What’s wrong with Steve Jobs: Yes, Jobs did have a liver transplant, but was it for metastatic insulinoma?

Over the weekend, the Wall Street Journal reported that the reason for Apple CEO Steve Job’s five month medical leave of absence from Apple is that he needed a liver transplant, which, according to the story, he underwent a couple of months ago in Memphis. In my discussion, I assumed, for the most part, the most likely clinical scenario, namely that Steve Jobs’ insulinoma had metastasized to his liver and that the liver transplant had been done for that indication, but, as some pointed out, it was possible that Jobs had somehow fried his liver without his tumor having metastasized. Unlikely, true, but possible. Unfortunately, news coming out over the last couple of days, while confirming that Jobs did indeed undergo a liver transplant, only shed a little more light on what happened and still leave a lot of questions. For instance, late Tuesday Methodist University Hospital in Memphis issued a press release:

James D. Eason, M.D., program director at Methodist University Hospital Transplant Institute, chief of transplantation and professor of surgery at the University of Tennessee Health Science Center confirmed today, with the patient’s permission, that Steve Jobs received a liver transplant at Methodist University Hospital Transplant Institute in partnership with the University of Tennessee Health Science Center in Memphis.

Mr. Jobs underwent a complete transplant evaluation and was listed for transplantation for an approved indication in accordance with the Transplant Institute policies and United Network for Organ Sharing (UNOS) policies.

He received a liver transplant because he was the patient with the highest MELD score (Model for End-Stage Liver Disease) of his blood type and, therefore, the sickest patient on the waiting list at the time a donor organ became available. Mr. Jobs is now recovering well and has an excellent prognosis.

Unfortunately, this press release leaves as many questions unanswered as it answers.

So, first off, we know that Steve Jobs did undergo a liver transplant. However, the indication is still unclear. The near universal assumption among medical experts who have been interviewed about his case is that the transplant was done for multiple liver metastases that were either too numerous or encompassed too many lobes to be resected. However, this press release implies that Jobs was sick. Real sick. The implication is that he had end stage liver disease, and the hospital points out that he was the sickest patient on the list with his blood type at the time the organ became available. Certainly I did in my post on the subject. So does the expert that the New York Times interviewed:

“If you were to postulate why he did it, I think the most likely reason would be that he had liver metastasis,” said Dr. Richard M. Goldberg, an expert on pancreatic cancer at the University of North Carolina, Chapel Hill, who is not involved in Mr. Jobs’s treatment.

Though other, noncancerous types of liver disease could also have led to a transplant, experts say cancer is the most likely explanation.

The liver is the most common site for the spread of pancreatic cancer, especially the rare kind that Mr. Jobs had, known as a neuroendocrine tumor, Dr. Goldberg said. That type of tumor tends to be slow-growing and far more treatable than the more common type of pancreatic cancer, which can be fatal within months.

When neuroendocrine tumors do metastasize, Dr. Goldberg said, they often spread only to the liver, rather than all over the body, and a transplant may be recommended.

Often, though, when tumors spread to the liver, surgeons can treat them by removing just part of the liver. The fact that Mr. Jobs needed a transplant suggests that he might have had diffuse disease throughout his liver, something that does not bode well, Dr. Goldberg said.

“The prognosis for somebody with metastatic liver disease is not nearly as good as for somebody who has disease confined to the pancreas,” Dr. Goldberg said.

“I think this confirms the speculation that there was more going on than had been previously acknowledged,” he said, “but it still doesn’t really tell us where things are likely to go from here.”

Indeed. According to the New York Times report and an AP report, Jobs was the “sickest” patient on the list at the time. Specifically, he had the highest Model for End-Stage Liver Disease (MELD) score at the time of transplant. The MELD score is a liver failure scoring system implemented in 2002 and used to prioritize patients on the transplant list. Unlike the case for kidney transplants, which can be put off for a long time because a patient can always remain on dialysis even if his kidneys do not function at all, in the case of liver transplants, there are no ways to temporize very long. Consequently, unlike the case for kidney transplants, where first come first served is closer to the model used, for liver transplants severity of the patient’s liver failure . Enter the MELD score, which can be calculated using this online calculator. It’s a straightforward equation:

MELD Score = 0.957 x Loge(creatinine mg/dL) + 0.378 x Loge(bilirubin mg/dL) + 1.120 x Loge(INR) + 0.6431

Basically, this equation is like a lot of other disease severity scores in that it models mortality rates and fits them to an equation involving key parameters. This equation works out to an expected three month in-hospital survival by MELD score of:

  • 40 or more – 100% mortality
  • 30-39 – 83% mortality
  • 20-29 – 76% mortality
  • 10-19 – 27% mortality
  • <10 - 4% mortality

Now, I know what you’re thinking. There’s no spot for liver cancer. That’s where things get dicey. One of the criticisms of the original MELD score is that it penalizes patients with hepatocellular cancer, who may be doing fairly well and have, based on biochemical parameters alone, a low MELD score. The reason is that the MELD score was designed primarily to stratify patients with nonmalignant end stage liver disease. To get around this problem, various adjustments to the MELD score have been proposed. However, virtually all of them are based on data for hepatocellular carcinoma (HCC), for which liver transplantation can be curative if there is no disease anywhere but in the liver. The issues involved were actually fairly well discussed in this Medscape article. Here’s what it says about MELD scores and HCC:

