Recent Advances in Liver Transplant

Recent advances in liver transplant have turned an operation whose first patient died on the table into one offering long-term survival, robotic donor surgery and grafts that cross blood groups. Dr. Dheeraj Manchanda, Associate Consultant - HPB Surgery and Liver Transplantation, BLK-Max Super Speciality Hospital, New Delhi, India, sets out when cirrhosis calls for a transplant, how a relative can donate safely, and where the field is heading.

His case rests on two facts that pull in opposite directions. Liver transplantation is, in his words, one of the most complex operations in surgery. It is also one of the younger subspecialties in medicine, and in roughly six decades it has come a long way.

This guide covers the full arc of his masterclass. Three companion articles go deeper: ABO-incompatible liver transplant, dual-lobe grafts and other complex cases, robotic donor hepatectomy and living donor safety, and immunosuppression, tacrolimus targets and long-term follow-up.

From the first attempt to a routine operation

Liver transplantation began with Dr. Thomas Starzl. His first case series reported three operations. The first patient, a child with extrahepatic biliary atresia, died on the operating table. The second, a 48-year-old man with cirrhosis and a primary liver cancer, died on day 22. The third was a 67-year-old with a bile duct cancer. The early problems were technical; over time they were solved, and the first successful liver transplant followed in 1967.

The indications have since widened well beyond end-stage cirrhosis. Liver cancer is now an established indication: the Milan criteria, published by Dr. Vincenzo Mazzaferro in 1996, defined which patients with hepatocellular carcinoma do well after transplant, and the timeline then extended to hilar cholangiocarcinoma, neuroendocrine tumours, colorectal liver metastases and intrahepatic cholangiocarcinoma. Dr. Manchanda's point is that transplant, not just resection, is now offered across the world for a range of malignancies.

Milestones of the Indian transplant programme

The Transplantation of Human Organs Act was passed in India in 1994. The first deceased donor liver transplant was attempted in 1995, and it took three more years for a deceased donor transplant to succeed. The first living donor liver transplant was a paediatric case, performed in November 1998. That child is now a doctor, which Dr. Manchanda offers as the plainest evidence of how long a transplanted liver can last.

Today the country has two major clusters of activity. Delhi and the National Capital Region in the north perform mostly living donor transplants; Chennai and Hyderabad in the south perform more deceased donor transplants. Dr. Manchanda attributes the split to cultural differences. Nationally, the dominant trend is towards living donor liver transplantation, and most recipients are adult men.

The gap between need and supply

India performs close to 3,000 liver transplants a year, against an estimated need of close to 30,000. Only about 10% of the patients who need a transplant receive one, even though there are, on paper, 90 to 100 active liver transplant centres.

Dr. Manchanda does not see capacity as the constraint. His own unit performs 20 to 25 transplants a month, close to 300 a year, has done close to 2,000 in all, and could do more. He identifies three other factors:

• Awareness. Patients told they need a transplant often go to another doctor because they do not believe a transplant is possible.
• Cost. The expense deters many families. Dr. Manchanda's view is that, measured against the long-term cost of continuing medical management of cirrhosis, a transplant is the cheaper option, a comparison most families never make. Indicative figures are on the liver transplant cost page.
• Donor suitability. About 35% of prospective donors at his centre are turned down, because they are overweight, because their liver anatomy is unsuitable, or because evaluation uncovers a disease of their own.

The male majority among recipients has a similar explanation. In his assessment it reflects culture more than physiology: men are usually the family's earner, and alcohol intake, in quantities large enough to damage the liver, is more prevalent among men.

What causes the liver disease behind a transplant

Cirrhosis is the common end point. In India, alcohol-related cirrhosis is the most frequent reason for liver transplantation, followed closely by viral hepatitis B and C. Both viruses remain common despite effective treatment for hepatitis C and a vaccine for hepatitis B. Metabolic liver disease, formerly called non-alcoholic steatohepatitis (NASH) and now termed metabolic dysfunction-associated steatohepatitis (MASH), is rising in incidence and mortality. Autoimmune hepatitis is the fourth most common cause.

When does a patient with cirrhosis need a transplant?

Not every patient with cirrhosis needs a transplant. Compensated cirrhosis causes no symptoms. Decompensated cirrhosis is the stage at which the disease begins to produce symptoms, and it is decompensation that raises the question of transplant. The clinical triggers are:

• jaundice
• ascites that keeps re-accumulating
• vomiting blood or passing blood in the stool
• hepatic encephalopathy, which ranges from daytime sleepiness and drowsiness to hepatic coma
• hepatocellular carcinoma
• acute liver failure and acute-on-chronic liver failure, where the patient cannot wait for a deceased donor and the graft must usually come from a living relative

The Model for End-Stage Liver Disease (MELD) score quantifies severity from three values: serum bilirubin, creatinine and the INR. According to Dr. Manchanda, the long-standing MELD cutoff was 15. The 2025 guideline from the American Association for the Study of Liver Diseases (AASLD) and the American Society of Transplantation replaces that fixed cutoff with a more inclusive approach: it notes that patients may gain a survival benefit from transplant at a MELD of 12 or more, and it states that a MELD score alone should never stand in the way of referral, particularly when complications of portal hypertension are present.

