Combined Transplantation Liver-Heart, Lung, and/or Pancreas

Indication

Combined heart and liver transplantation (CHLT) is still an evolving procedure, representing only 0.3% of all cardiac transplantation in a Unified Network for Organ Sharing (UNOS) database study spanning 28 years. The most common indications are cirrhosis secondary to cardiac disease, usually restrictive cardiomyopathy (most commonly from amyloidosis), and either palliated univentricular congenital heart disease or cardiomyopathy. As such, most patients are in the young adult range (median 28 years), and CHLT is rarely required in childhood. In the pediatric age group, CHLT has been performed in a small number of children with univentricular heart disease and metabolic disorders such as familial hypercholesterolemia.

In the setting of univentricular congenital heart disease palliated with a Fontan circulation, a combination of long-standing elevated right-sided pressures together with chronic hypoxia is thought to lead to liver cirrhosis, portal hypertension, and/or hepatocellular cancer. Hepatocellular cancer is being increasingly reported in this situation and may itself become an indication for liver transplantation (LT) ( Table 12.1 ).

Generally, the indication for heart transplantation is clear. The decision regarding whether to add LT is less clear because many patients have abnormal liver function tests pretransplant, and the majority of these will improve after heart transplantation. The International Society for Heart and Lung Transplantation has published updated criteria on listing for heart transplantation; however, considerations regarding liver disease are not specifically included. There are, however, some large single-center studies examining the effect of liver disease on outcome after heart transplantation, and these may guide the decision to consider LT. Both model for end-stage liver disease (MELD) and, in particular, modified MELD (international normalized ratio [INR] replaced with albumin, MELD-XI) scores over 20 were significantly associated with increased postoperative complications and mortality after cardiac transplantation. A “liver risk score” based on fibrosis on liver biopsy and MELD-XI was developed and used to compare 12-month mortality after cardiac transplant between those with scores above or below 45. There was a significant difference between uni- and multivariate analyses, suggesting that irreversible liver disease may be predictable at the time of evaluation for heart transplantation, prompting consideration of LT. Of course, there are unlikely to be equivalent data available in the pediatric age group, and hence, adult criteria must be used to guide the decision.

Apart from the degree of hepatic insufficiency, the presence of liver cancer or a metabolic condition (such as amyloidosis or hypercholesterolemia) as the underlying etiology of the heart disease will also prompt requirement for CHLT. In the setting of cirrhosis, careful workup for hepatocellular cancer needs to be undertaken. This may be problematic with the inability to perform magnetic resonance imaging because of the presence of a pacemaker and the risk of diagnostic liver biopsy in the setting of anticoagulation used in many patients with cardiac disease. Triple-phase computed tomography (CT) is therefore used to look for the classical arterial phase enhancement and portal venous washout phase features typical of hepatocellular carcinoma (HCC). There are more stringent imaging criteria for smaller (1–2 cm) compared with larger lesions (2–5 cm). Lesions are classified according to the liver imaging reporting and data system (LI-RADS) system on a scale from LR1 (definitely benign) to LR5 (definitely malignant). This system was developed in 2011 but most recently updated in 2017. Unfortunately, liver nodules are common in post-Fontan patients, and benign nodules can be confused for HCC. In this situation, ancillary features such as raised alpha-fetoprotein and higher central venous pressures may be used.

When the need for an LT is under question, a careful workup including liver biopsy, hepatic venous outflow pressure, pressure measurements to assess portal hypertension, and combined review and consensus between cardiac and LT teams is important.

Timing of Transplantation

CHLT requires careful consideration and extensive workup, with very few centers having performed more than a handful of cases. The supply of available organs for CHLT is limited, which has implications for both patient selection and timing of transplant. In addition, the priority given to CHLT over single-organ recipients varies in different regions and will impact waitlist mortality. In the United States, waitlist mortality of 27% preempted more favorable allocation policies for patients with cardiac disease and high MELD scores in the range of 20 to 29.

