Guidance for the Medical Evaluation of Potential Living Liver Donors

Summary and Goals

On June 16, 2006, HRSA published a notice in the Federal Register in which the Secretary of HHS directed the OPTN to develop policies regarding living organ donors and organ donor recipients. The notice stipulated that noncompliance with such policies will subject members to the same consequences as noncompliance with policies regarding deceased donor transplantation. In response, the Board of Directors adopted changes to the Bylaws requiring transplant programs that perform living donor transplants to develop and follow written protocols that address all phases of the living donation process, including the evaluation, pre-operative, operative, and post-operative care, as well as the submission of data.

To assist members, the Living Donor Committee developed a non-exhaustive set of elements to serve as a resource that could be used by transplant programs in developing their own program specific living liver donor medical evaluation protocols, as required by the Bylaws. Since this resource is not considered OPTN or UNOS policy, it does not carry the monitoring or enforcement implications of policy. It is not an official guideline for clinical practice, and it is not intended to be clinically prescriptive or to define a standard of care. This resource will not be used to determine member compliance with policies or Bylaws; rather it is a resource being provided to the members for examples and amplification of the elements mentioned in the Bylaws. It is intended for members’ voluntary use.

Both new and existing living donor transplant programs can use this guidance when developing medical evaluation protocols for their potential living donors.

I. Guidance for Creating Your Pre-Evaluation Guidance Protocol

Each potential donor is unique and no single evaluation protocol is applicable to all living donors; however, transplant centers must inform potential living donors about all phases of its evaluation protocol. The donor evaluation includes psychosocial and medical components, which should help determine if an individual is suitable for living donation. The psychosocial evaluation may reveal the presence of psychosocial problems that might complicate donation (e.g., lack of social support to aid in the individual’s post operative recovery). The medical evaluation may uncover conditions that could significantly increase the risk of donation to the potential living liver donor. The evaluation should also screen for diseases that the donor could transmit to the potential recipient, which is particularly important since the recipient will be taking immunosuppressive drugs. Lastly, this evaluation should define the anatomy of the liver so that the surgical team can assess the anatomical suitability of the organ and properly plan the surgery.

To the extent possible and early in the medical evaluation process, the transplant team should inform both the potential living liver donor and the intended recipient of alternatives to living donation. The team should also inform the potential living liver donor and intended recipient of donor and recipient outcomes at the institution compared to national outcome data.

The evaluating transplant center should include

a donor advocate or donor advocate

team to assist the donor

throughout the process.

It is important to inform the potential living donor that he/she can stop the medical evaluation or living donation process at any time. If a potential living donor chooses to not proceed with the evaluation or donation process, the center may state that the living donor did not meet the program’s criteria for donation to help avoid difficult social situations.

Communicating Donor Risk

Living liver donation involves risk. Most of the medical risks and complications associated with the partial hepatectomy procedure occur in the peri-operative period. These risks are relatively well known and can include:

• Risks associated with anesthesia;
• Surgical complications such as liver failure, blood loss, bile leak, blood clots, infection, pain, hernia; and less frequently bile duct stricture(2,3,4,5);
• Death - the risk of dying from living donor surgery is estimated to be between 0.1%-0.3% and possible as high as 0.5% when donating the right lobe(4)
• If all complications are considered, from the most minor to the most severe, approximately 1 of every 3 donors will experience a complication based upon multicenter consortium data. The great majority (95%) are considered minor or with no permanent sequelae. (22)
• Overall Donor Morbidity is estimated to be approximately 35 % (5).

  Recent OPTN data (6) reveal that: five out of 3632 (0.1%)living liver donors were subsequently listed for liver transplant between 4/1/1994 and 11/30/2008.Two were between 18-34 years of age, two between 35-49 years of age, and one was between 50-64 years of age. All living liver donors were placed on the liver transplant waiting list within 20 days after donation. Diagnoses of the five donors at time of listing were sub-fulminant hepatic failure (2), Budd-Chiari syndrome (2), and other (1).One living donor died after being placed on waiting list, three candidates received deceased donor liver transplants within 4 days after listing, and one candidate was removed from the waiting list due to improved health.

  The A2ALL study has improved our understanding of the short and medium term risks associated with living liver donation. Donors have reported chronic problems including bile strictures, re- operations, and chronic pain. Although data collection is ongoing, our ability to quantify complications which may arise beyond 5 years is currently limited.

