Liver Transplant: important information.

Who needs a liver transplant and who does not? What drugs can be used for immunosuppression? Remember that as the liver recovers and regenerates after a successful transplant its enzymes modify and destroy the drugs being used. Close monitoring of drug levels is essential.

In chronic liver failure the two most common reasons for a transplant are hepatocellular cancer and hepatitis C. These two may also be the causes;  alcoholic cirrhosis and nonalcoholic steatohepatitis .

In acute liver failure the outcome is either complete recovery or death so a follow up in a liver unit is justified.

In cirrhosis just the presence of cirrhosis is not a reason for a transplant but evidence of decompensation most often varices and ascites, the development of hepatorenal syndrome, which is an ominous marker and signals the need for immediate transplantation evaluation.

Development of the MELD score — MELD was originally developed to predict three-month mortality following transjugular intrahepatic portosystemic shunt (TIPS) placement and was derived using data from a population of 231 patients with cirrhosis who underwent elective TIPS placement. It is in lover transplant now used for organ allocation.

Patients with some primary liver neoplasms may be candidates for liver transplantation, provided the neoplasms meet specific criteria (eg, for patients with hepatocellular carcinoma [HCC], a single lesion ≤5 cm or up to three separate lesions all ❤ cm, no evidence of gross vascular invasion, and no regional nodal or distant metastases). In addition, there may be a role for liver transplantation in patients with neuroendocrine tumors that have metastasized to the liver, but experience in this setting is limited.

Several liver-based metabolic conditions with systemic manifestations may be treated with liver transplantation. In some cases (eg, alpha-1 antitrypsin deficiency and Wilson disease), patients are cured of the underlying disease with liver transplantation, though some clinical manifestations may not be reversible.

Other conditions that may require a liver transplant are; Familial amyloid polyneuropathy, Primary hyperoxaluria, Cystic fibrosis, Alpha-1 antitrypsin deficiency, some forms of glycogen storage disease (type I and type IV), Tyrosinemia, Hemochromatosis, Wilson disease, Acute intermittent porphyria.

The optimal Model for End-stage Liver Disease (MELD) score at which patients should undergo LDLT has yet to be determined.

Graft size constraints have generally limited the use of left lobe living donor liver transplantation (LDLT) to recipients who weigh less than 60 kg, but due to the desire for safer, smaller-scale resections with less liver removed, left lobe donation will continue to be explored in a wider range of circumstances. The right lobe accounts for approximately two-thirds of the liver mass and provides adequate tissue to support the metabolic needs of an adult recipient. The right lobe also fits correctly into the right subphrenic space, making the vascular anastomoses easier to perform.

Liver regeneration is rapid following living donor liver transplantation. In one report, the volume of small-for-size left lateral segment grafts increased by 60 to 200 percent within one month and approximated standard liver volume by about two months post-transplant. Substantial hepatic growth also occurs in the donor during the first month.

However, data regarding the benefits of HLA matching have been mixed. The degree of HLA matching was not associated with time to graft failure in patients with either autoimmune or non-autoimmune causes of liver disease. Some studies have found that perfect HLA matching (a rare occurrence) may even be deleterious by predisposing to graft-versus-host disease.

Immunobiollogy of liver transplant rejection.

Signal I: Alloantigen recognition 

Signal II: Lymphocyte activation (costimulation)

Signal III: Clonal expansion.

Inflammation.

A major issue with the immunosuppressive agents used for liver transplant recipients (particularly calcineurin inhibitors and mechanistic target of rapamycin inhibitors) is their extensive metabolism by CYP3A4. This creates the potential for drug-drug interactions that may produce toxicity or dangerously low levels of immunosuppressive agents, leading to an increased risk of rejection. As examples, antifungal agents, some antibiotics, and many of the drugs used in the treatment of HIV inhibit CYP3A4.

Four steroid formulations are used commonly in transplantation: hydrocortisoneprednisoneprednisolone, and methylprednisolone. These drugs have different relative potencies. Steroid use varies among transplant centers, and there is no agreement on an ideal protocol. A common regimen is a 1 gram bolus of methylprednisolone during the anhepatic phase, followed by 20 mg/day intravenously. Once the patient is able to take oral medications, he/she is switched to prednisone 20 mg/day. Tapering to zero is usually achieved over three to six months, although some centers leave patients on 5 mg/day indefinitely.

