Liver Transplantation - part 7 potx

71 Immunosuppression after Liver Transplantation 6 Treatment of Chronic Rejection Chronic rejection of the liver allograft has many names: chronic ductopenic rejection, vanishing bile du

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Treatment of Chronic Rejection

Chronic rejection of the liver allograft has many names: chronic ductopenic rejection, vanishing bile duct syndrome, chronic rejection Chronic ductopenic rejection may lead to loss of the graft It is treated by increased immunosuppression, including conversion to tacrolimus from cyclosporin or switching to Sirolimus

Withdrawal of Immunosuppression

The observation that some patients have maintained long-term good graft func-tion after discontinuing immunosuppression has led some centers to embark on carefully controlled trials of withdrawal of all immunosuppression in long-term (>5 years) survivors with good graft function, or in subjects with major impediments to continued use of immunosuppressant, such as malignant disease These studies have demonstrated that it is possible to withdraw all immunosuppression in about 20%

of carefully selected patients The remainder required maintenance immunosup-pressants or their reintroduction if they had been stopped The usual reason for failure to withdraw immunospressants was late onset acute cellular rejection, which was then controlled by adjusted phamacotherapy Those recipients grafted for non-autoimmune diseases, without episodes of acute rejection and with a good HLA match are more likely to be able to withdraw immunosuppression

Side-Effects of Immunosuppression

The side-effects of immunosuppression may be due either to

• The effect of immunosuppression itself (especially infection and malignancy)

• The effects of individual drugs

These are discussed in detail in Chapter 9

Tailoring the Immunosuppression to the Individual

Since different drugs have differing effects and side-effects both on the patient and the disease, it is important not to adopt one regime for all patients but to tailor the drug regime for the individual The probability of developing acute rejection is,

in part, dependent on the indication for transplantation so that patients grafted for viral hepatitis (especially B) and alcohol-associated liver disease have a much lower probability of developing early rejection than those grafted for autoimmune diseases such as PBC or AIH

Inter-Current Bacterial Infections

Currently available immunosuppressants will not only reduce the risk of rejection but will predispose the patient to infection The balance between over- and under-immunosuppression is even more difficult to maintain in the presence of active sepsis The general approach is to reduce the immunosuppression but the onset of graft rejection may not only herald the need for high-dose immunosuppression but hepatic impairment is associated with a further reduction in the host defences against infection In the presence of bacterial infection, early detection and vigorous treatment with appropriate antimicrobials is clearly required; depending on liver function,

steroids should be reduced initially Remember, however, in maintaining the bal-ance between rejection and infection, with rejection the graft will be lost but with infection the patient will be lost

Intercurrent Viral Infection

The most common viral infection during the early post-operative period is cy-tomegalovirus (CMV) CMV is associated with chronic rejection: this may be re-lated to a direct effect of CMV on the biliary epithelial cells and, in part, to the reduction in immunosuppression It is important, therefore, to reduce the immunosuppressive therapy in association with active antiviral treatment A com-mon practice is to stop azathioprine and reduce the calcineurin inhibitor

Tuberculosis

Because of the severe course of reactivation of tuberculosis in the patient on immunosuppression, most centers use prophylactic treatment with Isoniazid 100 mg/day in those at risk Isoniazid should be given with pyridoxine Treatment should

be for at least one year

The interaction between the immunosuppression and recurrent viral disease, such as HCV or HBV, is discussed in Chapter 8

Retransplantation for Chronic Rejection, Late Acute

Rejection and Early Ductopenic Rejection

These are associated with an increased risk of developing graft loss and therefore many centers are using a combination of corticosteroids, tacrolimus and mycophenolate or Sirolimus

Co-Morbid Conditions

Pregnancy and Breast Feeding

See Chapter 9: if the recipient is likely to become pregnant after transplantation, consideration should be given to the appropriate choice of drugs

Diabetes Mellitus

The tendency of calcineurin inhibitors to induce diabetes mellitus is controversial Tacrolimus may be more diabetogenic than cyclosporin Most transplant programs

do not switch from tacrolimus to cyclosporin, on account of diabetes mellitus Those diabetics given corticosteroids may have an increased requirement for insulin or oral agents

Renal Impairment

Renal impairment may occur following transplantation for many reasons (such

as IgA nephropathy, HCV associated glomerulonephritis, diabetic nephropathy or associated with the inappropriate prescription of non-steroidal anti-inflammatory drugs or nephrotoxic drugs such as gentamicin) In the presence of peri-operative renal failure, some centers avoid the use calcineurin inhibitors If renal impairment develops in associated with calcineurin inhibitor use, most centers will reduce or discontinue the calcineurin inhibitor (see Chapter 9)