  Risks of Living Liver Donor Evaluation

  Some of the possible risks associated with the medical evaluation may include:

• Mild to severe allergic reaction due to exposure to contrast materials used in abdominal imaging.
• The discovery of infections or malignancies unknown to the potential donor.
• Complications from liver biopsy (if needed) range from 0.2% and 1.79%.(7)
• The discovery of diseases that must be reported to health agencies.
• HLA testing (if performed) could reveal the true identity of family relationships, and create issues that the donor or other family members may not wish to be exposed. Test results may require unexpected decisions of the donor and medical team.
• Test results may require the need for additional testing and treatments, which may become the financial responsibility of the donor or donor’s insurance.

  Physician knowledge and experience are important components in this medical evaluation. The involved professionals’ medical judgment will always need to direct the course of the evaluation.

  Decision Regarding Donation

  The final decision regarding whether the living liver donor can donate an organ is based upon:

• The medical test results;
• The donor’s psychosocial evaluation;
• Assessment of risk based upon current medical knowledge;
• Willingness of the donor to proceed after receiving education about the entire donation process; and;
• Confirmation that the donor is an acceptable candidate based on the medical and psychological evaluation.

  The living liver donor should make the decision to donate with the help of his/her family, friends, the independent donor advocate (IDA), and the medical/surgical team.

  In cases of directed donation, if an individual decides to donate, the transplant team should consult with the potential recipient to determine if all parties agree to proceed with transplantation. Under these circumstances, the transplant team should inform the donor and recipient of the risks of both procedures (e.g. severity of recipient illness, donor anatomy, etc).

  Some living donors may be willing to accept relatively greater degrees of personal risk to give an organ to a transplant candidate in need. Transplant teams should consider the special circumstances of each potential donor when deciding about candidacy for donation.

  Transplant candidates may also vary in the degree of risk they are willing to take (e.g., risk for communicable disease or substandard donor organ quality).

Evaluation Guidance

This resource provides a list of tests and procedures that may be considered for assessing the medical and psychosocial suitability of a potential living liver donor. Transplant centers can use this list as a guide.

To date, no randomized controlled trials have been conducted to determine the tests required to evaluate a living liver donor. The process described in this resource represents the general medical practice of existing transplant programs that assess living donors.

This resource will be modified over time as improved screening tests become available. At all times, the transplant program should assess the risk of the screening procedures versus the benefit of information received. Again, transplant centers should view the process outlined below as a suggestion. Opinions on what processes to follow will vary.

Psychosocial Evaluation

As required in the bylaws (Attachment I, Appendix B), a psychosocial evaluation should be performed by a professional approved by the current bylaws. The person performing this evaluation should have experience in transplantation. This person may be a psychiatrist, psychologist, or social worker. The psychosocial evaluation should :( 2, 3, 8, and 9)

• Review psychosocial issues that might complicate the living liver donor’s recovery and identify potential risks for poor psychosocial outcome.
• Attempt to identify factors that warrant educational or therapeutic intervention before donation. If the evaluating professional suspects current or prior psychiatric disorders, including those related to substance abuse, this professional should provide the necessary referrals to the potential donor for further psychological or psychiatric evaluation.
• Attempt to determine the potential donor’s understanding of the short- and long-term medical risks associated with living donation.
• Allow the transplant program to explore the reason(s) why the potential donor volunteered to donate. The program should attempt to determine that the potential donor’s decision to donate is not due to coercion.
• Determine the potential donor’s ability to make an informed medical decision, and cope with the emotional and physical consequences of a major surgery. The potential living donor should receive adequate educational material and engage in discussions that will enable the potential living donor to develop a realistic assessment regarding donation and recovery, with social, emotional and financial support available as needed.
• Review the financial circumstances of the potential living liver donor (e.g., employment, insurance coverage, etc). Where applicable, the program should investigate the potential donor’s understanding of the possible financial implications of living donation and the availability of financial resources.
• Inform the potential donor that he/she may experience problems in obtaining future disability benefits or health insurance following donation.
• Inform the potential donor that health information obtained during his/her medical evaluation will be subject to the same patient confidentiality regulations as regular medical records.

