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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