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406
There are some centers that use fomepizole to treat severe episodes of acetamin-
ophen toxicity. Fomepizole is a competitive inhibitor of alcohol dehydrogenase,
which inhibits formation of toxic acetaminophen (APAP) metabolites; I have never
used it, but based on its mechanism of action, it would make sense to use it in those
who have concomitant acetaminophen and alcohol toxicity.
K. Saeian
https://t.me/medicina_free
407© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_98
Chapter 98
Candidates forLiver Transplant?
VeronicaLoy
A GI fellow who left your training program to join a group GI practice several
weeks ago asks to set up a meeting. He took over the practice of a retiring gastroen-
terologist and wants to discuss management of several patients. There were four
patients with ESLD who he thinks may warrant liver transplant evaluation. The
practice is located in a rural area, one and a half hours away from your academic
transplant center.
Do you think any of these patients are liver transplant candidates?
1. A 58-year-old male with alcoholic cirrhosis who has been abstinent 3years is
living in a shelter. He has been treated for encephalopathy, recurring ascites,
and varices. He takes his meds as prescribed and manages to have a friend drive
him to the hospital for all his ofce visits and procedures. He is on public assis-
tance. The former doctor did not refer him for transplant evaluation because of
his lack of social and nancial support.
This is a difcult case. I think that the rst concern is both nancial and social
support, and we need to consider why those are so important in the posttrans-
plant period. As we know, if the patient does not have access to the immunosup-
pressive medications for life, then the organ will be rejected. If that’s the case,
you’ve done the patient a disservice as well as the organ donor and another
potential recipient did not receive the organ. It is critical that we have a multidis-
ciplinary approach to assessing both nancial support and social support. Our
program has our own nancial liaison as well as a social worker, who hone in,
and try every avenue, to make sure that they can assure coverage for these
medicines.
V. Loy (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: vloy@mcw.edu
https://t.me/medicina_free
408
In this patient’s case, he has been taking his prescribed meds, he must have
public assistance, and Medicaid usually will cover these meds. Coverage and
compliance don’t seem to be a problem for him, so that bodes well.
However, the second thing we have to worry about is the infection risk. And
unfortunately, staying in shelters, most of the time, is something that the trans-
plant committee is really going to struggle with as far as reliable housing and
infection risk. It’s even a struggle for patients living in a nursing home because
of an increased risk of posttransplant infection. Typically, we prefer people that
have individualized housing. I think every transplant center is probably a little
different on how they would view this case. I’m pretty condent that in our cen-
ter living in a shelter would not be considered reliable housing.
What makes things more complicated is that there is a recent law about dis-
crimination and access to an organ transplant. Transplant programs must be
careful with the reasons for declining to list someone for transplant. The psycho-
social issues, especially for people with mental health or developmental delays,
are really challenging. There have been lawsuits when some of these patients
were declined. In this patient’s case, infection risk of rejection is a realistic rea-
son for declining to list the patient.
2. A 57-year-old female has NASH cirrhosis. She has had treatment for esophageal
varices and recurring ascites. Her BMI is 35. The previous doctor pushed her to
diet and lose weight. He insisted that she lose at least 20lbs. She was not having
much success, losing only about 5lbs. The doctor did not refer her for liver
transplant, thinking that she was not a candidate because of her obesity.
This is a very timely topic. What we know about organ transplant is that the
extremes of weight don’t do as well. The super obese or the very sarcopenic
patients don’t do well. In this case, the patient has a BMI of 35; that’s not a big
problem, and that patient certainly should be considered as a transplant candi-
date. Once you’re heading towards a BMI of 40, 45, or 50, that becomes more
challenging and controversial. It depends on where the person holds their weight.
If it’s all abdominal fat, that is more of a problem, especially if it’s a dual organ
transplant, like a liver-kidney, because the abdominal weight may cause prob-
lems with the kidney. But if they’re carrying all their weight in their legs and
their glutes, then that’s not really prohibitive to transplant. There are some really
good studies looking at outcomes in obese patients after transplant and they do
quite well as long as they’re not in the far extremes. In fact, obese patients tend
to do better than sarcopenic patients who have no muscle mass, very low BMIs,
and poor nutrition. The outcomes relate mostly to nutrition and functional status.