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Development of Lymphoma and Other Malignancy

This is discussed in Chapter 7 Lymphoma post transplantation may be associ-ated with EBV infection Treatment is with aggressive therapy of the lymphoma and

a reduction in the immunosuppressive regime; some centers discontinue all immu-nosuppression during chemotherapy

Suggested Reading

1 Micromedex Information System; http://www.micromedex.com; info@mdx.com

2 Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B et al De-fining the outcome of immunosuppression withdrawal after liver transplantation Hepatology 1998; 27:926-933

3 Jain A, Kashyap R, Marsh W, Rohal S, Khanna A, Fung JJ Reasons for long-term use of steroid in primary adult liver transplantation under tacrolimus Transplanta-tion 2001; 71(8):1102-1106

Liver Transplantation, edited by Michael R Lucey, James Neuberger and Abraham Shaked.

©2003 Landes Bioscience

CHAPTER 7

Graft Dysfunction

Geoffrey H Haydon

Introduction

The causes of graft dysfunction occurring after liver transplantation may be classified either according to the time period post-transplantation (Table 1) or to the etiology of the graft dysfunction It should be emphasised that any of these conditions may become evident at any time after liver transplantation, and Table 1 lists the most common times for presentation

Investigation of Graft Dysfunction

The general diagnostic approach is outlined in Table 2 Investigation of each of the complications above is considered under the appropriate heading

Primary graft non-function

Primary graft non-function is defined as failure of the graft to function in the first post operative week It is manifested by:

• Failure to regain consciousness

• Sustained elevations in transaminases

• Increasing coagulopathy

• Acidosis

• Poor bile production

Primary graft non-function may be due to:

• Massive hemorrhagic necrosis

• Ischemia/reperfusion injury

• Hepatic artery thrombosis

• Idiopathic

It may be difficult to distinguish non-function which will not recover, from early poor function wherein graft function will return to normal after a period of systematic support The value of agents such as prostaglandins and n-acetyl cysteine in these circumstances is uncertain

Immunological Complications

Acute Cellular Rejection (ACR)

-Definition:

• “Inflammation of the allograft elicited by genetic disparity between the

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donor and recipient, primarily affecting interlobular bile ducts and vas-cular endothelia, including portal veins and hepatic venules, and occa-sionally the hepatic artery and its branches”

-Incidence:

• Occurs in 20% to 80% of grafts

-Timing:

• First occurs between 5 and 30 days post-transplantation; 80% of ACR occurs in the first 10 weeks post-transplantation ACR may still occur thereafter

-Clinical Findings:

• Usually asymptomatic, although in late or severe cases, fever and hepatome-galy occur When bile is collected, it is noted to be pale and watery

Table 1 Etiology of graft dysfunction more than one-month post transplantation.

Time Period Post-OLT Diagnosis

1-6 months Acute cellular rejection

Opportunistic infection -Viral: CMV; EBV (HSV, VZV less common) Vascular

-Hepatic artery thrombosis Recurrent viral hepatitis Biliary tract abnormalities 6-12 months Acute cellular rejection

Recurrent viral hepatitis Biliary tract abnormalities Chronic ductopenic rejection Hepatic artery thrombosis

>12 months Recurrent viral hepatitis

Biliary tract abnormalities Acute cellular rejection Chronic ductopenic rejection Recurrent autoimmune disease (PSC; PBC; AICAH) Hepatic artery thrombosis

Steatohepatitis

Table 2 Graft dysfunction according to pathogenesis

• Immunological complications: acute cellular rejection; chronic ductopenic

rejection

• Primary viral infection: CMV; HSV; EBV

• Graft ischemia: hepatic artery thrombosis

• Biliary complications: biliary leaks; bile duct strictures; choledocholithiasis and cholangitis

• Recurrent disease: viral hepatitis (HCV; HBV); PBC; PSC; AICAH, NASH

7 -Investigations:

• Liver chemistry tests are usually abnormal (but non-specific) and blood leukocytosis and eosinophilia are frequently present The gold standard for diagnosis of acute cellular rejection remains liver histology The histological features are mixed inflammatory infiltrate in the portal triads, bile duct damage, and vascular endothelial damage The Banff criteria grade of the severity of histological injury (see Table 3)