Donor Medical Evaluation

The O bylaws state that a physician or surgeon experienced in living donation should perform a thorough medical evaluation. The goal of the medical evaluation is to: (1, 2, 3, 5, 10, and 11)

• Assess the compatibility of the potential donor to the recipient.
• Assess the general health of and surgical risk for the potential donor.
• Screen the potential donor for conditions that increase the donor’s surgical risk for liver resection
• Perform tests on the potential donor to identify the potential for transmission of donor-derived diseases to the recipient.
• Assess the anatomy of the potential donor’s liver, and assess the likelihood of successful transplantation of the partial liver graft given recipient anatomy, diagnosis, and disease severity.

Due to time constraints, in fulminant liver failure, some tests may not be possible to perform. But, all safeguards (e.g., communication of risk, psychosocial evaluation etc.) should be in place including the use of an IDA.

The Living Donor Committee will consult with relevant experts in the transplant community to periodically review and update this resource.

Components of the Medical Evaluation

1. General Medical History

   Physicians should assess the potential living liver donor for:

   • Significant medical conditions such as hypertension, diabetes, lung disease, heart disease, gastrointestinal disease, autoimmune disease, neurologic disease, genitourinary disease, history of cancer, history of infections, hematologic disorders, and bleeding/clotting disorders;
   • Smoking, alcohol and drug use/abuse, including intravenous drug use/abuse, and other high risk behavior(s);
   • Medications consumed currently and in the past (hepatotoxic, chronic use of pain medications, other);
   • Allergies;
   • Family history (coronary artery disease, cancer, clotting disorders, other);
   • Liver specific personal history: Risk factors for viral hepatitis, history of abnormal liver enzymes, Diabetes, Fatty liver disease, Jaundice, bleeding, and pruritis; and;
   • Liver Specific Family History: liver disease, autoimmune disease, diabetes, and viral hepatitis
2. Social History

   A mental health professional should conduct a full psychosocial evaluation of the potential donor. Part of the medical evaluation should attempt to determine psychosocial concerns that may warrant further investigation. Special emphasis of this evaluation should be on:

   • Employment, health insurance status, living arrangements, and social instability that may make donation difficult;
   • Psychiatric illness, alcohol or substance abuse, depression, and suicide attempts; and;
   • Motivation for donation.
3. Physical Exam
   • Height, weight, and body mass index (BMI); and
   • Examination of all major organ systems.
4. Liver-specific Exam
   • Assess for stigmata of liver disease
     • Hepatomegly
     • Splenomegly
     • Spider angiomata
     • Edema
     • Palmar erythema
5. Suggested General Laboratory Testing
   • CBC with platelet count
   • Prothrombin Time , INR, Partial Thromboelastin Time
   • Coagulation profile (consider factor V Leiden, Prothrombin II gene mutation)
   • Comprehensive panel (electrolytes, BUN, creatinine, calcium, phosphorus,)
   • HCG quantitative pregnancy test for women < 55 years old
   • Age and gender appropriate cancer screening tests

     The transplant program may choose to follow the screening recommendations from the American Cancer Society. (12)

   • Chest X-Ray
   • Electrocardiogram (ECG)
   • Evaluation for coronary artery disease, as suggested by the American College of Physicians (13)
   • Pulmonary function tests for smokers, as suggested by the American College of Anesthesiology and American Lung Association. (14)
6. Suggested Liver-specific Testing
   • Hepatic function panel
   • ANA
   • Ceruloplasmin
   • Iron, Iron Binding Capacity, ferritin
   • Alpha 1 antitrypsin level and phenotype (15)
   • Smooth Muscle Antibody
   • Anti Mitochondrial Antibody
7. Immunological Testing
   • ABO blood group typing as per OPTN/UNOS Policies for ABO confirmation
8. Suggested Metabolic Focused Testing
   1. Fasting blood glucose
   2. The evaluation team may consider fasting cholesterol levels (Cholesterol, Triglycerides, HDL Cholesterol, and LDL Cholesterol) with Fasting Lipid Profile if cholesterol/triglycerides are elevated.
9. Anatomic Assessment:

   Surgeons may use this assessment to determine if the liver is anatomically suitable for transplantation into the recipient, and to assess the adequacy of the donor’s residual liver volume. Evaluation would include

   assessment of projected graft volume, donor’s remnant volume, and vascular anatomy. Pre-operative imaging of the potential donor’s biliary anatomy is recommended.

