For a person with cirrhosis, a liver transplant can mean the difference between life and death. But if the person hoping to receive lifesaving treatment happens to be a woman, she is more likely to die waiting for that liver than if she were a man.
More than a decade of research shows that women in the United States with cirrhosis are less likely to receive a liver transplant, and more likely to die on the waitlist, than men. Sex-based differences in height, creatinine levels, and the higher prevalence of liver cancer in men versus women all contribute to the widespread disparity. Possible solutions include adjusting how the Model for End-Stage Liver Disease (MELD) score accounts for creatinine levels and incentivizing split-liver transplantation.
The liver transplant community has known about the problem since the early 2000s, but has yet to take serious steps to fix it, experts said. “It’s been a real challenge to try to get policy changed when dealing with other bigger issues like geographic disparity and now coronavirus,” Jennifer Lai, MD, MBA, a general and transplant hepatologist at the University of California, San Francisco, said. “It never feels like it rises to the top of peoples’ priority list.”
Shortly after the new MELD score system for liver transplantation was adopted in 2002, the transplant community noticed a persistent disadvantage for women who needed access to a liver transplant compared with men, said Elizabeth Verna, MD, MS, a transplant hepatologist and gastroenterologist at NewYork-Presbyterian/Columbia University Irving Medical Center, in New York City. Transplant specialists agree that the objectivity of the MELD score makes it far superior to the previous scoring method, which used a mix of lab tests and reported symptoms to categorize patients into four urgency groups. But the MELD score is still an imperfect way to allocate livers, according to Russell Rosenblatt, MD, MS, a transplant hepatologist at Weill Cornell Medicine, in New York City.
In 2018, a comprehensive review published in the journal Transplantation by researchers at Mayo Clinic and Stanford University quantified the disparity. Their prospective study of 90,720 registrants with the Organ Procurement and Transplantation Network (OPTN) database found that women were 20% less likely to be transplanted than men. Women also had a higher mortality than men four years after listing (22% vs. 18%; P<0.0001), the researchers found.
Biological Differences Partly to Blame
Part of the discrepancy is due to body size. Women are, on average, smaller in size and stature than men, Dr. Lai said. Meanwhile, men are more likely to die in car accidents or by other violent means that make them ideal organ donors. The result is a size mismatch: Many donated organs are simply too large to be transplanted into smaller patients.
Physical differences also influence creatinine levels, which are used as the marker of kidney function in the MELD score. Men have a higher level of muscle mass, and therefore higher creatinine levels at baseline. With less muscle mass on average, women have lower creatinine levels for the same renal function as men, said Alina Allen, MD, a transplant hepatologist in the liver transplant program at Mayo Clinic in Rochester, Minn., and a co-author on the 2018 study of sex-based disparity in liver transplant access. On average, according to that study, women received between 1 and 2.4 fewer MELD score points for the same renal function as men. The natural difference in creatinine levels between men and women results in fewer MELD points for women overall, putting them at a lower priority for a transplant.
Women and men also tend to suffer from different liver diseases that lead them to the transplant waitlist in the first place. Men are more likely to have liver cancers that require a transplant—and which lead to MELD score exception points to move them to the top of the list faster, Dr. Allen said. Women are more likely to suffer from conditions such as cholestatic liver disease and autoimmune hepatitis, which have no such exceptions built into the system.
“If the goal is to be as fair and balanced and unbiased as possible, we need to make sure major groups of patients are not majorly disadvantaged” by the markers that go into the scoring system, Dr. Verna said.
The 9% Gap
Adjusting the MELD score to compensate for the naturally different creatinine levels in men and women could be a place to start addressing this problem, Dr. Verna said. In the 2018 retrospective study, Dr. Allen and her colleagues found that adding just 1 point to women’s MELD scores, holding other factors like height and exception points equal, significantly increased their access to donor livers.
But Dr. Allen warned that adjusting the MELD score likely will not close the gap entirely. In a follow-up analysis, Dr. Allen and her colleagues compared women with men who have the same height, MELD score and renal function. Even when all of these factors were equal, women were still 9% less likely to have access to a liver transplant compared with men. “That means there are some unknown factors we cannot account for that still explains this 9% difference in transplantation,” Dr. Allen said.
Even after adjusting the MELD score, the difference in body size also remains a persistent problem. In the long term, investing in the training, expertise and resources to increase the number of split-liver procedures across the country could help address this difference, Dr. Lai said. Prioritizing small liver transplant candidates, which would ensure that a liver from a small donor goes to a small candidate, rather than a larger person at the top of the waitlist, could also help ameliorate this issue, she said.
While many experts in the liver transplant community are aware women awaiting transplant are at a disadvantage, the system has too many problems to address them all at the same time.
Over the past five years, the OPTN Liver and Intestine Transplantation Committee that evaluates and sets transplant policy has seen an “unprecedented amount of activity,” said Julie Heimbach, MD, of the Mayo Clinic Transplant Center and an immediate past chair of the committee. The group’s biggest focus has been the geographic disparity in transplant access, resulting in a major policy change that prioritized the sickest patients located closest to a donor organ, rather than relying on arbitrary geographic regions to help determine who was eligible for a particular organ. The change went into effect earlier this year. Now, the committee can turn to addressing other problems with liver transplant allocation, and the sex disparity is one issue members want to tackle, Dr. Heimbach said.
Dr. Heimbach said she hoped the committee could start investigating this problem, and possible solutions such as adjusting the points awarded for creatinine levels in the MELD score, later this year. The sex-based disparity is not quite so complicated as the geographic disparity question, which makes her optimistic about finding a workable solution. But in the middle of a global pandemic, it is impossible to say when the committee might be able to meet to deliberate the issue.
—Jillian Mock