Fatal hyperammonemia in the setting of late-onset argininosuccinic acid lyase enzyme deficiency (ASLD): a case report

Introduction

The urea cycle has several key roles which include production of citrulline, arginine, and ornithine, metabolism of ammonia (NH4⁺) into urea, and the main metabolism of adenosine monophosphate. It involves a constellation of various mitochondrial and cytosolic enzymatic reactions catalyzed by five main enzymes: carbamoyl phosphate synthetase I (CPS1), ornithine transcarbamylase (OTC), argininosuccinic acid synthase 1 (ASS1), argininosuccinic acid lyase (ASL), and arginase 1 (ARG1) (1,2). It also requires the presence of one cofactor-producing enzyme called N-acetyl glutamate synthetase (NAGS) for the conversion of acetyl-CoA and glutamate to N-acetylglutamate, one of the first steps in the cycle (1). Lastly, there are two essential amino acid transporters called ornithine translocase (ORNT1) and citrin, that are used for transport of ornithine into the mitochondrial space and aspartate out into the cytosol, respectively (1,3). Deficiencies in any of the six enzymes or either one of the two transporters can result in specific defects that lead to accumulation of several precursor metabolites and rapid buildup of ammonia and/or glutamine. These defects are called urea cycle deficiencies (UCD). The degree of accumulation largely depends on the severity of enzyme deficiency (1). In cases of severe or total absence of enzyme activity, presentation of disease typically occurs within the newborn period, since the immature liver emphasizes the extent of enzyme defect. Contrastingly, in cases with milder or partial UCD, disease is most commonly triggered in times of stress or illness, thus age of presentation varies.

In terms of estimated incidence, OTC has been recorded as the most frequent deficiency out of all the subtypes, with an incidence of 1:56,500. On the other hand, NAGS deficiency is the rarest with an estimated incidence of <1:2,000,000 (1). Argininosuccinic acid lyase deficiency (ASLD) has an incidence of 1:70,000 to 250,000 live births, which represents approximately 16% of all urea cycle disorders (1). It has an autosomal recessive pattern of inheritance located at chromosome 7, locus q711.21 (ASL gene OMIM *608310), which is most predominantly expressed in the liver, kidney, and brain (4). Within the urea acid cycle, ASL has the function of cleaving argininosuccinate into fumarate and arginine within the cytoplasm, the fourth step in the urea cycle (4). There are two phenotypic presentations based on onset of disease: a neonatal variant caused by complete absence of ASL enzyme, and a late-onset form seen in partial absence of the enzyme. The neonatal form is the most common type, presenting within the first days of birth with symptoms of acute hyperammonemic encephalopathy, including lethargy, nausea/vomiting, seizures, and hyperventilation (4). Contrastingly, the late-onset phenotype results in transient episodic hyperammonemia in the setting of an acute stressor (infections, excess protein intake, trauma, etc.) (4). The clinical picture is not specific, with signs and symptoms of neurological affection, liver disease, and trichorrhexis nodosa (1,5). Therefore, diagnosis is challenging, giving rise to delayed medical care and worsening prognosis. The most specific indicators of disease are biochemical findings that correlate with said enzymatic defect within the urea cycle. These findings include accumulation of argininosuccinic acid within the blood and urine, increased precursor citrulline, increased orotic acid excretion in urine, and decreased arginine due to obtunded production. Moreover, given that the urea cycle is an independent method for ammonia metabolism, any errors in this pathway can lead to failure to breakdown ammonia and ultimately its waste accumulation within the body (6,7). While molecular genetic testing is the primary method for confirming UCD diagnoses, enzymatic testing remains a crucial tool, especially when DNA-based investigations are not informative (1). Thus, suspicion of disease requires specific biochemical and genetic assessment, but this can become an intricate endeavor.