If you have a morbidly obese patient that has good nutrition and a good func-
tional status, that’s helpful, but many centers are doing bariatric surgery along
with the transplant if their weight is extreme. Some do it in the pre-op period,
some at the time of transplant, and others after they’ve recovered from the trans-
plant. There’s a little bit of controversy over which is the best way to do it. But a
lot of people are looking into bariatric surgery as it relates to liver transplant,
particularly in NASH patients.
V. L o y
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409
The Mayo Clinic has done a really nice study where they compared patients
who, like this patient, were told they had to lose weight prior to transplant. And
those patients did lose weight and were transplanted, and they were compared
with a group of patients who had bariatric surgery and then were transplanted. It
turned out that those patients who had bariatric surgery and then were trans-
planted actually did much better than those that lost weight on their own and
then got their transplant. That group tended to gain back a lot of their weight
after transplant. And progression to NASH cirrhosis posttransplant happens very
quickly in those who gain their weight back. So, I think, as we move forward in
the next decade, it probably will become the standard of care that these patients
with NASH cirrhosis have some sort of bariatric procedure along with their
transplant.
3. A 49-year-old male alcoholic presented with a GI bleed and required an ICU
admission with banding of varices. He was discharged from the hospital, but
over the next 3months, he has had repeat admissions with banding and then
bleeding from post-banding ulcers, ascites, and SBP.He has also had encepha-
lopathy controlled with lactulose. He has been abstinent since the rst admis-
sion. The previous doctor would not refer him for transplant because he has only
been abstinent for 3months.
I am really passionate about this one. Using duration of sobriety or abstinence
alone has been shown time and time again to not predict recidivism posttrans-
plant. And so, in this patient, I would absolutely encourage referring to a trans-
plant center. And at that center, there’ll be a multidisciplinary approach with a
psychology evaluation and a social work evaluation and really assess this
patient’s commitment to lifelong sobriety and their social support. Many centers
are integrating alcohol and drug addiction counseling along with their clinic
visits, and that’s been shown to improve the chances of patients having lifelong
sobriety.
It’s very important not just to use time alone as a reason not to refer someone
for transplant. It doesn’t predict posttransplant alcohol use. Even those who have
6months or a year of sobriety have the same recidivism rate as those who have
no sobriety. So, time should really not be a factor.
4. A 72-year-old female with NASH cirrhosis has ESLD.She has encephalopathy
requiring lactulose and rifaximin. She has had a prior TIPS procedure for vari-
ceal bleeds and gastric varices. Because the encephalopathy is hard to control,
the TIPS needed to be narrowed, and now the patient has chronic GI bleeding
from GAVE.The previous doctor would not refer her for liver transplant evalua-
tion because he thought she was too old.
Once again, similar to our last discussion, this is a misconception that many
people have; it’s really an outdated thought. There is actually no age cutoff for
transplant. Most transplant centers look at the physiological age, so the health of
the patient, their functional status, their cardiac comorbidities, and pulmonary
comorbidities are far more important than the age alone. So, this patient, depend-
ing on her other medical comorbidities could certainly be considered for transplant.
98 Candidates forLiver Transplant?
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411© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_99
Chapter 99
Frustrations withWaiting foraTransplant
VeronicaLoy
A 57-year-old male with alcoholic cirrhosis is referred for liver transplant evalua-
tion. He was diagnosed 2years earlier and has been abstinent since. He was found
on index endoscopy to have esophageal varices, which were banded and remain
obliterated on a recent endoscopy. He has been plagued with recurring ascites.
