Liver Transplantation in Northeast Florida

Winston R. Hewitt, M.D., FRCSC
Dr. Hewitt is a transplant surgeon at Mayo Clinic, Jacksonville, FL

The treatment of benign and malignant disease of the liver has experienced dramatic advances in the past few decades. Disorders that have previously carried dismal prognoses and precious few therapeutic alternatives are now managed as routine and with very favourable outcomes. It was not so many years ago that liver transplantation itself was considered experimental. Now patients with acute and chronic liver disease, tumors of the liver, genetic abnormalities in hepatic function, infectious disease within the liver and vascular disorders of the liver are managed by hepatologists and hepatobiliary surgeons in an attempt to return these people to their premorbid state of health. Some of the most important contributions have come from innovations relating to anesthesia, infectious disease, cardiology, radiology, hepatology and surgery. In bringing these techniques and technologies to Jacksonville and to Florida's "First Coast", The Mayo Clinic has significantly improved the lives of patients in our region.

Mayo Clinic Jacksonville (MCJ) at St. Luke's Hospital has been in operation since 1986. The introduction of a comprehensive liver disease program by MCJ in 1998 has allowed local residents to seek subspecialty consultation without having to be transported out of the area at additional risk to their health and unnecessary additional expense. The program has now flourished to include 5 hepatologists, 5 transplant surgeons (liver, kidney and pancreas) and 2 physician assistants. The experience of each individual within the Department of Transplantation is utilized in the team-concept approach of patient management. While the transplant program is only four years old it has grown rapidly and has performed the fourth most liver transplants in the United States in 2001¹. The program is still expanding while new technology is being incorporated. Exciting developments are on the horizon.

MCJ Liver Transplant Overview

The liver transplant team includes numerous health care professionals, all of whom play a role in the pre-operative and post-operative care of the liver transplant patient. The team includes physicians, ICU staff, physician assistants, nurses, pharmacists, social workers, nutritionists, respiratory therapists, physiotherapists and others. Each member of the team has a well-defined role but numerous overlaps exist.

Utilizing consultant input and results of various tests in the care of these patients can be challenging due to the vast amount of information generated for each patient. In order to focus the data and to make patient care more efficient a centralized, a computerized database of patient information is used to allow access at any time. This system can be accessed (with password protection, of course) from any where in the hospital… including patient rooms.

The process for the patient with liver disease begins with a referral to our center and an evaluation by a staff hepatologist. The evaluation involves a stepwise assessment protocol that includes laboratory tests, radiologic studies and tissue diagnostics depending upon the differential diagnosis (Table1).
 

After this initial evaluation the options available to the patient are reviewed and a plan for further work-up is instituted. If a patient is deemed to be an appropriate liver transplant candidate, an additional medical, surgical and psychosocial assessment is conducted to determine whether he/she meets the minimal listing criteria in the absence of contraindications. These results are presented at an evaluation conference that is attended by the entire transplant staff. Then the potential candidate is either accepted or denied access to a liver transplant at our center. While many patients are candidates for a liver transplant there are those who are not. They may not be candidates due to severe cardio-respiratory disease, extrahepatic malignancy or a host of other potential conditions. Some of these conditions are relative contraindications and others are absolute (Table 2).
 

While some of these patients with liver failure have disorders that can be improved upon with medical therapy alone others may have co-morbidities that will not improve until their hepatic failure is resolved.

The hepatorenal syndrome (HRS) is not uncommonly encountered in patients with liver failure. The HRS is broadly characterized as a disorder in renal function that is brought on by advanced liver disease, is usually fatal, and is completely reversible with improvement in hepatic function. The reversibility of HRS can be astonishingly rapid and may even be appreciated in the operating room after reperfusion of the new graft as the once-oliguric patient begins a brisk diuresis.

Similarly, porto-pulmonary hypertension may be encountered and can carry a significant risk of complications that may not be remediable unless a liver transplant is performed expeditiously. The diagnosis is sought after with a combination of echocardiographic and invasive hemodynamic findings in the appropriate setting of liver disease (Table 3). These patients may have orthodeoxyia resting or hypoxia and may require supplemental oxygen.
 

These patients too typically have a resolution of the pulmonary hypertension once their liver disease is resolved. This may take a significant amount of time and may even be irreversible.

These complications represent a few of the potentially lethal conditions that may be brought on by liver failure (acute or chronic). If the potential candidate is deemed too high risk to receive a liver transplant his/her care does not end abruptly at that point. These patients still are offered treatment to optimize and palliate their condition.