The differential diagnosis of deteriorating graft function is infection, graft ischemia and biliary obstruction The gold standard for diagnosis of ACR remains liver histology

-Treatment (this is described in Chapter 6)

-Prognosis:

• A single episode of easily reversed acute cellular rejection confers a better patient and graft survival than observed in patients who never experience rejection In contrast, acute cellular rejection that does not respond to increased immunosuppression (steroid resistant rejection) is associated with graft loss

Chronic Ductopenic Rejection

-Definition:

• Chronic ductopenic rejection is defined by two histopathological features: obliterative vasculopathy and bile duct loss (Table 4) It is also called chronic rejection and chronic vanishing bile duct syndrome

-Incidence:

• Most programs report less than 5% of grafts develop chronic ductopenic rejection

Table 3 Banff criteria grade of histologic injury

Subjective Grade Criteria

Indeterminate Portal inflammatory infiltrate that fails to meet criteria for the

diagnosis of acute rejection Mild Rejection infiltrate in a minority of the triads, that is generally

mild and confined within the portal spaces Moderate Rejection infiltrate expanding most or all of the triads Severe As above for moderate, with spillover into periportal areas

and moderate to severe perivenular inflammation that extends into hepatic parenchyma and is associated with perivenular hepatocyte necrosis

Banff grading of acute liver allograft rejection Global assessment of rejection grade made on review of the biopsy and after diagnosis of rejection has been established

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-Timing:

• Chronic ductopenic rejection may occur at any time after liver transplan-tation, but is usually seen in the first postoperative year

-Clinical Findings:

• As with ACR, most patients are free of symptoms Some have generalized systemic symptoms or complain of increasing jaundice and cholestatic symptoms

• Risk factors for chronic ductopenic rejections are shown in Table 4 -Investigations:

• Liver chemistry tests usually demonstrate a relentless rise in markers of cholestasis Liver biopsy is essential to make the diagnosis of chronic ductopenic rejection Special cytokeratin stains to identify biliary epithelia are useful when assessing bile duct loss Vascular lesions may be absent on

Table 4 Reported risk factors for chronic ductopenic rejection

Highly Probable:

-Retransplantation for chronic rejection

-Late acute rejection episodes

-Steroid-nonresponsive acute cellular rejection

Controversial Associations:

-Underlying liver disease

-AICAH -PBC -PSC -Positive lymphocytotoxic cross-match

-CMV infection

-Recipient age

-Donor/recipient of different ethnic origins

-Male donor allograft into female recipient

-Cyclosporin based immunosuppression (compared with tacrolimus regimes)

Table 5 Histological features and grading of chronic ductopenic rejection

Bile duct loss*, without centrilobular cholestasis, perivenular sclerosis, or

hepatocyte ballooning or necrosis and dropout

Bile duct loss*, with one of the following four findings:

-centrilobular cholestasis

-perivenular sclerosis

-hepatocellular ballooning

-hepatocyte necrosis and drop-out

Bile duct loss*, with at least two of the four following findings:

-centrilobular cholestasis

-perivenular sclerosis

-hepatocellular ballooning

-centrilobular necrosis and drop-out

*Bile duct loss: >50% of triads

needle biopsy specimens (Table 5)

• Hepatic angiography may show vascular injury

-Differential Diagnosis (Table 6)

-Treatment (this is described in Chapter 6)

-Prognosis:

• Approximately 30% of patients with chronic ductopenic rejection respond

to conventional additional immunosuppressive therapy In those who do not respond to standard immunosuppression, re-grafting is the only other option

De Novo Autoimmune Hepatitis

In a small number of liver transplant recipients a syndrome resembling autoim-mune hepatitis Develops It is characterised by biochemical hepatitis, autoantibod-ies and histologic appearances of inflammatory hepatitis The hepatitis usually responds to reintroduction or increased doses of corticosteroids

Graft Infection

Infection is a major cause of morbidity and mortality post-transplantation; there

is also a complex interplay between the immune system and infectious agents

CMV Disease

-Timing:

• Commonly within 2-3 months, and rarely within the first month of trans-plantation

-Clinical Presentation:

• Triad: fever; leukopenia; thrombocytopenia

• May present as: hepatitis; pneumonitis; GI tract infection (esophagitis, gastritis, duodenititis, and colitis)

-Diagnosis of CMV Disease:

• Abnormal liver chemistry tests

• CMV PCR positive when there is active viremia or shedding of virus (specificity 50-60%)

• Typical CMV inclusion bodies demonstrated on liver biopsy May also be seen in rectal or duodenal biopsies

