ABO-Incompatible Liver Transplant and Complex Cases

ABO-incompatible liver transplant allows a family member whose blood group does not match the patient's to donate part of his or her liver. Antibodies against the donor's blood group are cleared by plasmapheresis, their production is blocked with rituximab, and immunosuppression begins before surgery.

Dr. Dheeraj Manchanda, Associate Consultant - HPB Surgery and Liver Transplantation, BLK-Max Super Speciality Hospital, New Delhi, India, describes the protocol and the other techniques that now rescue cases once considered impossible. Those techniques share a purpose: widening the pool of patients who can receive a living donor transplant. A family with no blood-group-compatible donor, a donor whose liver is too small, a child too small for any adult graft, a patient whose kidneys have also failed, a patient whose vena cava is blocked: each was once a reason to say no. This article covers each in turn. For the overall picture of indications, timing and outcomes, see the pillar guide, recent advances in liver transplant.

Why blood group is the only match the liver needs

The first test in any donor evaluation is blood group, and for a liver it is almost the only immunological test. The liver has an immunomodulatory property: it dampens the recipient's immune response against it. As a result, only the blood groups of patient and donor need to be checked.

Kidney transplantation is the opposite case. Before a kidney transplant, the team must perform intensive human leukocyte antigen (HLA) matching and cross-matching. For a liver, as Dr. Manchanda puts it, one need only imagine how simple it is: check the blood group of the patient and the donor.

Under standard donor criteria, the donor's blood group is either O, the universal donor, or the same as the patient's. That still excludes many families. A wife with blood group A cannot conventionally donate to a husband with blood group B, for example. ABO-incompatible transplantation removes that barrier.

How an ABO-incompatible liver transplant works

The obstacle is the patient's pre-existing antibodies against the donor's blood group antigens, the anti-A or anti-B antibodies. If these meet the graft, they can trigger antibody-mediated rejection. The protocol therefore has two aims: remove the antibodies already circulating, and stop the body making new ones.

The ABO-incompatible protocol: rituximab, then immunosuppression

1. Rituximab first. Rituximab, a monoclonal antibody that depletes the B cells responsible for antibody production, is given first. It stops the generation of further antibodies.
2. Immunosuppression before surgery. About 14 days after rituximab, the patient starts tacrolimus and mycophenolate before the operation.
3. Transplant after a week of immunosuppression. After about a week on these drugs, the patient proceeds to transplant.
4. Titres guide plasmapheresis. Throughout, the team tracks the anti-A or anti-B antibody titres. The titre level decides whether plasmapheresis is needed first, before surgery, or during the operation.

Plasmapheresis and immunoadsorption: clearing existing antibodies

Pre-existing antibodies are cleared by plasmapheresis, which removes the patient's plasma and with it the circulating antibodies. Where antibody levels are particularly high, the team can add immunoadsorption, which passes the plasma through a column that selectively binds anti-A or anti-B antibodies.

The result is that a related donor who would once have been rejected on blood group alone can now donate. For a family in which the only willing and medically fit relative has the wrong blood group, this is the difference between a transplant and none.

Dual-lobe liver transplant: two donors, one recipient

Dual-lobe transplant is, in Dr. Manchanda's words, one of his favourite procedures. The patient receives liver grafts from two donors, implanted side by side.

It answers a volume problem. Every donor's liver is measured by volumetry before surgery, and the key figure is the graft-to-recipient weight ratio (GRWR): the weight of the graft in grams divided by the recipient's weight in kilograms. The minimum his team expects from a single donor is 0.8; below that, the surgeon needs to modulate the inflow of blood through the portal vein into the graft. When a single donor can provide a GRWR of less than 0.6, the graft is insufficient, and the team advises the family to consider a dual-lobe transplant.

Several configurations exist. The most common is a right lobe from one donor and a left lobe from the other. The two grafts are implanted sequentially and reperfused sequentially: usually the right lobe first, then the left. Two donors undergo surgery, so the donor-safety standards described in robotic donor hepatectomy and living liver donor safety apply to both.

Paediatric liver transplant: the problem of too much liver

In adults, the graft may be too small. In children, the problem is reversed: the graft from an adult donor is often too large. This is most acute in very small children, those weighing less than 10 kilograms.