MELD score and the timing of transplant

Thirty-day mortality after transplant tracks the MELD score at the time of surgery. Once MELD crosses 30, mortality and complications begin to climb. The same is true once the disease involves other organs: the kidneys through acute kidney injury, or the brain through hepatic encephalopathy.

Where does the new liver come from?

A liver transplant replaces the diseased liver with a healthy one from one of two sources. A deceased donor is a person declared brain dead, usually after a neurological event or trauma. A living donor is a healthy family member who voluntarily consents to give part of his or her liver. Living donation is now the dominant source in India.

Living donor transplantation hinges on one principle: donor safety. Two people undergo surgery, but only the patient needs it. The donor's evaluation is therefore designed, as Dr. Manchanda puts it, not to select a donor but to disqualify anyone unsuitable. The donor criteria, the staged evaluation, graft planning and the move to robotic surgery are covered in robotic donor hepatectomy and living liver donor safety.

Matching donor and recipient: the liver's advantage

The liver modulates the immune response, so only the blood groups of patient and donor need checking. This is in stark contrast to kidney transplantation, which requires extensive HLA matching and cross-matching. Matching blood group alone was already a wide window. Programmes have now moved beyond it: with rituximab, plasmapheresis and early immunosuppression, a relative whose blood group does not match can still donate. That protocol, together with dual-lobe grafts from two donors, reduced grafts for small children, combined liver-kidney transplant and caval replacement, is set out in ABO-incompatible liver transplant and complex cases.

The operation and its risks

The graft is connected in sequence: the hepatic vein to the inferior vena cava for outflow, then the portal vein, then the hepatic artery, and finally the bile duct, joined either to the recipient's bile duct or to a loop of small intestine (a hepaticojejunostomy).

Families walking into his office often ask for a guarantee. Dr. Manchanda's answer is that liver transplantation, like any operation, has its share of complications:

• Early: bleeding, bile leak, rejection, and vascular complications such as hepatic artery or portal vein thrombosis.
• Late: chronic rejection, usually in patients who do not adhere to their immunosuppression; infections; metabolic complications of the drugs, including diabetes, hypertension and coronary artery disease; and post-transplant lymphoproliferative disorders (PTLD), an uncontrolled growth of immune cells called lymphocytes, when patients are over-immunosuppressed.

At his centre the most common complication is acute cellular rejection, managed by increasing the immunosuppression. Biliary complications, leaks and strictures, run at about 10%. Hepatic artery thrombosis, antibody-mediated rejection and portal vein thrombosis are rare.

Liver transplant outcomes: what survival to expect

One-year survival after liver transplant, across all causes of liver disease, is about 85 to 90%. At ten years it is around 60%, as other conditions take their toll over time.

Dr. Manchanda's own centre reports a 30-day mortality, the first marker of a transplant programme's quality, of about 3.5%. Mortality is about 7% at one year and about 8% at five years; beyond five years, once patients have resumed their own lifestyles, the figure is 9.67%.

The longer view matters more to patients. The symptoms of cirrhosis resolve, and recipients return to a normal life: exercise, gym training and demanding activities such as trekking. Women have conceived and carried successful pregnancies after transplant. His slides illustrate the transformation: one patient who needed three or four people to help her walk immediately after surgery walked into his office for her six-month follow-up; another, on BiPAP immediately after transplant, was taking part in adventure sports a year later. The life of a recipient on lifelong medication, and the follow-up it demands, are covered in immunosuppression after liver transplant.

Recent advances in liver transplant: where the field is heading

Dr. Manchanda identifies three frontiers.

Expanding the criteria for liver cancer. Practice has moved from the Milan criteria to the wider UCSF criteria and now to advanced multifocal tumours brought within criteria by trans-arterial chemoembolisation or trans-arterial radioembolisation. Centres worldwide are also transplanting patients with tumour thrombus in the portal vein after radiation to the thrombus, provided a PET scan six weeks later shows it has cleared.

Robotic surgery for donor and recipient. Robotic donor hepatectomy is already routine at his centre, and the team is working towards robotic recipient operations.

Withdrawing immunosuppression. Lifelong immunosuppression, and the infection risk that comes with it, is the Achilles heel of all organ transplantation. The liver's own immunomodulatory property has allowed some patients to stop their drugs entirely. Dr. Manchanda can readily recall at least three patients who were free of immunosuppression about five years after transplant. Current research is focused on making this possible more widely; it remains the exception, and stopping immunosuppression is only ever done under the transplant team's supervision.

Further out, he is sceptical of xenotransplantation. Livers from other animals have been attempted; they function initially, but long-term results have not been encouraging. Asked to choose, he would bet on lab-grown livers.

Related reading

Two other masterclasses on the site cover neighbouring ground from different angles: Dr. Sandeep Jha's basics of living donor liver transplant and Dr. Ashish George's liver transplant guide. The questions doctors put to Dr. Manchanda during the session, on HIV-positive recipients, liver regeneration in donors and operating-theatre sequencing among them, are on the Live Discussion page. His profile is on the Dr. Dheeraj Manchanda page, and other masterclasses in the field are gathered under hepatobiliary and liver transplant surgery.