Liver Transplantation for Urea Cycle Disorders: Analysis of the United

Network for Organ Sharing Database

L. Yua, S.C. Rayhillb, E.K. Hsuc, and C.S. Landisa,*
a
University of Washington, Division of Gastroenetrology and Hepatology, Seattle, Washington, USA; bUniversity of Washington,
Department of Surgery, Seattle, Washington, USA; and cDepartment of Pediatrics, University of Washington School of Medicine,
Seattle, Washington, USA

ABSTRACT
Background. Urea cycle disorders (UCD) are caused by rare inherited defects in the
urea cycle enzymes leading to diminished ability to convert ammonia to urea in the liver.
The resulting excess of circulating ammonia can lead to central nervous system toxicity and
irreversible neurologic damage. Most cases are identified in children. However, UCDs can
also be diagnosed in adulthood, and liver transplant is occasionally required.
Methods. We examined the UNOS database to evaluate outcomes in adult and pediatric
patients who underwent liver transplant as treatment for a UCD. We identified 265 pe-
diatric and 13 adult patients who underwent liver transplant for a UCD between 1987
and 2010.
Results. The majority (68%) of these patients were transplanted before age 5 years.
Ornithine transcarbamylase (OTC) deficiency was the most common UCD in both adults
and children who underwent transplant. UCD patients who underwent liver transplant
were younger, more likely to be male (67%), had lower pediatric end-stage liver disease/
model for end-stage liver disease scores, and were more likely to be Caucasian or Asian
compared with all other patients transplanted during the same time period. UCD
patients did not have an increased utilization of living donor transplantation in this US
cohort. Univariate and multivariate risk factor analyses were performed and did not
reveal any significant factors that were predictive of post-transplant death or graft loss.
Conclusions. Excellent outcomes were seen in both children and adults with UCDs who
underwent transplant with overall 1-, 5-, and 10-year survivals of 93%, 89%, and 87%,
respectively.

U REA CYCLE DISORDERS (UCDs) are caused by

defects of urea synthesis and related to metabolism.
UCDs are the most common liver-based inborn errors of
metabolism, with an incidence of approximately 1:30,000 to
46,000 live births. These metabolic pathways are located
mainly or exclusively in the liver. Ornithine transcarbamylase
(OTC) deficiency is inherited in an X-linked manner and the
other 5 UCDs in an autosomal recessive manner [1].
UCDs generally present clinically in early infancy with hyper-
ammonemia and encephalopathy. However, presentation can
be variable, ranging from fatal neonatal hyper-ammonemia,
particularly in X-linked OTC deficiency, to asymptomatic, as
in the partial enzyme deficiency of female OTC deficiency.
After repeated attacks of hyper-ammonemia, irreversible
neurological sequelae can accumulate and cause significant
reduction in the functional capacity of these patients [2].
Medical management of UCDs is oriented toward stra-
tegies to reduce ammonia levels, which include reducing
protein intake and various ammonia scavenging therapies
[3,4]. However, medical therapies cannot completely pre-
vent episodes of acute hyper-ammonemia and progressive
neurological damage. Liver transplant is often used for
these patients because it is considered curative [5].
*Address correspondence to Charles S. Landis, Division of
Gastroenterology and Hepatology, University of Washington
Medical Center, 1959 NE Pacific Street, Seattle, WA 98195-6424.
E-mail: clandis@medicine.washington.edu

ª 2015 by Elsevier Inc. All rights reserved. 0041-1345/15

360 Park Avenue South, New York, NY 10010-1710 http://dx.doi.org/10.1016/j.transproceed.2015.09.020

Transplantation Proceedings, 47, 2413e2418 (2015) 2413

2414 YU, RAYHILL, HSU ET AL

Table 1. Recipient and Donor Characteristics of Patients Transplanted for Urea Cycle Disorders and All Other Transplants Between
1988 and 2010
Pediatric Adult
UCD All others UCD All Others
Characteristic n ¼ 265 n ¼ 12198 P Value n ¼ 13 n ¼ 92,929 P Value

