primary non-function and initial graft
dysfunction
Primary graft non-function:
 clinical features of initial poor function of the graft during the first week.
 Hyperbilirubinemia, prolonged INR with continuous deterioration of labs.
 Multiorgan failure syndrome and ultimately death.
Risk factors:
 Non-optimal donors: older donor age, presence of steatosis, and
prolonged cold ischemia .
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EARLY CAUSES

28. Acute cellular rejection [ACR]
 It can occur in the first 30 days especially at day 8.
 About 60% of the patient develop ACR in the 1st year depending on the utilized
immunosuppressive protocol.
 Risk factors:
 lack of adequate immunosuppression, young recipient age, higher initial aspartate
transaminase (AST) level, human leukocyte antigen DR mismatch.
 Longer cold ischemic time, older donor age , autoimmune disease as the original hepatic
cause.
 Clinical picture:
 Elevated LFTs but poorly correlated.
 Liver biopsy is the gold standard [mixed portal inflammation, endotheliitis, eosinophils in the
portal tract, and bile duct damage].
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EARLY CAUSES

29. Small-for-size syndrome
 It can be seen with reduced and split livers and living donor liver
transplantation.
 Impact:
 early graft dysfunction, including protracted cholestasis, coagulopathy, renal
dysfunction, and possible sepsis.
 It is associated with marked increased portal pressure [portal hyperperfusion from
portal pressure exceeding sinusoidal compliance].
 Proper graft size depends on:
 Graft volume and recipient size are important for determining the graft recipient weight
ratio.
 GTWR should be >0.8 with minimum liver volume is 40% to 50% of the recipient's
liver volume.
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EARLY CAUSES

30. Drug-induced cholestasis
 Really a lot of drugs are used post-LT so there is a big chance of Drug-
induced cholestasis.
 Azathioprine:
 May be associated with myelotoxicity, mild cholestasis with bile duct injury, veno-
occlusive disease and focal nodular hyperplasia.
 Cyclosporine:
 Is mild and dose dependent.
 It inhibits ATP-dependent pathways of exporting bile salts and secretion of glutathione.
 Tacrolimus:
 High doses are cholestatic.
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EARLY CAUSES

31.  Trimethoprim-sulfametoxazole:
 is used to treat Pneumocystis carinii infections and is used for its prophylaxis.
 It may cause cholestasis especially in women that improves within 6 months after
stopping the drug.
 Ketoconazole, itraconazole, and fluconazole:
 ketoconazole can cause cholestatic hepatitis for months. Reports of FHF.
 Fluconazole also has been reported to cause cholestatic hepatitis.
 Case reports of itraconazole-induced liver disease.
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EARLY CAUSES

32. Infections
 Sepsis-induced cholestasis:
 Cholestasis is a marker for the severity of sepsis.
 It is a marker of mortality.
 60% to 80% post LT develop infections.
 Risk factors:
 amount of intraoperative and perioperative blood products transfused, the interval of intubation
and stay on intensive care unit.
 Renal dysfunction, immunosuppression and comorbid conditions (e.g., diabetes, lymphopenia,
or neutropenia), and the presence of other infections.
 Early infections [<6m]:
 within 2 months are related to surgical and nosocomial risk factors.
 Late infections [>6m]
 are related to chronic rejection or are caused by opportunistic infections related to longstanding
immunosuppressive therapy.
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EARLY CAUSES

33.  Bacterial infection:
 Up to 70% of patients.
 Usually chest, wound, intra-abdominal (peritonitis, cholangitis, hepatic abscesses),
line-related, and nosocomial infections.
 Risk factors:
 transplant surgery lasting longer than 12 hours, bilirubin concentration more than 12 mg/dL before
transplant, duration of antibiotic therapy longer than 5 days, multiple plasma transfusion, and
multiple abdominal operations.
 Organism:
 Pseudomonas aeruginosa and Klebsiella pneumoniae.
 methicillin-resistant Staphylococcus aureus.
 Fungal infections:
 Usually fatal.
 Candida, Aspergillus.
 Rarely coccidioidomycosis, histoplasmosis, or cryptococcosis.
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EARLY CAUSES

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35. Late
intrahepatic
cholestasis
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EARLY CAUSES