The liver transplant candidate who is accepted for liver transplantation is educated regarding their disease and how best to avoid complications. They are also advised about the entire process of transplantation including what is to be expected of them both pre- and post-transplant. They are then aligned with a nurse coordinator to address issues that arise during the course of their illness. They are also provided with a long-range regional pager to alert them if a suitable organ becomes available to them. The current average waiting time for those on the "waiting list" is approximately 5 months. This compares extremely favorably to other centers. The waiting time depends in part upon a number of factors that include blood type, accumulated waiting time, body habitus and MELD (model for end-stage liver disease) score ². The MELD (MELD Score = 10 {0.957 Ln(sCr) + 0.378 Ln(tbil) + 1.12 Ln(INR) + 0.643} where sCr is serum creatinine, tbil is total bilirubin and INR is international normalized ratio) score is a numerical system that has replaced the previously used UNOS status system ³. With the MELD scoring system in place only objective physiologic results play a role in prioritizing patients on the waiting list.

For those patients waiting on the list, an agonizing struggle between time and illness progression is endured until a suitable organ can finally be procured for them. They are then called in to the hospital and the inpatient transplant process can begin. While much attention is usually focused on the liver transplant operation, the transplant procedure itself is only a part of the overall process. To ensure optimal functioning of the graft postoperatively, continual monitoring is required. This monitoring is achieved by patient communication, routine screening exams and bloodwork. The average length of in-hospital stay after transplant is 10 days but patients are expected to remain in the Jacksonville area for 3 weeks following the transplant. After this time, most patients are permitted to return to their homes. Their local physicians may then monitor their bloodwork, medications and immunosuppression with close support from the MCJ transplant team. The education and involvement of the transplant recipient is tremendously important, as they are the frontline for problems that may arise. The patient must master their medications, monitor their health, and maintain a level of diligence necessary to maximize their time spent out of the hospital.

Often patients who have received a liver transplant may be admitted to a hospital for testing or treatment that does not directly involve their liver graft. Due to the complex medical regimen that these patients are typically following, we recommend that the transplant team be involved throughout such an admission in order to avoid potential medication interactions and dosage problems with the antirejection medications.

Not all patients who are referred to our center for a liver transplantation consult will require a liver transplant. There are those patients who are early enough in their disease to be managed by medication and serial exams only. Sometimes there are those who benefit from early surgical intervention (e.g. surgical shunt) to assist with management of the disease or to halt disease progression (e.g. Budd-Chiari syndrome). Eventually they may require a transplant but the risk of complications after a transplant operation must not outweigh the risk of death due to their own disease process and progression. Our own center statistics demonstrate an 87.9% 1-year patient survival and a 77.7% 1-year graft survival.

Present Challenges

The spectrum of disease encountered at our transplant program (Table 1) mirrors that of most other large centers. Hepatitis C (HCV) either alone or in combination with other liver-based diseases is the most common indication for transplantation at the Mayo Clinic Jacksonville. This is not surprising considering the prevalence of HCV within the American population. Approximately 2.7 million people in the US carry the HCV RNA virus ⁴. Patients who harbor hepatitis C are at risk for a number of complications both hepatic and systemic. Given the large number of people who are at risk this translates into a potential epidemic of HCV-related disease. Many of these people will go on to receive a liver transplant.

There is a prevalent misperception that patients who are HCV-positive are not treatable and are doomed to cirrhosis and hepatic failure. The study by Kenny-Walsh (5) has shown that the disease progression may not only be slower than expected but that the progression to cirrhosis occurs in fewer than previously thought. In addition, even in those with active disease, therapy exists to treat the disease. While the management of this patient population is difficult, it is not a fruitless endeavour.

Our center utilizes a combination of medical and surgical modalities to diagnose and treat HCV without necessarily proceeding directly to transplantation. Early treatment and close follow-up with appropriate bloodwork, radiologic imaging and biopsy may significantly change the course of this disease. The introduction of interferon-a (IFN) and ribavirin combination therapy in the management of this disease has resulted in some truly dramatic disease remissions. Broadly speaking though, of the 50% of patients who respond to IFN-ribavirin only 50% will have a durable result ⁴.

Hepatitis C also can be challenging to treat after liver transplantation because infection of the graft can be expected in every case. This makes the diagnosis and treatment of acute cellular rejection more complex. The balance between immunocompetence and immunosuppression must take into account the presence of the hepatic viral infection that may flare up and lead to destruction of the graft. Interferon and ribavirin can be used after liver transplant as well. This antiviral therapy does have potential side effects. There are those patients who lose their allograft due to recurrent HCV infection, with or without antiviral therapy, and it is these patients that potentially may present an enormous problem for transplant centers.