   Based on these findings, the surgeon can determine the suitability of the liver, and any additional risks associated with anatomical variants. The radiologic imaging may reveal unexpected findings that will need to be investigated. These findings may be related or unrelated to the organ of interest.

   The test of choice will depend upon the local radiological expertise and surgical preference, but may include CT angiogram, MR angiogram or angiogram, used singly or in combination. An assessment for steatosis should be undertaken. (17,18) A liver biopsy may be warranted if the imaging suggests significant fatty liver in the potential donor.

10. Liver Biopsy

    Liver biopsy may be indicated at the discretion of the center. Indications for a biopsy may include: (2,19)

    • Abnormal liver function tests;
    • Steatosis on imaging;

      • BMI >30;

    • Genetic relation to a person with autoimmune or genetic liver disease;
    • HBV core positive serology; and,
    • Prior history of alcohol abuse.
11. Transmissible disease testing:

    Screening tests are used to identify the risk of transmitting an infection or disease to a recipient. This screening may also identify a condition that may require the donor to seek treatment or may increase the risk of donation. Infectious disease testing typically includes testing for the following: (20)

    • CMV (Cytomegalovirus);
    • HIV 1, 2 (Human Immunodeficiency Virus);
    • HBsAg (Hepatitis B surface antigen)*;
    • HBcAb (Hepatitis B core antibody)*;
    • HBsAb (Hepatitis B surface antibody);
    • HCV (Hepatitis C Virus); or,
    • RPR (Rapid Plasma Reagin Test for syphilis)

      *HBV DNA should be considered if HBcAB is positive

      Depending on transplant program preference and donor risk profile, physicians may test for other diseases such as:

    • EBV (Epstein Barr Virus) – VCA or EBNA antibody test may be performed if the recipient is EBV seronegative
    • Tuberculosis
    • HTLV-1/2
    • Additional infectious diseases endemic to certain geographic areas
12. Cancer screening:

    Cancer screening tests should follow the practices advised by the American Cancer Society (ACS) Screenings that should be performed based on gender, age, or family history include:

    • Cervical cancer;
    • Breast cancer;
    • Prostate cancer;
    • Colon cancer; and,
    • Skin cancer.

IV. Possible Exclusion Criteria

A variety of criteria may make an individual unsuitable for living liver donation. Some of these may include: (2, 3, 5, 8, 11, 22, 23, 24)

• Age < 18 years of age, or mentally incapable to make an informed decision;
• Upper age limit >60 years of age;
• Diabetes;
• Significant history of thrombosis or embolism;
• Bleeding disorders;
• Uncontrollable psychiatric illness;
• Morbid obesity;
• Clinically significant coronary and/or peripheral vascular artery disease;
• Symptomatic valvular disease;
• Chronic lung disease with impairment of oxygenation or ventilation;
• Recent malignancy or cancers with long times to recurrence (e.g., breast cancer);
• Vascular or biliary abnormalities in the donor liver that make the likelihood of successful transplantation low or increase the risk in the potential donor;
• Hepatitis C virus infection;
• Fatty liver disease (>20% steatosis);
• Asymptomatic ZZ, Z-null, null-null and S-null alpha 1 antitrypsin genotype; those with low Alpha 1 antitrypsin levels may have untype-able phenotypes and may be excluded.
• Multiple or complex upper abdominal surgeries;
• Recipient graft to body weight ratio (GBWR) < 0.8; or,
• Donor remnant volume less than 30% of native liver volume. Living Donor Follow-up

The living donor organ recipient’s transplant center is required to submit information to OTPN Contractor about the status of each living donor for a minimum of two years. Information received to determine if living donors experience short term health complications and how living donation may impact quality of life. Follow up information submitted by transplant centers is the only method currently available to obtain information on living donors. (To clarify, the recommendations in this resource are provided to assist transplant centers with the development of their center-specific medical evaluation protocols. This resource will not be used to assess the medical evaluation protocols of members for policy compliance).

Medical Evaluation after Living Donation

Following partial liver donation, the living donor should remain informed about his/her health and have basic medical evaluations with testing performed as would be appropriate for health maintenance and follow up of the donor according to the Recommendations from the United States Preventative Services Task Force (http://www.ahrq.gov/clinic/pocketgd.htm) and are in compliance with applicable reporting requirements.

