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Keywords:

  • Living donor liver transplant;
  • ornithine transcarbamylase deficiency

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

Ornithine transcarbamylase (OTC) deficiency (OTCD) is an X-linked urea cycle disorder. Being an X-linked disease, the onset and severity of the disease may vary among female carriers. Some of them start to develop the disease early in life, whereas others remain asymptomatic throughout their lives. Our patient was a 42-year-old man who developed severe hyperammonemia and fatal brain edema after receiving a right lobe graft from an asymptomatic female living donor with unrecognized OTCD. The donor developed hyperammonemia and disturbed level of consciousness that was managed successfully by hemodialysis. Molecular testing of the OTC gene in the donor revealed a heterozygous nonsense mutation (c.429T > A) in exon 5.


Abbreviations
LDLT

living donor liver transplant

OTCD

ornithine transcarbamylase deficiency

POD

postoperative day

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of the urea cycle, which is the metabolic pathway that transforms nitrogen to urea for excretion from the body. A mutant enzyme protein impairs the reaction, leading to condensation of carbamyl phosphate and ornithine to form citrulline. This impairment reduces the incorporation of ammonia, which, in turn, causes symptomatic hyperammonemia. The gene coding for this enzyme is intramitochondrial and expressed in the liver [1]. As an X-linked trait, the mutant OTC gene is regularly manifest in hemizygous males, with severe adverse effects. In contrast, many heterozygous females are affected variably; they occasionally suffer mental retardation and even death from hyperammonemia, but sometimes remain asymptomatic [2]. The severity of disease in female carriers is conditioned by the nature of the mutation and the random inactivation of the X chromosome. Although OTCD is a disease of infancy or childhood, the initial age of onset can occur at 40–50 years or older, and is typically triggered when the patient is under stress [3]. In this case, we report the clinical course of an asymptomatic female donor with unrecognized OTCD after right lobe donation along with the recipient. Institutional ethical approval was obtained for publication.

Case Report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

A 42-year-old male recipient underwent uncomplicated living donor liver transplant (LDLT) for hepatitis-C-virus-related end-stage liver disease and hepatocellular carcinoma. He did not have encephalopathy before transplant and had no history of metabolic or neuropsychiatric disorders. He underwent uneventful surgery with no blood transfusion, and received a right lobe graft with 0.9% graft-to-recipient weight ratio. The recipient was extubated immediately postoperatively and Doppler ultrasound showed normal venous and arterial blood flow. Antimicrobial prophylaxis included 4.5 g/day piperacillin–tazobactam. He started immunosuppression therapy in the form of steroids, mycophenolate mofetil and tacrolimus. On postoperative day (POD) 2, he started to develop somnolence, with progressive deterioration in his level of consciousness, and was intubated again. A follow-up Doppler ultrasound was normal, and the liver profile was improving (Table 1). All bacteriological and virological workup was negative. Brain computed tomography showed edema, and serum ammonia was 762 μmol/L (reference range, 15–45 μmol/L) (Figure 1).

Table 1. Laboratory values of liver transplant recipient with associated clinical course
D0 extubationD1D2 somnolence and reintubation hemodialysis startedD3D4D5 death 
  1. ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio.

Sodium (mmol/L)140144142139145146
Bilirubin (mg/dL)5.37.13.12.21.66.4
AST (U/L)3812801471325056
ALT (U/L)186169161956890
INR4.23.12.01.81.42.2
Ammonia (μmol/L)  762322  
Lactate (mmol/L)4.31.211.20.93.3
image

Figure 1. CT scan of the recipient shows mild cerebral edema

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The donor was the patient's sister, a 36-year-old mother of two girls with a history of two abortions. She had no other significant family, medical or surgical history. She reported being a vegetarian. Preoperative donor liver biopsy was normal with no evidence of hepatic steatosis or occult hepatitis. The donor operation was uneventful. The residual liver volume was 40%. Doppler ultrasound of the left lobe was normal with normal cholangiography at the end of the operation. On POD 3, the donor became irritable and confused, and her level of consciousness deteriorated markedly. Her laboratory results confirmed adequate liver function with no significant coagulopathy. Magnetic resonance imaging of the brain was normal. However, her serum ammonia level was 280 μmol/L. In the context of hyperammonemia in the donor and the recipient despite normal liver function, a urea cycle disorder, particularly OTCD, was suspected. In consequence, urine analysis for urea cycle metabolites was sent on POD 3. Orotic acid was 1963 mmol/mol creatinine (normal, 4.4) for the recipient and 593 mmol/mol for the donor.

Both recipient and donor started continuous renal replacement therapy and oral sodium benzoate on POD 2 and 3, respectively. The donor improved and recovered completely 24 h after starting hemodialysis. Her ammonia level decreased to 24 μmol/L. She was transferred to the ward on POD 5 and sent home on POD 12. In contrast, the recipient's neurological condition deteriorated markedly; brain death was diagnosed on POD 5, and life support was withdrawn. The family refused a postmortem examination.