The standard graft for a child is the left lateral segment, which contains segments 2 and 3. In Dr. Manchanda's practice, children weighing more than 10 kg can instead receive a left lobe graft, which also includes segment 4.

In very small children, even a left lateral graft may not fit. Two problems arise. The liver may not fit in the abdominal cavity, risking abdominal compartment syndrome. And the graft may be too big for the blood flow that the child's small portal vein and hepatic artery can supply.

The solution is to reduce the graft:

• Lateral reduction trims the left lateral graft.
• A hyper-reduced, monosegment graft gives the child a single segment, usually segment 3, the lateralmost part of the liver.
• Shaving off excess mass from the donor graft so that the child's abdomen can accept it.

Each technique serves the same end: a graft whose size matches both the child's abdomen and the child's blood supply.

Combined liver-kidney transplant

Some patients need both organs. The most common indication is coexisting chronic kidney disease and chronic liver disease. There are also primary indications in which the liver itself may look healthy but carries an enzyme defect that damages the kidneys, such as primary hyperoxaluria; amyloidosis is another indication Dr. Manchanda lists. In these conditions, replacing the liver corrects the defect and replacing the kidney restores renal function. Indicative figures for each organ are on the liver transplant cost and kidney transplant cost pages.

The sequence at his centre is fixed: liver first, then kidney. The hospital's urology team removes the donor kidney laparoscopically and is moving towards implanting the recipient kidney with the robot.

Replacing the vena cava

Some transplants require replacing the segment of inferior vena cava (IVC) that runs behind the liver, the retrohepatic cava. Dr. Manchanda describes this as seemingly radical, but his team has performed it. The classic setting is Budd-Chiari syndrome, in which the cava becomes stenosed, and other diseases in which the cava is so involved that the liver cannot be removed without taking the cava with it.

The team replaces the IVC with a 20 or 22 mm Dacron graft, the synthetic conduit they use most commonly, and then implants the donor liver onto the replaced cava.

Transplanting patients who are HIV positive

HIV infection does not rule out a liver transplant. Dr. Manchanda's team has performed liver transplants in HIV-positive patients. The condition is that the patient retains some immunity of his or her own, judged by the CD4 count, which the team monitors after surgery.

The obvious objection is that transplant immunosuppression lowers immunity further in a patient whose immunity is already compromised. His team's answer is to keep the overall dose of immunosuppression lower in these patients, which allows them to do well. In his experience, their mortality and long-term morbidity are the same as other recipients', and his HIV-positive patients remain on long-term follow-up and are doing well. More broadly, published series show that carefully selected HIV-positive recipients with controlled infection can achieve outcomes close to those of HIV-negative recipients, while outcomes have historically been poorer in patients co-infected with hepatitis C.

Liver cancer and the shrinking list of contraindications

Liver cancer is the other frontier where indications are widening. Selection began with the Milan criteria, moved to the broader UCSF criteria, and now extends to advanced multifocal tumours, provided they are first downstaged by trans-arterial chemoembolisation or trans-arterial radioembolisation. Centres worldwide are also moving towards transplanting patients whose cancer has formed a tumour thrombus in the portal vein, after radiation to the thrombus and only if a PET scan six weeks later shows that it has cleared.

For cancer cases, the operating sequence changes. The recipient's operation begins first with an inspection laparotomy, an exploratory opening of the abdomen to look for spread, and the donor's surgery begins only once the team has confirmed there is no peritoneal metastasis and no deposits on the diaphragm, the spleen or the surface of the bowel. The reasons for that sequence, and the opposite order in non-cancer cases, are set out in the donor safety article. Dr. Ashish George's masterclass covers transplant for liver cancer in more depth in liver transplant for HCC, UCSF criteria and downstaging.

What these advances mean for families

Taken together, these techniques change the conversation with a family. The question used to be whether a compatible, adequately sized donor existed. Now the questions are different: can antibody titres be brought down, can two relatives donate together, can a graft be reduced to fit a child, can a kidney be added, can the cava be replaced. Each advance adds complexity to an operation that Dr. Manchanda already counts among the most complex in surgery, and each still rests on the same foundation of donor safety.

The drugs that sustain these grafts, tacrolimus targets among them, are covered in immunosuppression after liver transplant. Questions from the session are collected on the Live Discussion page.