Age 2.6 " 4.0 4.8 " 5.6 <.001 28 " 12 51 " 11 <.001
Sex (% female patients) 33 52 <.001 69 36 .015
Ethnicity (%)†
Caucasian 68 58 <.001 70 76 NS
Black 8.7 18 <.001 7 8.0 NS
Hispanic 15 18 NS 0 11 NS
Asian 6.8 3.8 <.001 23 4.0 NS
Other 1.5 2.2 NS 0 1 NS
BMI* 18.6 " 4.3 18.2 " 4.4 NS 25.4 " 3.9 35.7 " 5.4 NS
Albumin (g/L) 3.6 " 0.80 3.1 " 0.80 <.001 3.4 " 0.56 2.9 " 0.73 .006
Creatinine (mg/dL) 0.38 " 0.45 0.60 " 0.90 <.001 1.0 " 0.77 1.5 " 1.3 NS
Bilirubin (mg/dL) 1.28 " 3.72 12.3 " 12.0 <.001 4.2 " 7.9 8.1 " 10.8 NS
INR‡ 1.29 " 0.65 1.99 " 2.54 <.001 1.2 " 0.32 1.9 " 1.5 NS
ALT (IU/mL)† 205 " 670 357 " 931 .048 42.8 " 45.2 206 " 709 NS
PELD or MELD 0.47 " 8.0 15.9 " 13.8 <.001 13.2 " 10.2 21.2 " 10.0 .026
MELD exception 41 23 <.001 73 27 .003
(after 2002) (%)
Cold ischemia time (hours)* 7.8 " 4.7 8.8 " 5.3 .005 7.6 " 2.4 8.4 " 4.6 NS
Living donor (%) 6.0 10.7 .015 7.7 3.1 NS
Donor age (years) 9.9 " 1 1.6 13.9 " 14.7 <.001 42 " 15 38 " 17 NS
Donor BMI* 20.8 " 10.9 43.5 " 721 NS 25 " 3.9 26 " 5.3 NS
*Data 75% complete; 90%.
†
Data 50% complete; 75%.
‡
Data <50% complete.

Most UCDs are mainly or exclusively expressed in the liver.
Therefore, the enzyme defect is essentially cured by a liver
transplant. However, liver transplant carries risks of its own
including surgical risk and long-term risk of for infection and
malignancy related to immunosuppression. Data are limited
regarding the long-term outcomes of liver transplant for
UCDs. Morioka et al [6] published a review of the review of
the worldwide English literature and 13 cases at Kyoto Uni-
versity. They report excellent survival of approximately 90%
at 5 years. However, this study was limited by small numbers
and limitations as the result of a literature reviewebased
approach. More recently, Perito et al [7] analyzed the United
Network for Organ Sharing (UNOS) database data for com-
bined outcomes in pediatric patients with UCDs and organic
acidemias. Excellent outcomes were noted in the combined
group. UCDs and OAs can present with common symptoms,
but the metabolic pathways involved and the medical thera-
pies are distinct. Therefore, a combined outcome may not
accurately reflect outcomes in the individual disorders.
With increasing frequency, UCDs are diagnosed in
adulthood, often in the setting of an acute illness triggering
increased nitrogen turnover [8]. The majority of cases
diagnosed in adulthood are mild and can be controlled with
medical therapy alone. However, liver transplant is occa-
sionally required [9], and fatal cases of adult onset UCDs
have been reported [10,11].
The UNOS dataset is a nationwide registry of organ
transplants performed in the United States since 1987. In
this study, we queried the UNOS dataset to determine the
characteristics and outcomes of patients who underwent
liver transplant for a UCD. To our knowledge, this is the
largest and most comprehensive study of its kind.
METHODS
Case Identification
Patients with UCDs were identified from the UNOS Standard
Transplant Analysis and Research files of liver transplant recipients
between October 1987 and May 2010. UNOS does not have specific
diagnosis codes for UCDs. Therefore, patients with UCDs were
identified by text-searching the diagnosis fields in the UNOS data-
base for text containing “urea,” “ornithine,” “OTC,” “carbamoyl,”
“CPS” (carbamoylphosphate synthetase I), “argin,” or “citrul.”
Patients identified with a specific or an unidentified UCD were
included in the study. Available data were >90% complete for age,
sex, bilirubin, creatinine, and albumin. Available data were >75%
complete for recipient body mass index (BMI), donor BMI, and
cold ischemia time. Available data were >50% complete for ala-
naine aminotransferase (ALT) and ethnicity data. International
normalized ratio (INR) was documented in less than 50% of the
data. Data on pediatric end-stage liver disease (PELD), model for
end-stage liver disease (MELD), and the use of PELD/MELD ex-
ceptions were only available for data collected after March 2002.
Patient data were excluded if abnormal and/or unrealistic values for
albumin (<0.5 or >6 g/dL), bilirubin (<0.1 or >50 mg/dL), creat-
inine (<0.1 or >15 mg/dL), or BMI (>55 kg/m2) were identified.
Statistical Analysis
All statistical analyses were performed with the use of the SSPS 20.0
statistical package (SPSS Inc, Chicago, Ill, United States). A P value
LIVER TRANSPLANTATION FOR UREA CYCLE DISORDERS 2415