Initially diuretics were used but when doses needed to be increased, he developed
renal insufciency. He now comes in for weekly paracentesis during which 5–7
liters of uid is usually removed. He has had one episode of SBP and remains on
prophylactic ciprooxacin. He has had several episodes of hepatic encephalopathy:
the rst when his creatinine was elevated and the second when he had SBP.He was
placed on lactulose, which he takes regularly, except when he is in situations where
he needs to avoid having diarrhea. When he doesn’t take his lactulose, he gets very
sleepy. His INR is 1.9, albumin is 3.4, bilirubin is 1.3, AST is 30, ALT is 50, Alk phos
is 90, creatinine is 1.2, Na is 136, and MELD is 16. His local gastroenterologist tells
him that with his MELD score, he probably won’t qualify for a liver transplant for
a while.
1. How do you deal with patients who are suffering from complications of cir-
rhosis but can’t qualify for a transplant for protracted periods because
their MELD is not high enough?
This is an ongoing, common problem. But I would advocate for evaluation
and, if possible, listing for transplant. We understand that with the MELD score
of 16, they’re not likely to get an organ quickly. However, the medical condition
can deteriorate very quickly for these patients. We know that people with diuretic
V. Loy (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: vloy@mcw.edu
https://t.me/medicina_free
412
resistant or diuretic refractory ascites have a 50% 2-year mortality, which is very
high. We tend to see them develop SBP and liver decompensation, or they have
a bleed after a paracentesis and their liver decompensates, so these complica-
tions can happen very quickly. Therefore, the benet of listing them early. I feel
that even though the MELD is on the low side, at 16, I advocate listing if it’s over
15. But sometimes, we see these patients with a MELD score of eight, and I still
think with diuretic resistant or refractory ascites or patients with varices that we
should try to get them on the transplant list because things change quickly and it
allows the patient and their family time to be educated and learn and understand.
And we can work on other things. Often, during the transplant evaluation, we
uncover other risks that we need to mitigate, like maybe they need to stop smok-
ing. And we can work on these things for the best results with transplant. Also,
if this patient did not have a history of encephalopathy, I would look into doing
a TIPS at this time, but because of the encephalopathy, I won’t.
Additionally, there are other avenues to help get a patient a liver transplant
sooner, such as living donor liver transplantation. A patient needs to be assessed
early to see if they might qualify for this.
In summary, I would try to get the patient listed, and then, I would continue
to do what this gastroenterologist is doing with the repeated paracentesis, low
sodium diet, and antibiotic prophylaxis.
2. What do you think about a system where the sicker, higher risk patients are
the ones who are having this aggressive operation? Wouldn’t you rather
your patient receives the transplant when they are less sick?
The system is not always logical but it’s meant to be fair. The people who
need the transplant the most have access to the transplant. However, we do know
that, in terms of posttransplant outcomes, there is a tipping point at which
patients have worse survival after transplant because they were so sick going into
the transplant. The ideal time to get a transplant is probably at a MELD of 24–30
instead of a MELD of 40. These patients are not as sarcopenic; they can recover
quicker. They don’t have as many complications, they’re not as
immunocompromised.
I agree it would be phenomenal to offer a transplant when a patient is less
sick, and I think we’re making some progress toward transplanting patients at a
lower MELD.Ideally, anyone who needs a transplant would have access to it,
but the real issue is an organ donor shortage. The demand far outstrips the
resources.
One way we’re making progress is by using other types of liver donations
besides just brain-dead donors. In some of these patients with the lower MELD
scores, there might be the option of using a living donor transplant, if they qual-
ify. However, patients with a lot of portal hypertension, like this one, are gener-
ally not ideal candidates for a living donor transplant, they often need a whole
donor graft.
Another potential source of livers is to use not only brain-dead donors but
also donations after cardiac death. Another group is the hepatitis C-positive
donors. We’re using them a lot more now because we can eradicate hepatitis C
V. L o y
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413
easily after the transplant. Another new thing that’s happened in the last couple
of years is the machine perfusion-donor livers. Here, they take organs that
previously would have been discarded because of their questionable quality.
This may be the case if a liver had a lot of steatosis or the donor was elderly.
There is now available hypothermic and normothermic machine perfusion for
these donor organs, which can optimize the graft allowing for transplant in some
cases where previously they would’ve gone unused. The transplant surgeon will
take the donor liver and hook it up to this perfusion device, and they’re able to
monitor the liver and see if this liver will work in the recipient. Another tech-
nique is to do organ procurement the traditional way, then put the liver in the
cooler and get on the airplane, and then when they get back to their own hospital,
hook it up to a pump. This is something they’ve been doing with kidneys for
some time now.