In this report, we present the case of a 51-year-old male who presented with pressor-dependent shock in the setting of obstructive uropathy with significant hyperacute elevations of ammonia throughout his hospital course that resulted in death. We present this article in accordance with the CARE reporting checklist (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-3/rc).

Case presentation

A 51-year-old male with past medical history of hypertension, nonischemic cardiomyopathy with ejection fraction of 40% to 45% status post-implantable cardioverter defibrillator, chronic pancreatitis, chronic kidney disease (CKD), asthma, and recurrent nephrolithiasis was brought to the emergency department by his significant other with concerns for altered mental status. Radiographic evidence was significant for obstructive uropathy to the right kidney with associative hydronephrosis, in the setting of chronically atrophic left renal kidney. The patient promptly underwent intubation and cystoscopy with basket extraction of right ureteral calculi and right ureteral stent placement. The patient required subsequent admission to the medical intensive care unit. The patient was started on empiric antibiotic coverage with piperacillin-tazobactam, for a total of 5-day therapy. Blood cultures were sent out and grew Corynebacterium species isolated from two bottles. The patient was found in acute renal failure on CKD, with a creatinine of 7.27 mg/dL from a baseline of 1.3 to 1.5 mg/dL, as well as associated fractional excretion of sodium of 6.8% suggestive of obstructive etiology. Of significance, liver enzymes were found within normal limits, aspartate transaminase (AST) 24 U/L and alanine transaminase (ALT) 35 U/L, as well as total bilirubin 2.4 mg/dL and direct bilirubin 0.8 mg/dL. Moreover, ammonia level was noted to be elevated at 99 µmol/L. Over the course of the first 24 hours from admission however, concerns grew as the patient continued to remain not responsive despite discontinuation of sedatives. Biochemical findings were significant for increase of ammonia to 509 µmol/L, lactic acidosis (lactic acid 3.2 mmol/L and beta-hydroxybutyrate 35 mg/dL), and sudden elevation of hepatic enzymes with AST at 327 U/L and ALT at 325 U/L. Head computer tomography (CT) demonstrated diffuse cerebral edema without herniation or hemorrhage. A metabolic panel was sent off for evaluation in the setting of suspected urea cycle defect. The results were significant for urine orotic acid 8.9 mmol/mol creatinine (reference value 0.4–1.2 mmol/mol creatinine), plasma citrulline 155 nmol/mL (reference value 17–46 nmol/mL), and argininosuccinic acid 477 nmol/mL (normal value <2 nmol/mL). These findings confirmed hyperammonemia in the setting of ASLD. At this time, family was consulted, and they denied any associated past personal or family history of metabolic disease. Upon interviewing the significant other, it was revealed that the patient had experienced episodes of altered mental status for 6 months preceding hospitalization, often linked to recurring episodes of nephrolithiasis. Nonetheless, the treatment was based on a multidisciplinary approach with involvement of nephrology, neurology, neurosurgery, nutrition, urology, physical therapy, speech therapy, and pulmonary critical care as the primary treating team. Reduction of ammonia to normal levels was achieved via continuous renal replacement therapy (CRRT) with subsequent transition to intermediate hemodialysis. The patient’s hospital stay demonstrated favorable progression for the first weeks. However, after approximately 4 weeks of hospitalization during which patient remained stable, the patient was suddenly found nonresponsive, hemodynamically unstable, and with development of new seizure activity with subsequent maximal requirement of pressor support with norepinephrine, vasopressin, and epinephrine. Laboratory findings were significant for potassium 7.5 mEq/L, lactic acid 14.1 mmol/L, and ammonia elevated at 761 µmol/L. A second amino acid test was sent off, which was significant for elevated plasma citrulline of 163 nmol/mL and plasma argininosuccinic acid if 838 nmol/mL. These values were higher than those from the first study. Plasma ornithine was decreased to 21 nmol/mL (reference 38–130 nmol/mL). Per relative’s wishes, patient’s code status was changed to Do Not Resuscitate (DNR) and palliative care was chosen. The patient expired shortly after withdrawal of pressor support.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

The patient described above presented with a case of late-onset ASLD accompanied by encephalopathic hyperammonemia, ultimately leading to death. It was unclear if, prior to admission, the patient had shown signs or symptoms of this condition, and no family history of metabolic disease was reported. Regardless, severe metabolic decompensation due to accumulation of ammonia to levels over 500 µmol/L provided clearer indication for suspicion of urea cycle disorder as part of the differential diagnosis.