Most liver transplant recipients with HCV-induced liver failure will have to be considered for re-transplantation at some point and the transplant program is met with a formidable decision. It is feasible that the vast majority of liver transplants at a large center could be related to HCV cirrhosis with a huge component being performed due to recurrent disease post-transplant. A dilemma arises when considering whether to re-transplant a recurrent HCV cirrhotic or to do a primary transplant in a non-HCV cirrhotic. There are those patients who, if re-transplanted for early recurrent HCV cirrhosis, will continue to destroy grafts if permitted to do so. These patients are therefore reviewed on a case-by-case basis by the team to determine whether or not they would be appropriate re-transplant candidates. The management of these patients is evolving and will no doubt continue to improve as more data becomes available.

The Future

A well-known limitation of liver transplantation is the limited supply of appropriate donor organs. The unfortunate reality is that the discrepancy between supply and demand in transplantation continues to widen. Thousands of patients patients die each year waiting for a liver transplant.

There is a great deal of interest in the transplant community over the use of livers from donors who would not have been considered suitable in past decades. These include split livers, living donors and non heart-beating donors The aggressive use of donors previously thought to be unsuitable (advanced donor age, hepatitis B core antibody positive, HCV positive, hepatic steatosis, etc.) for whole organ transplantation permit patients to receive organs in a timely fashion and avoid life-threatening complications. While the use of these organs has been helpful we believe that it is important to have an experienced surgeon inspect and procure them so that the incidence of post-transplant dysfunction is minimized. At our center one of the transplant surgeons always goes out to retrieve these organs. A biopsy of these organs is sometimes used to assess the degree of microscopic abnormality and may play a role in donor graft selection.

The splitting of a donor liver into two transplantable grafts is a valuable method to increase the availability but is particularly important if pediatric patients are on the waiting list. These grafts are typically divided into an extended right lobe graft (hepatic segments I, IV-VIII) with vena cava and a smaller left lateral segment graft (segments II, III). The liver may also be separated into a formal left lobe (segments I, II, III, IV and vena cava) and a formal right lobe (segments V, VI, VII, VIII). These grafts will regenerate within a couple weeks once transplanted into a full volume liver. The split liver recipients usually require a more post-operative supportive care as their new liver recovers.

Transplantation by its very nature is fraught with bioethical dilemmas. These issues are particularly evident when considering living donor liver transplantation (LDLT). The procedure involves the transplantation of a part of a healthy person's liver. The adult-to-adult LDLT operation involving a donor right lobe has a higher morbidity and mortality risk than an adult-to-child LDLT involving the left lateral segment. The right lobe operation leaves the donor with approximately 40% of the native liver remaining and a cut edge of the liver that may post-operatively bleed or leak bile. The feared post-operative complications include portal vein thrombosis, bile duct injury, hepatic insufficiency and death. The risk of mortality to the donor is not negligible, as reports from around the world have demonstrated. These donors are patients who are healthy and subjected to a major abdominal procedure for the benefit of someone else, so the risks must be minimized as much as possible. The native liver will regenerate fully within a few weeks in the absence of problems. Currently, only a small portion of patients listed for transplantation has an appropriate donors for LDLT; still this could become an important source of grafts.

Another rare option is the use of livers in donors with severe neurological injury but not satisfying criteria for brain death. These organs are procured after the donor family gives consent, life support is withdrawn and the patient has cardiovascular collapse. Experience with this procedure is growing and more candidates are being identified.

The liver transplantation program at Mayo Clinic Jacksonville is relatively new but has rapidly grown to be one of the largest centers in the nation. The philosophy of the program is to continue to evaluate new techniques and technologies, and to adopt those that will lead to improved patient care. The rapid growth experienced by our center has not and will not change the primary principles upon which the Clinic was founded. The Mayo Clinic Liver Transplantation team continues to expand and is well positioned to remain at the forefront of the transplant community.

References

1. UNOS database. www.unos.org
2. Wiesner RH, McDiarmid SV, Kamath PS, Edwards EB, Malinchoc M, Kremers WK, Krom RA, Kim WR. MELD and PELD: application of survival models to liver allocation. Liver Transpl 2001; 7:567-80
3. UNOS policies. www.unos.org
4. Lauer GM. Walker BD. Hepatitis C virus infection. New England Journal of Medicine 2001; 345:41-52.0
5. Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. New England Journal of Medicine 1999; 340:1228-33.

Jacksonville Medicine / June/July, 2002