Timing of listing is generally based on cardiac criteria, because liver failure and HCC are relatively rare as the indications for CHLT.

Surgical Considerations and Graft Selection

Several factors related to the donor, including age, size matching, degree of illness of the recipient using intensive care unit (ICU) scores, and even donor biomarkers, have been used to try to identify donor-specific factors that may correlate with recipient outcome. Although donor selection criteria overall have been relaxed for heart-only recipients, there is no established donor risk index in common use, partly because many of the factors above have not been shown in recent studies to affect recipient outcome significantly. In pediatrics, where donor acceptance criteria have been stricter in the past, a study has shown that in a high-volume center, outcomes of recipients using grafts rejected by other centers are not inferior.

Graft selection criteria in CHLT are based on expert opinion. Low levels of preexisting donor-specific antibodies, a “good” graft that is 90% to 160% size matched to that of the recipient, and a liver graft that does not require size reduction are factors that have been identified as important for donor selection.

A variety of techniques exist for CHLT depending on whether cardiopulmonary bypass (CPB) is used for both procedures or whether it is ceased after the cardiac transplant with reversal of anticoagulation, with the LT being performed with or without venovenous bypass. Considerations include balancing the risk of CPB with the risks of exposure to the cardiac graft and subsequent metabolic disturbance (hyperkalemia, fluid overload, and acidosis), which occurs with hepatic reperfusion. En bloc transplantation, where the liver and heart are connected by the inferior vena cava, has also been performed, as has sequential transplantation using different donors in several case reports. Beal and colleagues have published a summary of these techniques from 2004 to 2015. More recently, transplant surgeons from the Mayo Clinic, Rochester, Minnesota, have proposed that LT might be performed before heart transplantation in select cases. The main indication is the highly sensitized recipient, often those with congenital heart disease who have had multiple operations and transfusions. For this group, they select donors that are local, of good quality (can withstand a longer ischemic time), and with close human leukocyte antigen matching. Both cardiac and liver dissection are undertaken first and recipient hepatectomy is undertaken while the organs are in transit. Only four transplants, all successful, have been described using this technique to date (RC Daly, SS Kushwaha, B Geske, unpublished data, 2016).

Post-operative Management

The challenge is to optimize hepatic venous outflow in the setting of potential impaired right ventricular function. As patients are usually managed in the cardiac ICU, the cardiac and liver transplant team assumes responsibility for day-to-day management. LT management is also as per protocol in most centers, with close liaison between the teams.

Immunosuppression

In the setting of a combined heart-and-liver transplant, immunosuppression regimens used for the heart are followed with the assumption that LTs require less immunosuppression and that the addition of the liver will allow a reduction in immunosuppression compared with isolated heart transplants. The usual regimens include a combination of prednisolone, tacrolimus, and mycophenolate mofetil (MMF), with the prednisolone being weaned after 12 months or so.

Transplant Surveillance: Monitoring and Management

Standard post-transplant monitoring applies to CHLT for rejection, infection, and functional recovery. For rejection, serial measures of cardiac function, tacrolimus levels, liver biochemistry, INR, and routine endomyocardial biopsies in the first 14 days are undertaken. Liver biopsies are performed when clinically indicated for isolated LTs.

Outcomes

Overall, 1- and 5-year post-CHLT survival (85.9% and 74.3% respectively; n = 92) is comparable with that of both isolated heart transplant and isolated LT. The presence of congenital heart disease, often with several previous surgeries, does not adversely impact outcome. The 1-, 5-, and 10-year survival rates for adult patients with congenital heart disease and CHLT are 86%, 83%, and 83%, respectively. Recent data suggest that the addition of a liver allograft results in superior survival to isolated heart transplant. This may be related to the significantly lower episodes of acute rejection in CHLT compared with isolated heart transplant (7.5% vs. 38%; P = .001). There is insufficient literature to provide meaningful outcome data for this procedure in children.