Typically, a human adult produces approximately 1,000 mmol of ammonia daily, which is mostly disposed of via its catabolism through the urea cycle or by its oxidation to ammonium (7). In the end, the homeostatic predisposition of the body leads to a target plasma ammonia concentration of less than 40 µmol/L (6,7). States of elevated ammonia can paint a toxic metabolic clinical picture of neurologic disturbances that can be fatal. Plasma levels of ammonia ranging from 100–200 µmol/L can lead to nonspecific neurologic symptoms including confusion, nausea/vomiting, lethargy, or other cognitive or psychomotor abnormalities. Subsequently, levels of >300 µmol/L are alarming and can more accurately indicate severe disease such as coma, brain herniation, or death (6,7). Liver disease is a well-documented catalyst for metabolic disturbances secondary to hyperammonemia. They account for 90% of the cases in adults (7). Unfortunately, in the context of no hepatic dysfunction or baseline state, the differential diagnosis for disease becomes difficult. Some literature denotes a nonspecific but varied number of non-hepatic etiologies including enzymatic deficiencies, side effects from medications or toxin related causes (valproic acid or chemotherapy), hyperalimentation, and recent surgery (i.e., bariatric intervention) (8). For the case explained above, initial concern for elevated ammonia was attributed to possible development of ischemic liver in the setting of ongoing distributive shock secondary to obstructive uropathy. However, concern for a different underlying etiology persisted because, although the elevation of AST and ALT was substantial, it was not significant to “more than 20 times the upper limit of normal”, which is more typical for acute liver failure (9). Moreover, the international normalized ratio remained within normal limits (less than 1.5). Therefore, ultimately the decision was made to consider enzymatic etiologies as the primary cause. A metabolic profile including amino acid levels, nutrition panel, and urine orotic acid was sent out. And as stated above, based on the specific amino acid abnormalities found in this patient, a case of late-onset ASLD was confirmed.

The rarity of delayed-onset UCD is well established. There are limited case reports that narrate encounters of patients presenting with acute disease, later linked to urea cycle abnormalities. There was a recent study published back in 2019 which presented the case of a 48-year-old female who had presented with broad symptomatology of lethargy and weakness and was found with OTC deficiency (10). Similar to our patient above, she had an extensive workup to rule out other potential etiologies including toxic, vasculitic, and infectious processes. Her hospital course was complicated by respiratory failure requiring intensive care unit stay. After stabilization of acute presentation, genetic testing was considered to explore UCD, and her diagnosis was confirmed post-discharge. Correspondingly, a report published back in 2010 in the journal of Transplantation Proceedings presented the case of a 45-year-old male with brain herniation from hyperammonemia-induced edema following his second renal transplantation. This was found in the absence of hepatic or renal damage. After thorough investigation, he was diagnosed with OTC deficiency as well (11).