3. What percentage of patients develop HCC or develop medical complica-
tions that make them inoperable while waiting to be transplanted?
This is very common because of problems waiting for access to a donor.
There is only so long that you can keep someone’s cancer within Milan criteria.
There’s only so long that you can keep someone with end-organ failure alive
before they get an infection that prohibits transplant.
Many patients will develop hemodynamic instability with which there’s no
way they could survive a transplant. What is the waiting list mortality rate? It’s
variable across the country, depending on access to grafts. But nationwide, I
would guess the wait list mortality rate is about 20%.
With HCC in particular, there have been some changes in organ allocation.
So, some patients who are listed with MELD exception points, depending on
where they live, may have better access to organs, while others have less access
to organs. We’ve seen that some of our patients with tumor exception points are
on our wait list for up to 200, even 300days. But keeping cancer in check for a
year is quite challenging.
99 Frustrations withWaiting foraTransplant
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415© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_100
Chapter 100
Complications Posttransplant
VeronicaLoy
A 57-year-old female receives a liver transplant for PBC.She is started on predni-
sone, tacrolimus, and mycophenolate. Within the rst 3months, she develops mul-
tiple medical problems. She has developed hypertension, which was not present
previously, she progressed from having prediabetes to diabetes, and her creatinine
has risen from 1.4 to 1.8.
Can you discuss the contribution of her antirejection meds to these different
medical problems and how you might manage the antirejection meds per. se.
When transplants were initiated in the late 1960s and early 1970s, the main cause
of death was acute cellular rejection. Things have come a really long way, thanks to
our superior antirejection meds. We have available calcineurin inhibitors, mycophe-
nolate, and azathioprine and prednisone. We are at a point where patients are living
a long time. The expectation is that survival at 10 years should be 70% or more.
Transplant rejection still remains a concern; up to 30% of patients may develop
rejection, but we can manage that much better now.
Now the major problems we are dealing with are the side effects from long-term
use of these antirejection medications. One concern is new cancers, and we encoun-
ter a lot of these, particularly skin cancers. Depending on the etiology of the patient’s
disease, we have to be very careful looking for other types of new malignancies. Of
course, infections are a big concern.
This case points out two other very challenging side effects of antirejection
meds, the metabolic syndrome and hypertension. Cardiovascular events, heart
attack and stroke, are all happening at a far greater rate in transplant recipients com-
pared with their nontransplant recipient counterparts.
V. Loy (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: vloy@mcw.edu
https://t.me/medicina_free
416
Additionally, data shows that at 5–10years posttransplant, the rate at which peo-
ple have kidney disease, CKD3 or CKD4, approaches almost 70%. Historically, it’s
a very high percentage of people who receive the transplant of a heart or a liver who
ultimately end up needing to talk about going on dialysis or having a kidney
transplant.
The long-term effects of immunosuppression are a big problem. How can we
manage this? I think looking at strategies for minimizing immunosuppression is
very important. The level of immunosuppression that the patient is maintained on in
the immediate posttransplant period will predict how they do 10years later. So, the
goal is to work on minimizing medication without putting the patient at risk of
rejection. There’s a lot of research in the area. The strategy used in this patient’s
case of using three drugs rather than using a high-dose calcineurin inhibitor alone is
an important step. With the calcineurin inhibitors, we’re worrying most about renal
insufciency, but they also contribute to hypertension, hyperlipidemia, and diabe-
tes. By using mycophenolate and prednisone, we may be reducing the risk of kidney
damage, but there is a trade-off with some of these other problems and metabolic
conditions.
There’s also another class of agents, the mTOR inhibitors, which are sometimes
used with a strategy of minimizing the dose of calcineurin inhibitor. The hope is that
this will prevent renal insufciency and may possibly help reduce the recurrence of
cancers. In this patient, I might have titrated some of the dosages of medicines she
was on to try to avoid some of these complications.
