Every year more than 6,000 people with liver disease or facing liver failure receive whole-organ transplantations in the U.S. Although the procedure is relatively safe and effective, problems remain: Demand outpaces supply; whereas the current U.S. waiting list stands at more than 15,000 only about 6,000 donations are made yearly. The procedure can cost more than $300,000 and immunosuppressants, drugs that prevent the immune system from rejecting the new organ, can lead to dangerous infections and uncontrolled bleeding.
A new approach may provide a stopgap or, in time, an entirely new alternative. Called hepatocyte transplantation, the technique replaces approximately 10 percent of the liver with healthy cells from a deceased donor. The patient’s organ is not removed, decreasing recovery time, complications and cost. With fewer than 150 U.S. recipients so far, the approach is in its early days.
If certain hurdles—such as the limited supply of cells and limited space in the patient’s liver—are overcome, hepatocyte transplantation may become an option for many liver disease sufferers. Some metabolic disorders, normally treated with whole-organ transplant, could be corrected with this less-intensive approach instead. For patients facing acute liver failure, hepatocyte transplantation could help their livers function until they recover. Some diseases for which liver transplantation would not be appropriate, such as amino acid disorders like phenylketonuria (PKU) and tyrosinemia, could also be treated with the new approach. And for those for whom no alternative exists and a transplant remains the only option, the procedure could also be used as a temporary measure, repeated as necessary until patients rose to the top of the waiting list—about 1,500 people die each year awaiting a transplant.
Hepatocytes are the liver’s main functional cells. In donated livers deemed unsuitable for transplantation the hepatocytes are usually still able to regenerate inside another liver. To extract them, the liver is chopped up and an enzyme called collagenase digests the fibrous matrix holding the cells together. White and red blood cells are removed, as are the bile duct cells. What remains are hepatocytes.
Within 48 hours these fresh cells are infused into a patient through the portal vein, which carries blood to the liver, or through the umbilical vein at the navel, which flows into the portal vein. The new cells squeeze through spaces between the cells lining the portal vein and enter the liver where they meld with the patient’s own hepatocytes. “Then they just stay and live there,” says Ira Fox, a gastroenterologist pioneering the technique at the University of Pittsburgh. About one billion new cells can be introduced at each infusion,
The technique is suitable for liver diseases where the organ structure is still intact. “If you don’t need to replace 100 percent of the deficient organ, then why not just try giving however many cells you need to provide stability?” says Jerry Vockley, pediatrician and chief of medical genetics at Children’s Hospital of Pittsburgh and an investigator on a clinical trial, led by Fox, of liver cell transplant for PKU. That condition leaves the body unable to break down phenylalanine, an amino acid present in many foods.
Other inherited metabolic diseases besides PKU include urea cycle disorders in which the body cannot eliminate the ammonia resulting from normal protein metabolism and the bile acid disorder known as Crigler–Najjar syndrome. For many of these conditions, replacement of around 10 percent of the liver could lead to significant health improvements. Acute liver failure, in which function is lost rapidly but the organ’s architecture remains intact, is another potential indication.
Hepatocyte transplantation could treat an estimated half of the metabolic disorders currently indicated for liver transplants, replacing “perhaps up to 10 percent of pediatric transplant candidates,” Fox says, along with many adult patients. Anyone living with PKU—the disorder occurs in about one of every 15,000 newborns in the U.S.—could also benefit. The most common indications for adult liver transplant, cirrhosis-induced liver failure and hepatitis C, cannot be treated by cell-only transplantation because the abnormal structure of the diseased organ will not allow new cells to survive.
The approach does carry some risks: Infusing too many cells at once can increase the pressure in the portal vein, leading to gastrointestinal bleeding; the hepatocytes can migrate into the circulatory system and block the arteries in the lungs; and patients still require immunosuppression, although the drugs may be tapered off in the months following the transplant. (Some patients can stop them entirely.) But the risk of these complications is “extremely low,” says Fox, who notes that the procedure can be stopped at any time. If a patient gets an infection or other serious complication, then immunosuppressants are halted, the infused cells are ousted and the liver returns to its previous state.
Although hepatocyte transplantation is still experimental, “I think we’re pretty close to knowing what we’re doing,” Vockley says. And challenges remain. One is the limited supply of hepatocytes. Donated livers that prove unsuitable for whole-organ transplantation provide a sufficient supply of hepatocytes, but extracting the cells is difficult. Growing them from stem cells in the laboratory could provide an alternate source, although significant engineering challenges (such as generating enough cells and eliminating those with tumor-forming potential) still need to be overcome.
Carving out space in the liver for infused cells is another challenge. To help them fit, Fox is exploring radiation to kill off some host liver cells prior to the infusion. Ensuring that the new cells are permanently incorporated into the liver is also an issue, but Vockley and Fox are optimistic that new techniques for identifying cell rejection early and honing the immunosuppressant regimen will lead to such long-term engraftment. Immunosuppressant complications are also of concern. At King’s College Hospital, London, pediatrician Anil Dhawan, who has performed 33 hepatocyte transplants since 2003, coats donor cells with alginate, a natural gel that hides them from immune attack, eliminating the need for immunosuppressants.
Dhawan, who is a scientific advisor to Cytonet, a commercial liver cell provider, recently treated a two-day-old boy with a severe urea cycle defect using hepatocyte transplantation. After testing the approach in other disorders Fox and Vockley are now focused on PKU patients who must maintain an incredibly restricted diet to avoid neurological impairment. In one patient a hepatocyte transplant reduced her phenylalanine level by almost half. Her difficulties following a proper diet were causing cognitive problems and the transplant enabled her to safely liberalize her diet and reduce her risk of injury. For Fox, “that’s a success story.”