Patients with hepatocellular carcinoma may initially have preserved synthetic liver function that will not be prioritized well by MELD score calculation, thus underestimating their urgency. Prior to implementation of the MELD score as the allocation method, there have been some attempts to mathematically calculate risk of HCC progression to estimate how this factor would contribute to the new allocation schema.[26] Previously HCC-adjusted MELD scheme stratified patients with T1 HCC (single lesion≤1.9 cm) with a MELD score equivalent to a 15% (most recently adjusted to 8%) 3-month mortality, and T2 HCC (one nodule 2-5 cm, or two to three nodules all ≤3 cm) with a score equivalent to a 30% (now adjusted to 15%) 3-month mortality. Additional points equivalent to a 10% increase in pretransplant mortality are also given every 3 months until the patient is transplanted or no longer suitable for transplant. T3 HCC (one nodule >5 cm or two to three nodules at least one >3 cm) and T4 HCC (four or more nodules of any size or gross vascular invasion) are not eligible for listing.[3] There is criticism that this schema was made without much prior data on the pattern and rate of dropouts, and that liver cancer patients may have been unfairly given an advantage. Efforts to verify the fairness of the scheme suggest that further refinement is still needed.[27,28]

The problem with applying this to Jobs’ case is that there is very little evidence to guide a valid method of estimating a MELD score for someone with metastases to the liver from a neuroendocrine tumor. It’s essentially flying blind; actually, it’s almost a pure guess. There is, of course, one case in which applying MELD to a patient like Steve Jobs, and that would be if his liver metastases were so widespread that they were causing liver failure severe enough to give him a moderate to high MELD score even without the correction for malignancy, which in the case of an insulinoma is nothing more than a guesstimate. Given that neuroendocrine tumors are usually fairly indolent and slow growing, it’s hard to see how one can even estimate three month mortality rates. In any case, if it is true that Jobs had a high MELD score without consideration of malignancy, then before his transplant Jobs was much, much sicker than anyone had let on. He could very well have been near death’s door. If this wasn’t the case, then I have a hard time understanding how Jobs’ doctors came up with a high MELD score for his neuroendocrine tumor. My guess is that Jobs really was in serious end stage liver disease, and, given the limited information, that’s all it is–a guess. If that is the case, and his end stage liver disease was due to his liver being chock full of insulinoma, then I’d be very worried that it won’t be long before it recurs in the new liver.

In the AP article, a surgeon whom I used to know (and wouldn’t he be surprised if he ever found out that he actually knew an obnoxious pseudonymous blogger?) speculates:

Patients in such bad shape would get priority on any organ transplant list, and if Jobs did have a recurrence of cancer, that would give him even higher preference, said Dr. Roderich Schwarz a pancreatic cancer specialist at the University of Texas-Southwestern Medical Center in Dallas.

Liver transplants in such cases can cure the cancer, although patients remain at risk for another recurrence, Schwarz said. In addition, the powerful immune-suppressing medicine they must take to keep the body from rejecting the transplanted liver also can increase their risks for recurrence.

Either way, it’s a bad situation. The best I can reconstruct it is that Jobs probably had bad end stage liver disease with liver metastases. His short-term prognosis after his liver transplant is most likely quite good. However, without knowing how extensive his liver metastases were, it’s almost impossible to speculate about his long term prognosis, especially in the absence of so little data for the efficacy of liver transplant in producing long term survival when used to treat liver metastases of a neuroendocrine tumor.

As for the ethical issues regarding this transplant that I expressed a bit of discomfort with, that blogging private surgeon from my old stomping grounds from residency, Buckeye Surgeon, takes issue with such complaints. He’s actually mostly right. Jobs did nothing illegal, even if he was listed for transplant in multiple states. Where Buckeye Surgeon goes a bit wrong is in asserting that it’s not possible to game the system. True, in most cases it’s not. The criteria are based on biochemical measures of liver failure; i.e., hard numbers. However, in the case of malignancy, physician judgment comes in as to how urgent the transplant is. For HCC, there are reasonable, albeit incomplete, guidelines. However, in the case of a neuroendocrine tumor, where there is so little data on whether or not transplantation can result in long term survival, whatever the surgeons decide upon for a MELD score is likely to be a guess more than anything else, especially if the transplant patient hasn’t yet developed severe biochemical derangements from his liver failure yet. I’m not saying that’s what happened in Jobs’ case. Indeed, i rather suspect that the real explanation for his undergoing transplant is that he was much, much sicker than advertised, with a much, much worse liver than anyone had let on. Be that as it may, none of this doesn’t change the fact that liver transplant for neuroendocrine tumors has relatively weak data to support it, all in the form of small case series. Indeed, the case series that Buckeye Surgeon cited even concluded:

OLT [orthotopic liver transplantation] can achieve control of hormonal symptoms and prolong survival in selected patients with liver metastasis of carcinoid tumors. It does not seem indicated for other NET [neuroendocrine tumors].

However, I also note that this study is 12 years old, and transplantation techniques have improved in the interim. In any case, though, any estimate for a MELD score for Jobs would have had huge error bars if it were primarily based on his neuroendocrine tumor metastases rather than cold, hard lab values indicating a dying liver.

There’s one thing that I would hope to see from Jobs’ case, and that’s a discussion of the importance of transplantation and organ donation. UNOS and various state and regional organ sharing organizations do try to work to minimize disparities in waiting time for organs based on geography, but there is only so much they can do. Part of the reason for the questions and criticisms of how Jobs managed to use his wealth and power to improve his odds as much as is legally possible is that there are such regional disparities in wait times. If there were not, neither Jobs nor anyone else would feel as compelled to do something like move to Memphis temporarily in order to take advantage of Tennessee’s shorter wait lists for liver transplant. The best way to overcome these disparities is to increase the number of organ donors. Far too many people still die waiting for organ transplants, and far too few people donate their organs. If the Steve Jobs case encourages more people to sign their donor cards, and, far more importantly given that the organ donor card does nothing except inform people of a person’s intent and that permission for organ harvest still has to be given by the family, to tell their family that they want to donate their organs, it will be a good thing indeed.