Table 6 Differential diagnosis of cholestatic liver disease in the transplanted liver

Chronic ductopenic rejection

Biliary obstruction

Viral hepatitis (viral cholestatic hepatitis)

Sepsis

Drug hepatotoxicity

Recurrent primary biliary cirrhosis

Recurrent primary sclerosing cholangitis

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• CMV PCR of liver biopsy

-Risk Factors for CMV Infection:

• The respective serological status of the donor and recipient is most im-portant and must be documented: seronegative recipients of a graft from

a seropositive donor have the highest risk of infection

• Infection may be transmitted by the graft; blood products; reactivation of previous infection or superinfection by a CMV variant

• Patients with septic biliary complications (including hepatic artery thrombosis)

• Patients transplanted for fulminant hepatic failure

• Recipients treated with muromab OKT3 or thymoglobulin The risk of CMV in recipients of monoclonals directed against the IL-2 receptor remains uncertain

-Prophylaxis against CMV Infection:

• Ganciclovir and acyclovir are highly effective against CMV reactivation; re-infection or new disease

• Studies comparing the two drugs suggest that ganciclovir produces a more significant reduction in infection than acyclovir

• Individual programs determine policy regarding prophylactic regimes against CMV Prophylaxis may be restricted to high risk patients, but are not essential for all recipients

-Treatment of CMV Graft Infection

• Immunosuppression should be reduced (azathioprine usually stopped)

• A 14 day course of intravenous ganciclovir (10 mg/kg/day IV in 2 doses)

is most effective Many programs follow this with 6 weeks oral ganciclovir

• Second line therapy: Foscarnet 60 mg/kg every 8 hours for 14 days (avoid

in renal failure); CMV Ig

• Third line therapy: Cidofovir 5 mg/kg once weekly for 2 weeks, followed

by 5mg/kg every 2 weeks (also avoid in renal failure)

EBV Hepatitis (Table 7)

-Timing:

• No specific timing after liver transplantation

-Clinical Presentation:

• Infectious mononucleosis syndrome (fever; fatigue; lymphadenopathy; pharyngitis)

-Diagnosis of EBV hepatitis

• Abnormal liver chemistry tests

• Liver biopsy: well-differentiated mononuclear B lymphocytic portal infiltrate without bile duct damage EBV does not infect hepatocytes, biliary epithelium or vascular endothelium

• PCR for EBV DNA (serum and biopsy sample)

-Prophylaxis against EBV Infection:

• None is necessary

-Treatment of EBV hepatitis:

• A decrease in the immunosuppressive therapy will result in resolution of both symptoms and histopathological findings

-Outcome of EBV infection after liver transplantation:

• Excellent prognosis

Post-Transplant Lymphoproliferative Disorders (PTLD) (Table 7)

Malignancies occur in solid organ transplant recipients with a frequency

10-1000 times that of the normal population After skin cancer, lymphoma has the second highest incidence in the immunosuppressed patient The association of EBV with post-transplant lymphoproliferative disorders has been well described and the presence of EBV-specific proteins and fragments of EBV genome demonstrated consistently in PTLD There are three clinical disorders of differing presentations and prognosis, which may involve graft dysfunction in PTLD

Polyclonal B-cell Hyperplasia

-Clinical Presentation:

Table 7 Clinical and histological features of EBV related graft dysfunction

Disease/ Clinical features Histology Therapy Outcome disorder

Post-transplant Fatigue, fever, Mild increase in Acyclovir Self-limited infectious rash, sore throat, portal infiltrates disease/

(IM)

Polyclonal B- Similar to acute Prominent Decreased Responds to cell hyperplasia IM with severe portal immunosup- antiviral

hepatitis, bone lymphocyte pression; treatment/ marrow failure and (plasma treat with resolves and ARDS cell) infiltrate acyclovir or

ganciclovir Polyclonal Nodal and extra- Polymorphic Withdraw Most progress proliferation B- nodal lympho- lymphocytic immunosup- to lymphoma cell lymphoma cytic proliferation infiltrate pression; treat and have a

in patients treated with acyclovir, low survival

Monoclonal Nodal and extra- Polymorphic to Withdraw Aggressive polymorphic nodal lympho- monomorphic immunosup- disease with B-cell cytic proliferation lymphocytic pression; treat survival rate lymphoma in patients treated proliferation with chemo- of less than

with immuno- depending on therapy; radio- 1 year suppressive the stage of therapy or

medications disease surgical resection