Recurrent pancreatitis in ornithine transcarbamylase deficiency

Prada, Carlos E.; Kaul, Ajay; Hopkin, Robert J.; Page, Kimberley I.; Nathan, Jaimie D.; Cohen, Mitchell B.; Heubi, James E.; Leslie, Nancy; Burrow, T.

doi:10.1016/j.ymgme.2012.06.005

Cited by 4 publications

(3 citation statements)

References 10 publications

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“…It has also been documented previously that L -ornithine elicits mitochondrial depolarization and potentially toxic reactive oxygen species production in pancreatic acinar cells (Chvanov et al, 2015). Individuals who lack ornithine transcarbamylase (OTC), functional enzyme that converts L -ornithine into L-citrulline in the mitochondria, are at risk of AP (Anadiotis et al, 2001; Prada et al, 2012; Machado et al, 2013). It is also notable that the mitochondrial isoform of arginase (Arg2) plays a critical role in obesity-associated pancreatic cancer (Zaytouni et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine

et al. 2019

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Pancreatic acinar cells require high rates of amino acid uptake for digestive enzyme synthesis, but excessive concentrations can trigger acute pancreatitis (AP) by mechanisms that are not well understood. We have used three basic natural amino acids L-arginine, L-ornithine, and L-histidine to determine mechanisms of amino acid-induced pancreatic injury and whether these are common to all three amino acids. Caffeine markedly inhibited necrotic cell death pathway activation in isolated pancreatic acinar cells induced by L-arginine, but not L-ornithine, whereas caffeine accelerated L-histidine-induced cell death. Both necroptosis inhibitors of RIPK1 and RIPK3 and a necroptosis activator/apoptosis inhibitor z-VAD increased cell death caused by L-histidine, but not L-arginine or L-ornithine. Cyclophilin D knock-out (Ppif-/-) significantly attenuated cell death induced by L-histidine, but not L-arginine, or L-ornithine. Allosteric modulators of calcium-sensing receptor (CaSR) and G-protein coupled receptor class C group 6 member A (GPRC6A) had inhibitory effects on cell death induced by L-arginine but not L-ornithine or L-histidine. We developed a novel amino acid-induced AP murine model with high doses of L-histidine and confirmed AP severity was significantly reduced in Ppif-/- vs. wild type mice. In L-arginine-induced AP neither Ppif-/-, caffeine, or allosteric modulators of CaSR or GPRC6A reduced pancreatic damage, even though CaSR inhibition with NPS-2143 significantly reduced pancreatic and systemic injury in caerulein-induced AP. These findings demonstrate marked differences in the mechanisms of pancreatic injury induced by different basic amino acids and suggest the lack of effect of treatments on L-arginine-induced AP may be due to conversion to L-ornithine in the urea cycle.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine

et al. 2019

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“…Three OTCD patients with recurrent pancreatitis have been reported. Only one of them had an additional mutation in a gene associated with hereditary pancreatitis and so the relation between recurrent pancreatitis and OTCD is still unexplained . Male OTCD patients mostly present as neonates.…”

Section: Recommendations For Specific Disordersmentioning

confidence: 99%

“…Only one of them had an additional mutation in a gene associated with hereditary pancreatitis and so the relation between recurrent pancreatitis and OTCD is still unexplained. 265 Male OTCD patients mostly present as neonates. They belong to the group of UCD patients with the highest mortality (60%) during initial presentation.…”

Section: Otc Deficiencymentioning

confidence: 99%

Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision

Häberle

Burlina²,

Chakrapani

et al. 2019

J of Inher Metab Disea

335

478

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In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years increased awareness among health professionals and patient families. However, underrecognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research.

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Hepatic and Gastrointestinal Manifestations of Urea Cycle Defect: A Perspective

Parveen

2024

Annals of Pediatric Gastroenterology and Hepatology ISPGHAN

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Recurrent pancreatitis in ornithine transcarbamylase deficiency

Cited by 4 publications

References 10 publications

Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine

Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine

Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision

Hepatic and Gastrointestinal Manifestations of Urea Cycle Defect: A Perspective

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