Cyclosporine was initially formulated as Sandimmune, a corn oil-based preparation with inconsistent absorption, especially in the absence of bile flow. This is clearly a problem after liver transplantation, so the nonaqueous, microemulsified version (Neoral) has become the preferred formulation. Monitor blood levels frequently as the regenerating liver may destroy it. Cyclosporine can be administered intravenously, although it is usually given orally as a tablet or an oral suspension. The intravenous dose is approximately 30 percent of the oral dose because of improved bioavailability, and because it is given as a continuous infusion.

Cyclosporine versus tacrolimus — By the mid-1990s, most centers agreed that tacrolimus was associated with superior graft and patient survival. All patients received azathioprine and prednisolone.

Calcineurin inhibitors and renal failure — CNI-induced renal failure is a serious problem after orthotopic liver transplant (OLT). The problem has been exacerbated by the switch to a MELD-based organ allocation system, which is weighted towards higher serum creatinine. A lower dosing, often with the addition of an auxiliary agent like mycophenolate mofetil (MMF) or a monoclonal antibody in patients with preoperative renal impairment can be used. It is important to attain adequate tacrolimus levels quickly.

Patients with HCV infection — The availability of highly effective antiviral agents (DAAs) has greatly simplified post-OLT HCV therapy. Antiviral agents may interfere with drug metabolism because of effects on CYP3A4 and/or P-glycoprotein (gp). In addition, the rate of calcineurin inhibitor clearance may increase with a declining viral load. For these reasons, calcineurin inhibitor levels should be monitored closely after starting DAAs.

Sirolimus — Sirolimus (Rapamune), a macrolide antibiotic produced by Streptomyces hygroscopicus, is a potent immunosuppressive agent approved by the US Food and Drug Administration (FDA) for renal transplantation in 1999. Targets the same receptors as tacrolimus. It is free of nephrotoxicity and neurotoxicity but is considered second line of therapy.

Everolimus — Because prolonged use of calcineurin inhibitors (CNI), such as tacrolimus, is associated with renal disease, everolimus (EVR) has been studied as an alternative for long term immunosuppression. The FDA recommends that both mTORs, everolimus and sirolimus, not be used earlier than 30 days after liver transplantation because of an increased risk of hepatic artery thrombosis in the early post-transplantation period

Mycophenolate mofetil and mycophenolate sodium. MMF does not cause neurotoxicity or nephrotoxicity, and is widely used as a calcineurin inhibitor (CNI)- or steroid-sparing agent. The most common side effects are bone marrow suppression and gastrointestinal complaints, including abdominal pain, ileus, nausea, vomiting, and oral ulceration. These symptoms are usually dose-related and improve with temporary or permanent dose reduction. Usual dosing is 1 g twice daily. 

 Azathioprine is a prodrug of 6-mercaptopurine, which is an antimetabolite that inhibits purine synthesis. By preventing the de novo synthesis of purines, and thus interfering with RNA and DNA synthesis, azathioprine inhibits the replication of T and B cells. It is typically given at a dose of 1.5 to 2.0 mg/kg/day.

Polyclonal antibodies have been used for induction of immunosuppression or treatment of steroid-resistant rejection.

Monoclonal antibodies. Basiliximab — Basiliximab (Simulect) and daclizumab (Zenapax) are humanized monoclonal antibodies against the IL-2 receptor.

Among the newer antibodies being tried out are; Belatacept (LEA29Y) and Efalizumab.

Contraindications for liver transplant.

●Cardiopulmonary disease that cannot be corrected and is a prohibitive risk for surgery

●Acquired immunodeficiency syndrome (AIDS)

●Malignancy outside of the liver not meeting oncologic criteria for cure

●Hepatocellular carcinoma with metastatic spread

●Intrahepatic cholangiocarcinoma

●Hemangiosarcoma

●Anatomic abnormalities that preclude liver transplantation

●Uncontrolled sepsis

●Acute liver failure with a sustained intracranial pressure >50 mmHg or a cerebral perfusion pressure <40 mmHg

●Persistent nonadherence with medical care

●Lack of adequate social support

 

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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