group, 265 (2.1%) required liver transplant for a UCD. Of

the 83,604 adults in the database, only 13 (0.015%) were
transplanted for a UCD. Characteristics of these recipients
are presented in Table 1. Two patients with UCD, 1 adult
and 1 child, underwent combined liver and kidney trans-
plant. Mean age at liver transplant was 2.6 years (SD " 4.0)
for children and 28 years (SD " 12) for adults. The PELD/
MELD and score was significantly lower in both groups
compared the mean PELD/MELD score for all patients
transplanted over the same time period. A greater propor-
tion of patients transplanted for UCD received PELD/
MELD exception points as well.
The age and specific UCD diagnosis distribution is shown
in Fig 1. The most common UCD was OTC. The diagnosis
distribution was similar across all age groups. A similar
distribution of UCD diagnosis types was seen in adults

Fig 1. (A) Distribution of the types of urea cycle disorders (UCD)

by age group. The following UCD diagnoses were identified: orni-
thine transcarbamylase (OTC), carbamoylphosphate synthetase I
(CPS), argininosuccinate lyase deficiency (ASL), argininosucci-
nate synthetase deficiency (ASS, also known as citrulinemia
type 1), and arginase deficiency (ARG)]. No patients were identi-
fied to have a urea cycle transporter defect: ornithine transplo-
case (ORNT1) or citrin deficiency (citrullinemia type II).
However, many patients were given a diagnosis of “citrulinemia”
with a specific type not identified. We classified all of these cases
as citrulinemia type 1 (ASS). The most common UCD across all
age groups was OTC. A significant number of patients were iden-
tified has having a UCD, but a specific type was not entered. This
group is listed as UCD-NOS. (B) Distribution of transplants for a
UCD by age. The most frequent age for transplant was before
age 1 year.