All living liver donors should be encouraged to maintain lifestyle choices that will protect their overall health and in particular, their liver health. These donors should be advised to consider vaccination for Hepatitis A and B. Living Liver donors should be advised to establish a health evaluation schedule as recommended by the American College of Physicians. However, these evaluations may become the financial responsibility of the living liver donor.

Works Cited

1. Bylaws, Appendix B, Attachment I, Section XIII, D (2) and (4), Designated Transplant Program Criteria
2. Barr ML, Belghiti J, Villamil FG, Pomfret EA, et al A report of the Vancouver Forum on the care of the liver organ donor: lung, liver, pancreas and intestine data and medical guidelines. Transplantation 2006; 81(10): 1373- 1385.
3. New York State Committee on Quality Improvement in Living Liver Donation. A report to New York State Transplant Council and New York State Department of Health. Available at: http://www.health.state.ny.us.
4. Ringe B, Strong RW; The dilemma of living liver donor death: to report or not to report? Transplantation, 2008; 85(6):790-792.
5. Patel S, Orloff M, Tsoulfas G, Kashyap R, et al. Living donor liver transplant in the United States: identifying donors at risk for perioperative complications. American Journal of Transplantation. 2007;7:2344-2349.
6. Organ Procurement and Transplant Network data request
7. Mells, G, Neuberger, J. Protocol Liver Allograft Biopsies. Transplantation 2008. 85(12):1686-1692.
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9. Dew MA, Jacobs CL, Jowsey SG, Hanto R, Miller C, Delmonico FL; Guidelines for the psychosocial evaluation of living unrelated kidney donors in the United States. Am J Transpl 2007 May;7(5):1047-54.
10. Trotter JF, Wisniewski KA, Terrault NA, Everhart JE, et al. Outcomes of donor evaluation in adult-to-adult living donor liver transplantation. Hepatology. 2007;46(5):1476-1484.
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12. Smith RA et al. Cancer screening in the United States 2007: A review of current guidelines, practices and prospectives. CA Cancer J Clin 2007;57:90-104.
13. Fleisher LA et al ACC/AHA 2007 guidelines on peri-operative cardiovascular evaluation and care for non-cardiac surgery: Executive summary. J Am Col Cardiol 2007; 17:1708-1730
14. Qaseem A et al. Risk assessment for and strategies to reduce peri-operative pulmonary complications for patients undergoing noncardiothoracic surgery: A guideline from the American College of Physicians. Ann Intern Med 2006; 144:575-580.
15. Graziadel IW, Joseph JJ, Wiener RH, Therneau TM, et al. Increased risk of chronic liver failure in adults with heterozygous alpha 1 antitripsin deficiency. Hepatology. 1998;28(4):1058-1063.
16. Abdul-Ghani, MA et al. What is the best predictor of future type-2 diabetes? Diabetes Care 2007; 30:1544-1548.
17. Mishra P, Younossi ZM. Abdominal Ultrasound for Diagnosis of Nonalcoholic Fatty Liver Disease (NAFLD).Am J Gastroenterol. 2007 Dec;102(12):2716-7.
18. Grattagliano I, Portincasa P, Palmieri VO, Palasciano G. Managing nonalcoholic fatty liver disease: recommendations for family physicians. Can Fam Physician. 2007 May;53(5):857-63. Review
19. Simpson MA, Verbesey JE, Khettry U, Morin DS, et al. Successful algorithm for selective liver biopsy in the right hepatic lobe live donor (RHLD). American Journal of Transplantation. 2008;8: 832-838.
20. Green M, Avery RK, Preskasaitis J eds, “Guidelines for the Prevention and Management of Infectious Complications of Solid Organ Transplantation” Am J Transpl 2004: 4(Suppl. 10).
21. Rogers NM, Peh CA, Faull R, Pannell M, Cooper J, Russ GR. Transmission of toxoplasmosis in two renal allograft recipients receiving an organ from the same donor.Transpl Infect Dis. 2007 Jul 1.
22. Ghobrial, RM, Freise CE, Trotter JF, Tong L, et al. Donor morbidity after living donation for liver transplantation. Gastroenterology. 2008;135:468-476.
23. Akamatsu N, Sugawara Y, Tamura S, Kaneko J et al. Impact of live donor age on liver transplantation. Transplant Proceedings. 2007;39: 3189-3193.
24. Shackleton CR, Vierling JM, Nissen N, Martin P, et al. Morbididty in Live Liver donors. Arch Surg. 2005; 140:888-895.