[2015] post lt cholestasis
TRANSCRIPT
Post LT Cholestasis
Ayman Alsebaey, MD,
Lecturer of Hepatology,
National Liver Institute.
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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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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.
8 Fusai 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.
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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How to think?
----------------- The causes
skeleton 11
Donor related
Recipient Related
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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
Preservation
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
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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Early Causes
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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
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
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
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
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
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
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. 32
EARLY CAUSES
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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Late intrahepatic cholestasis
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EARLY CAUSES
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
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
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
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
40 DIFFUSE INTRAHEPATIC BILE STRICTURES
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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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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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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
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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Thank You
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