36. Chronic rejection
Relentless increase in serum bilirubin and alkaline phosphatase
levels
Chronic or ductopenic rejection is of low incidence nowadays 2-5%.
It may develop in the first year or later.
There is cholestatic pattern not responding to immunosuppresives.
It is diagnosed with liver biopsy where there is loss of the bile ducts in at
least 50% of portal tracts and foam cell arteriopathy or obliterative
arteritis with wall thickening.
It may be preceded by recurrent attacks of ACR.
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LATE CAUSES

37. Late hepatic artery thrombosis
 It usually after 30days of LT.
 The hepatic artery supplies blood to the biliary tree through its biliary
branches.
 There is ischemia of the biliary system and the liver.
 Biliary leak or strictures or hepatic abscesses
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LATE CAUSES

38. ABO incompatibility
 ABO-incompatible liver grafts could be transplanted without adverse results.
 It may be associated with biliary strictures [non-anastomotic], hepatic artery
thrombosis, and chronic rejection.
 adsorbent filters to remove blood group antibodies are used to prevent
hyperacute rejection
 There is lower graft survival
 2-fold increase in mortality 3 months after LT.
 Should be restricted to emergency LT or living donor LT
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LATE CAUSES

39. Biliary complications
 Up to 40% of the patients. LDLT
>DDLT
 Types:
 Stricture:
 Anastomotic post 4-8 weeks [40% of
cases].
 Non-anastomotic post months to years.
 Biliary Leak.
 Risk factors:
 Ischemic injury; HAT, prolonged
ischemic time.
 Immunologic injury related to ABO
incompatibility.
 CMV infection and chronic ductopenic
rejection.
 Pre-existing autoimmune liver disease.
 Diagnosis:
 T-tube cholangiography, MRCP.
 ERCP is diagnostic and therapeutic.
 Treatment:
 Endoscopic dilatation and stenting or
surgery.
 Multiple strictures may result in a need
for re-transplantation.
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LATE CAUSES

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DIFFUSE INTRAHEPATIC BILE STRICTURES

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42. Recurrence of primary cholestatic disease
 Recurrence of primary cholestatic liver disease can be an important cause of
protracted cholestasis.
 PBC.
 10-20% recurrence.
 Risk factors: donor and recipient age, immunosuppression therapy (treatment with tacrolimus
compared with cyclosporine), and the warm ischemia time
 Cyclosporine may be protective.
 PSC.
 10% recurrence.
 Risk factors: are considered maintenance steroid therapy (> 3 months) and the presence of
ulcerative colitis after liver transplantation
 Short survival.
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LATE CAUSES

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44. Recurrent viral disease
 Cholestasis is not the main feature in recurrent viral disease.
 There is a severe fatal type that is called fibrosing cholestatic hepatitis.
 It occurs with recurring hepatitis B and C and presents with high bilirubin and progressive graft
failure.
 Cholestatic hepatitis CMV.
 Cholestaric hepatitis B:
 develops 2 to 10 months after liver transplantation in 5% of patients.
 It has been associated with greater potency of immunosuppressive treatment.
 Rarely seen now with prophylactic antiviral therapy.
 Cholestatic recurrent hepatitis C:
 Risk factors: HCV RNA pre and post LT, old donors, over immunosuppression.
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LATE CAUSES

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 CHOLESTATIC HEPATITIS C CRITERIA:
 Occurs more than one month post-transplantation.
 The patient is significantly immunosuppressed.
 Serum bilirubin is greater than 100 µmol/L or 6 mg/dl.
 AP and GTT are greater than five times the upper limit of normal.
 HCV load is very high (not defined, but certainly more than 6 log10).
 Histological features of hepatocyte ballooning, particularly in zone 3.
 Absence of hepatic artery thrombosis and biliary strictures.
 All of these features should be present to make the diagnosis.
 It was resistant to treatment [studies before era of DAAs].
 So low viral load before transplant is mandatory.

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48. Post-transplant lymphoproliferative
disorder
 Seen in 1% to 3.3 % of adult cases in the 1st year.
 T-cell lymphomas [14%].
 non-Hodgkin's lymphoma [93%].
 More common in children.
 Usually associated with EBV.
 Better prognosis than lymphoma itself.
 16% of cases develop chronic cholestasis.
 It may be infiltrative.
 Treatment: reduced Immunosuppression and Rituximab therapy.
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LATE CAUSES

49. Kaposi's sarcoma
 It is very rare.
 Kaposi's sarcoma is strongly associated with HHSV 8
 Incidence : 0.1% to 1 % in patients who have undergone liver transplantation.
 Liver and biliary tree involvement [infiltrative effect].
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LATE CAUSES

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51. Thank
You
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