ASLD is an autosomal recessive disease that presents in the setting of ASLD. It leads to accumulation of enzymatic substrates such as argininosuccinate and citrulline, as well as a deficient production of arginine and subsequent impaired urea synthesis (1,12). As mentioned above, ASLD has been reported as the second most common UCD, with an estimated prevalence of 1 in 70,000 live births (13). It can present during the neonatal period with total enzyme absence as acute hyperammonemia, or in the adult with episodic presentations of metabolic disturbances due to partial deficiency. Late-onset ASLD is typically triggered in the presence of a stressor, such as infection. As previously mentioned, the patient above had undergone cystoscopy repair and stent placement for an obstructive uropathy picture. The patient was further found in a septic state with initial requirements for pressor support. Thus, in the context of ongoing acute disease that further associated to a metabolic profile of hyperammonemia, elevated plasma argininosuccinate, and elevated plasma citrulline, a diagnosis of late-onset ASLD was finally made. It is worth noting that the blood cultures drawn on admission were done so after a first dose of empiric piperacillin-tazobactam. The cultures obtained grew Corynebacterium, an organism known to have urea-splitting properties. These organisms produce the enzyme urease which catalyzes the hydrolysis of urea to ammonia, leading to increased production of ammonia. Other culprits that possess these characteristics include Proteus mirabilis and Klebsiella species. With that in mind, the state of hyperammonemia in our patient could have been multifactorial. Potentially, the high levels of plasma ammonia could have developed due to a synergistic collaboration between toxin accumulation from ASLD and bacteria-induced urea splitting. Moreover, given that empiric antibiotics were started prior to the collection of blood cultures, there is a possibility of having more than one organism involved, which could have been masked by the ongoing antibiotic therapy.

Another potential exacerbating factor to elevated ammonia levels regardless of underlying etiology is nutritional support. While normalization of ammonia levels is of top priority in the management of UCDs, nutritional requirements are benign therapeutic measures that can be addressed from the start. And although protein intake should be restricted to minimize breakdown into nitrogen products, an extreme protein restriction can induce peripheral protein breakdown and a further increase of nitrogen load. This can occur in the setting of prolonged fasting, which can stimulate amino acid catabolism and as a result, further promote production of ammonia as a byproduct (14). Therefore, attaining a crucial equilibrium becomes an imperative step to ensure adequate nutritional support in the management of individuals with UCD. The patient in our case was kept nil per os during the earlier stages of his acute insult. And although enteral nutrition was started shortly after via nasogastric tube feedings, the duration the patient remained fasting might have exacerbated ammonia production in addition to the inherent urea cycle production.

The considerable neurological damage seen in UCD, and specifically in this case with ASLD, results from elevated ammonia levels. Cerebral edema is the most prominent complication in the setting of hyperammonemia. It causes increased cerebral fluid, elevating intracranial pressure and decreasing cerebral perfusion, ultimately leading to overall ischemia and herniation (7). The precise underlying mechanism is poorly understood, and there are multiple plausible hypotheses in play, but it is thought to be associated with astrocyte swelling. Ammonia can bypass the blood brain barrier via diffusion. Studies have shown that ammonia may be taken up by astrocytes, which contain glutamine synthetase. This process converts accumulated ammonia into glutamine, leading to osmolarity-induced swelling of astrocytes (7). Another hypothesis, proposed by Albrecht et al., supports the ‘Trojan Horse’ concept suggesting that excess ammonia leads to the subsequent accumulation of intracellular glutamine, which then facilitates its uptake into mitochondria (15). Naturally, excess ammonia stimulates the production of glutamine through oxidative deamination processes. Glutamine synthetase utilizes NH3 and glutamate as reactants to yield glutamine. Additionally, it is believed that glutamine acts as a Trojan horse, transporting ammonia into the mitochondria, resulting in oxidative stress and swelling of astrocytes. Ultimately, glutamate serves as an excitatory neurotransmitter, so decreased levels of glutamate can lead to depressed neural activity, resulting in lethargy or a comatose state (6). Nonetheless, in our case above, neurological concern arose when the patient was found nonresponsive despite de-escalation of sedatives. His physical examination was significant for no withdrawal to pain stimuli, no cough or gag reflex, no pupillary reflex, and extraocular muscles without tracking; however, his pupils were equal and mildly reactive to light. CT head imaging demonstrated findings consistent with mild to moderate diffuse cerebral edema without herniation or hemorrhage. A repeat CT head and CT angiography confirmed the presence of cerebral edema, characterized by the effacement of bihemispheric sulci and hypodensity of both thalami. These findings were most consistent with hypoxic-ischemic injury rather than toxic/metabolic encephalopathy. After approximately 15 days of admission and with appropriate therapy, including strict CRRT, the radiographic evidence cleared, and there was associated clinical neurological improvement. However, despite these interventions, the patient experienced fatal decompensation during a second episode of hyperacute hyperammonemia.