Molecular analysis of the OTC gene was performed by PCR and bidirectional sequencing for the coding region and exon–intron splice junctions. The obtained sequences were compared with the Ensembl transcript sequence ENST00000039007 and revealed a heterozygous nonsense mutation (c.429T > A) in exon 5 (Figure 2). In addition to the nonsense mutation, a polymorphism was detected (c.299–18C > T). This polymorphism was of no clinical relevance, being in a noncoding region.

image

Figure 2. PCR amplification of a fragment of exon 5 of OTC gene (forward direction) showing a change of T to A (c.429T > A), forming a stop codon (TAA) and a nonsense mutation

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body. A defect in the urea cycle results in accumulation of nitrogen as ammonia, glutamate and alanine [4]. Patients with OTCD have low OTC activity in the liver, with the result that they experience repeated episodes of hyperammonemia. Acute exposure of brain astrocytes to high levels of ammonia results in cell swelling, which may be complicated by life-threatening cerebral edema and brain herniation [5]. The inheritance pattern of all the urea cycle disorders is autosomal recessive, except for OTCD, which is X linked. OTCD is the most frequent inherited defect of urea genesis, with an estimated prevalence of one in every 40 000–80 000 births [6].

The human OTC gene is located on the short arm of the X chromosome (Xp21.1), and is formed of 10 exons and nine introns that comprise 68 968 bases. It encodes a mitochondrial matrix enzyme OTC that catalyzes the formation of citrulline from carbamyl phosphate and ornithine. More than 341 mutations have been identified in the OTC gene over the past few years, including missense, nonsense, frame shift and splicing mutations, along with small insertions and deletions [7]. In the current case, a novel mutation (c.429T > A) was detected in the donor. It resulted from a single third base change in codon 143 from T to A, leading to formation of a stop codon (TAA) and hence a nonsense mutation. The original amino acid at this codon is tyrosine (TAT). To the best of our knowledge, this mutation has not been reported in the literature, whereas the only reported polymorphism at this position is (c.429T > C), which leads to no change in the amino acid tyrosine because it is represented by two codons: TAT and TAC.

In OTCD, like any other X-linked disorder, hemizygous males are usually affected more severely than females. Patients who have partial enzyme deficiencies, such as female carriers of OTCD, may have atypical presentations after the newborn period. According to Lyon's hypothesis [8], the degree to which patients are affected depends upon random inactivation of one of the X chromosomes during early fetal life, and consequently, the proportion of the active X chromosomes that carry the mutated OTC allele compared to those that carry the intact allele. Several environmental factors may also contribute to the timing of disease onset and manifestations. These factors include a high-protein diet and exposure to stressful conditions [9]. Our donor was a vegetarian with low protein consumption; her diet may have been a cofactor in the asymptomatic state of this patient, despite possessing a nonsense mutation that affected enzyme formation significantly.

Acute neurological deterioration that occurred in the recipient postoperatively was thought to be of cerebrovascular origin. However, a high level of ammonia, despite adequate postoperative liver function, led us to suspect OTCD. In contrast to the recipient, in the donor, the acute onset of irritability was initially thought to be postoperative delirium. However, suspicion of OTCD in the recipient led us to measure the ammonia level in the donor. High levels of orotic acid in the urine in both the donor and recipient confirmed the diagnosis of OTCD [10].

Hyperammonemic crisis was more severe in the recipient than the donor, despite the transfer of 60% of the donor's liver volume. This condition might have been caused by exacerbation of underlying OTCD by reperfusion injury of the liver graft.

The mainstay of treatment of OTCD has been to reduce the production of nitrogenous wastes and lower the ammonia levels as quickly as possible. This could be achieved by ceasing protein intake and administering compounds that facilitate the removal of ammonia through an alternate pathway, including oral sodium phenylbutyrate and oral sodium benzoate [5]. Recent guidelines recommend starting hemodialysis quickly, even if the diagnosis has not been confirmed, especially if the ammonia level exceeds 200 μmol/L [11]. Although hemodialysis was effective in reducing the ammonia level in the recipient, progressive brain edema and brain death could not be prevented. The donor regained consciousness within 24 h after starting continuous venovenous hemofiltration and, at the time of writing, she has not experienced any other neurological symptom. Some authors have argued that regeneration of the liver maintains the X chromosome inactivation pattern [12].

To date, there is no evidence of any negative consequences in either the donor or the recipient from using a heterozygous donor [12-14]. To the best of our knowledge, this is the first case to report a complicated course of adult-to-adult LDLT with underlying OTC deficiency. Multiple studies have shown that adult heterozygous carriers for OTCD can be used as donors only if their liver OTC activity is normal. In most of these series, left lateral hepatectomy was performed from heterozygous mothers to their offspring with OTCD [14, 15]. In our case, part of the right liver was donated with a residual liver volume of 40%, which might be an important factor in precipitating hyperammonemia in the donor.

In LDLT, the safety of the donor is most important. Although our donor was managed successfully and discharged from the hospital, we cannot predict the outcome of this patient because there is still a possibility that she will develop late-onset disease [16]. Routine screening for OTC deficiency is not a standard practice unless the liver transplant is used for treatment of urea cycle disorders. However, our case report could indicate that potential living donors should be tested more extensively to avoid fatal outcomes.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References