Now there is ongoing research about immunosuppression withdrawal. There are
ongoing trials to determine which patients could actually come off immunosuppres-
sion completely. I don’t think it’s yet at the point where I would feel comfortable
doing that, although some hepatologists have moved in this direction. I would work,
instead, on managing the comorbidities, trying to help the patient have better con-
trol of the hypertension, the diabetes, and the lipids. And ultimately, if renal func-
tion continues to decline, getting a nephrologist involved early on.
After 3months, the patient comes in complaining of some increased fatigue and
weakness, and liver enzymes show a signicant increase from her posttransplant
baseline. Her AST increased from 30 to 90, the ALT from 40 to 120, the Alk phos
from 100 to 160, and the bilirubin from 1.3–2.3. She is not taking any OTC meds—
nothing but what has been prescribed for her.
What are some possible explanations for this and how would you manage it?
You would certainly worry about rejection here, especially if you previously
decided to reduce immunosuppression. The other common problem I always want
to rule out in a patient like this is infection. CMV is very common; even far post-
transplant and any infection is going to cause a rise in the liver enzymes and perhaps
a cholestatic liver injury, which this patient has. Any infection, including c diff, is a
possibility, so I would screen for infection.
I also usually get some imaging to make sure that there’s no problem with the
bile duct. You know that’s very common posttransplant as well.
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The other thing I would worry about in this patient is the possibility of PBC
recurrence posttransplant or even autoimmune hepatitis. The rate of recurrence of
PBC posttransplant is high.
In addition to rejection, I would work the patient up for infection, recurrent dis-
ease, any bile duct injury, or steatosis of the liver. For this patient, you’re probably
going to do a liver biopsy at some point. I wouldn’t send someone for a biopsy based
on one set of labs, but if the problem were to persist for a couple of weeks or even a
month or if the labs were quickly deteriorating, I would get this patient in for
a biopsy.
A liver biopsy is done that reveals lymphocytic inltration within portal tracts,
mild inammation of bile ducts, and lymphocytic inltration of portal and hepatic
venules. A Doppler US shows normal blood ow without thrombosis but suggests
extrahepatic biliary dilation. An MRCP is done that shows a mild extrahepatic
stricture of questionable signicance.
This looks like rejection, but the management of rejection depends on the sever-
ity of the rejection and which drugs and at what dosages the patient was on prior to
developing the rejection. The pathologist will generally give you the level of rejec-
tion based on the Banff criteria. They’re going to tell you, is this mild, moderate, or
severe rejection?
If it is mild, sometimes just increasing immunosuppression is enough. If a patient
was on cyclosporine only, then switching them to tacrolimus or adding mycopheno-
late would be my strategy for managing mild rejection. For moderate and severe
rejection, it’s going to take more than that. Usually, you’re going to need to use an
IV dosage of solumedrol, and if it’s refractory to that, sometimes even more aggres-
sive IV therapies for acute cellular rejection are required. And then, once they are
improved, you need to increase their outpatient regimen as well.
This patient’s case is tough because presumably she’s still taking prednisone,
tacrolimus, and mycophenolate. We’re not given the dosage, but you may have to
increase the prednisone and increase the trough level of the tacrolimus.
When you see patients coming from a different transplant center, what ini-
tial therapy might you be less pleased with?
I think the etiology of disease is very important to consider. For autoimmune
hepatitis, PSC, and PBC, a lot of those patients are tapered completely off pred-
nisone. But realize that they have an immune-mediated indication for transplant,
and most of these do recur posttransplant. So, I think that these patients should be
maintained on at least a low dose of prednisone. Oftentimes, I’ll see that
they’re not.
Now another drug that has fallen out of favor is cyclosporine, but depending on
where and how long-ago patients were transplanted, we may see them on cyclospo-
rine. It’s not as strong an immunosuppressive agent, and it causes more renal insuf-
ciency and comorbid problems than tacrolimus. If patients are on cyclosporine, I’ll
often switch it. Some patients get started on cyclosporine because they have mental
status alteration posttransplant while taking tacrolimus and may be labeled with
100 Complications Posttransplant
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