(a-level) of 0.05 or less, 2-tailed, was chosen as the level of statistical

significance. Group membership was compared by use of c2 analysis.
Independent-samples t tests were used to compare outcomes by
groups on continuous measures. Risk factors for death and graft loss
were analyzed by means of multivariate logistic regression.
Fig 2. Kaplan-Meier patient (A) and graft (B) survival curves for
RESULTS liver transplants performed in patients with urea cycle disorders
(UCDs) between 1987 and 2010. There were no statistically sig-
Characteristics of the Sample
nificant differences in patient or graft survival between age
During the 23-year period between 1987 and 2010, 12,198 groups. Inset table shows 30-day, 1-year, and 5-year survival
were children identified in the UNOS database. In this percentages.
2416
Table 2. Causes of Death for Patients Transplanted for UCDs
Cause of Death (n ¼ 27) Number of Patients (%)
Infection 12 (44.4)
Multi-organ failure 7 (26.0)
Graft failure 4 (14.8)
Hemorrhage 1 (3.7)
Neurologic 1 (3.7)
PTLD 1 (3.7)
Malignancy, NOS 1 (3.7)
compared with pediatric cases. The type of UCD was not
documented in 11% of cases (UCD-NOS in Fig 1).
Table 1 shows the age distribution for patients trans-
planted for UCDs over the study period. The most frequent
age for transplant was less than age 1 year (37%). and the
majority of patients were transplanted before age 5 years
(68%). However, a broad range of ages was seen, with 1
patient being transplanted at age 62 years.
Survival
Kaplan-Meier survival curves are shown in Fig 2A. There
were no statistically significant differences in patient or graft
survival between age groups. Overall, patient and graft
survival compared favorably to liver transplant for all other
causes during the same time period (not shown). One-year
and 5-year patient survival rates were 97% and 89%,
respectively, for children transplanted for a UCD. One-year
and 5-year graft survival rates were 100% and 90%,
respectively, in adults. Early death and graft loss (<30 days)
occurred in 3% and 15% of the patients and grafts,
respectively. A total of 27 patients (10%) who underwent
liver transplant for UCDs died during the study period. The
causes of death are shown in Table 2. The primary cause of
death was infection. The cause of graft loss was available for
53 of 59 graft losses. The main causes of graft loss were
vascular thrombosis, primary graft failure, biliary compli-
cations, and infection (Table 3).
Risk Factors for Death or Graft Failure
Risk factors for death or graft failure were analyzed by both
univariate and multivariate logistic regression analysis. For
these analyses, we used variables listed in Table 1. No fac-
tors were identified that were predictive of death or graft
loss.
DISCUSSION
UCDs are rare metabolic disorders that can be cured through
liver transplant. The data presented here confirm that
excellent long-term survival is seen with liver transplant for
the treatment of UCDs. Medical management typically in-
cludes alternate pathway ammonia scavenging therapies,
dietary modifications, and hemodialysis as needed. Although
no randomized trials have been performed, long-term sur-
vival with medical therapy appears comparable to liver
transplant [12]. However, patients selected for medical
YU, RAYHILL, HSU ET AL
management of a UCD may represent a subset of patients
with mild disease. Clinically, liver transplant is generally
reserved for patients in whom medical therapy fails or for
neonatal onset of a UCD [1].
In a large multicenter trial including more than 300 pa-
tients treated with combined sodium phenylacetate and
sodium benzoate for hyper-ammonemia, 83% survival was
reported after up to 11 years of follow-up [12]. However,
death was strongly correlated with age at presentation of a
UCD. Newborns (age less than 30 days) had the lowest
overall survival, at 35%. In our analysis, data for newborns
were not available because the UNOS dataset does not re-
cord age in days. In a sub-analysis, we used weight to give a
rough estimate of age, with the average 30-day-old newborn
weighing approximately 5 kg. We identified 17 patients
transplanted for a UCD who weighed less than 5 kg at the
time of transplant. The 5-year survival rate for these pa-
tients was 84%, which suggests that transplant survival is
equivalent in newborns compared with other age groups.
Regardless of survival equivalence, a patient medically
treated for a UCD can expect to require close medical
follow-up and recurrence of hyper-ammonemic crises.
Because liver transplant cures the underlying metabolic
abnormality, recurrent hyper-ammonemia is not seen, and
the quality of life after liver transplant would be expected to
be improved. Patients with UCDs treated medically are
more likely to have intellectual disabilities [13] and sub-
optimal neurologic outcomes [14]. The UNOS database
does not provide cognitive function or developmental data
that would be useful to further evaluate outcomes in UCD
patients after transplant. Limited studies suggest that
neurologic outcome may be better if liver transplantation
occurs before age 1 year. Campeau et al [5] report that
developmental quotient scores were improved in patients