Another frequently reported consequence of chronic ASLD found in literature is the development of elevated blood pressure. Kho et al. have proposed the theory of endothelial dysfunction caused by ASLD, leading to a reduction in nitric oxide (NO) production and thus, development of primary hypertension. They propose that a lack of ASL can hinder production of important substrates required for the overall synthesis of NO (5,16). Our patient presented with a well-established history of hypertension, and subsequent examination revealed a relatively well-controlled blood pressure, ranging 120–130 mmHg systolically. And while direct confirmation of the patient’s hypertension stemming from an underlying ASLD remains elusive, a plausible association can be inferred.

One of the biggest limitations in the management of metabolic disease lies in acquiring the necessary diagnostic evidence. Quantitative plasma amino acid analysis is a useful tool to establish diagnosis of and differentiate amongst urea cycle disorders. This is possible by interpreting the enzymatic concentration of precursor and successor metabolites to determine which step along the cycle is affected. The profile should consist of plasma levels of arginine, citrulline, orotic acid, glutamine, argininosuccinic acid, essential amino acids, and branched-chain amino acids (1). Plasma amino acid metabolic analyses, unfortunately, may experience delays in providing results, especially in cases of acute presentations. In our case above, the metabolic set that was sent out for testing required approximately 2 weeks for the results to return. This is significant because, despite having an objective differential diagnosis and a clinically appropriate management plan, identification of the enzymatic error provides a basis for diagnosis, treatment, and prognosis of the metabolic disorder. However, the literature is very limited regarding the expected turnaround time. There are no studies that seek to analyze the morbidity and mortality or prognosis following target-specific therapy in the acute patient with metabolic disease after an objective diagnosis with amino acid testing. A plausible explanation for the scarcity of material is the rarity of disease, especially amongst the population with development of late-onset presentation. Furthermore, consideration for early testing is tempered by its predisposition to manifest acutely. And ultimately, genetic testing emerges as the preferred approach for individuals with a significant family history, with some literature emphasizing its importance, especially for those with a documented three-generation family history (1).

Conclusions

Hyperammonemia, regardless of its cause, can be fatal due to its severe toxicity to the brain. When ammonia levels acutely rise, symptoms develop rapidly, and clinical toxicity becomes apparent quickly. Following a thorough biochemical evaluation, the patient’s metabolic profile revealed findings consistent with ASLD, which, given his age at presentation, was likely a partial deficiency (late-onset). Initially, UCD was suspected, but due to delayed laboratory results (approximately 2 weeks for amino acid levels), targeted management for ASLD was not possible. However, clinical judgment prompted immediate initiation of toxin removal measures and supportive therapy through a multidisciplinary approach. Had we known earlier that the patient had ASLD, we would have started nitrogen scavenging therapy with benzoate, arginine hydrochloride, phenylacetate, and phenylbutyrate. Additionally, oral protein intake could have been discontinued, and oral intake supplemented with intravenous lipids and/or glucose, along with a supplemented diet with arginine base. Fundamentally, urea cycle disease should be considered in the adult population presented with nonhepatic, unexplained hyperammonemia. This can allow for prompt management via protein restriction, removal of ammonia, and avoidance of exacerbating drugs. Regardless of the outcome, this case underscores the impact of delayed laboratory results and highlights the need for improvement in this area. Moving forward, efforts should be directed towards implementing quality improvement tools to enhance the efficiency of laboratory services.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-3/rc

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-3/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-3/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report was not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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