who underwent transplantation before age 1 year compared
with patients transplanted at age 3 years. They postulated
that early transplantation limits the cumulative number
hyper-ammonemic episodes, reducing the potential for
irreversible neurologic damage, and thus improving long-
term outcomes in these patients. The most common age
for liver transplant for UCDs in this study was less than 1
year, and overall survival for this age group was comparable
to all other age groups.
Recently, results from a combined cohort of pediatric
patients with UCDs (n ¼ 186) and/or organic acidemias
Table 3. Causes of Graft Failure for Patients Transplanted for
UCDs
Cause of Graft Failure (n ¼ 53) Number of Patients (%)
Vascular thrombosis 22 (41.5)
Primary graft failure 10 (18.9)
Biliary complications 7 (13.2)
Infection 7 (13.2)
Acute rejection 4 (7.5)
Chronic rejection 2 (3.8)
Recurrent disease 1 (1.9)
LIVER TRANSPLANTATION FOR UREA CYCLE DISORDERS
(OAs) (n ¼ 137) was presented [7]. Overall, transplant
outcomes were excellent for patients in this cohort, partic-
ularly in patients transplanted after age 5 years, who had
99% 5-year survival. We focused on outcomes in UCDs
alone because it may not be valid to combine outcomes for
two distinct disease processes. OAs represent a diverse
family of metabolic diseases caused by defects in amino acid
metabolism. Liver transplant outcomes for more common
forms of organic acidemia, including maples syrup urine
disease, and methylmalonic academia, have been studied
with favorable outcomes reported [15,16]. Unlike the anal-
ysis presented here, neither of these studies included adult
patients, ostensibly because most OAs generally become
clinically apparent during the newborn period or early in-
fancy [17].
We did not see an increased utilization of living donor liver
transplant (LDLT) in this cohort of US patients undergoing
liver transplant. Wakiya et al [18] indicated that LDLT is a
viable option for OTC patients. The caveat is that if a relative is
used as a living donor, they should be tested to rule out a
clinically silent UCD in the donor liver. The lack of utilization
of LDLT this US cohort probably reflects a deceased utilization
of LDLT overall in the United States compared with Japan
rather than a specific bias toward UCD patients [19].
OTC is the most common type of UCD and also the most
common type of UCD to receive a liver transplant. OTC is
an X-linked disorder, and this accounts for the male pre-
dominance of UCD patients in this and other liver trans-
plant cohorts [6]. No difference in survival was seen that was
based on type of UCD at the time of transplant.
UCDs are increasingly being identified in adults. There is
an abundance of case reports of adult patients diagnosed
with UCDs [8e10,20e25]. The presentation of a UCD in
adults is similar to presentation in pediatric cases with
repeated episodes of encephalopathy and hyper-
ammonemia. However, given that UCDs are so rare in
adults, there is usually a significant delay in diagnosis [8,23].
Most cases of adult-onset UCDs can be managed with di-
etary restriction and ammonia scavenging therapies alone.
Most presentations of encephalopathy and hyper-
ammonemia are triggered by stress-induced increased ni-
trogen turnover. Several recent reports indicate that gastric
bypass can trigger adult-onset UCDs as well [26,27].
Although only 13 adult patients were identified in this study,
excellent survival was seen. In general, adult patients had
baseline characteristics similar to pediatric UCD patients.
They were transplanted with low native MELD scores and
were more likely to receive MELD exceptions compared with
all other transplants during the same time period. Thus, liver
transplant appears to be a good option for an adult UCD
patient who is refractory to medical therapy.
There are several limitations of this study. The UNOS
database does not have a specific diagnosis code for UCDs.
Therefore, we relied on text entry for diagnoses. We used a
text search for partial words and abbreviations to attempt to
capture all diagnoses. However, diagnoses entered that were
grossly misspelled or not entered at all would have been
2417
missed. Therefore, we have probably underestimated the
total number of patients transplanted for UCDs. Further-
more, there is no information regarding how the UCD di-
agnoses were made. Some of the cases identified here may
represent misdiagnoses. Finally, important outcome data
relevant to this study, including developmental and neuro-
logic complications, were not reliably available.
CONCLUSIONS
UCDs are rare indications for liver transplant, especially in
adults. Excellent post-transplant survival was seen in both
children and adults who underwent liver transplant for
UCD. This can probably be attributed to 2 main factors: 1)
UCD patients do not have chronic liver disease leading into
transplant, and 2) liver transplant cures the underlying
metabolic defect, eliminating the risk of recurrent disease.
Outcomes were similar across all ages, and liver transplant
should be considered early in neonatal cases of UCD and
those considered refractory to optimal medical therapy.
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