Metabolically based liver damage pathophysiology in patients with urea cycle disorders-A new hypothesis

The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liverdamage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.

Hyperammonemia crisis following parturition in a female patient with ornithine transcarbamylase deficiency

Ornithine transcarbamylase deficiency(OTCD) is an X-linked disorder,with an estimated prevalence of 1 per 80000 live births.Female patients with OTCD develop metabolic crises that are easily provoked by non-predictable common disorders,such as genetic(private mutations and lyonization) and external factors;however,the outcomes of these conditions may differ.We resuscitated a female patient with OTCD from hyperammonemic crisis after she gave birth.Hyperammonemia after parturition in a female patient with OTCD can be fatal,and this type of hyperammonemia persists for an extended period of time.Here,we describe the cause and treatment of hyperammonemia in a female patient with OTCD after parturition.Once hyperammonemia crisis occurs after giving birth,it is difficult to improve the metabolic state.Therefore,it is important to perform an early intervention before hyperammonemia occurs in patients with OTCD or in carriers after parturition.

Pediatric metabolic liver diseases:Evolving role of liver transplantation

Metabolic liver diseases(MLD)are the second most common indication for liver transplantation(LT)in children.This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation.LT is also performed in metabolic disorders for end-stage liver disease,its sequelae including hepatocellular cancer.It is also performed for preventing metabolic crisis’,arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia.Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis,cholestasis,inflammation,variable amount of fibrosis,and cirrhosis.The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT.A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters.Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver.The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.

Liver transplantation for late-onset ornithine transcarbamylase deficiency:A case report

BACKGROUND Ornithine transcarbamylase deficiency(OTCD)is an X-linked inherited disorder and characterized by marked elevation of blood ammonia.The goal of treatment is to minimize the neurological damage caused by hyperammonemia.OTCD can be cured by liver transplantation(LT).Post-transplant patients can discontinue anti-hyperammonemia agents and consume a regular diet without the risk of developing hyperammonemia.The neurological damage caused by hyperammonemia is almost irreversible.CASE SUMMARY An 11.7-year-old boy presented with headache,vomiting,and altered consciousness.The patient was diagnosed with late-onset OTCD.After nitrogen scavenging treatment and a protein-free diet,ammonia levels were reduced to normal on the third day of admission.Nevertheless,the patient remained in a moderate coma.After discussion,LT was performed.Following LT,the patient’s blood ammonia and biochemical indicators stabilized in the normal range,he regained consciousness,and his nervous system function significantly recovered.Two months after LT,blood amino acids and urine organic acids were normal,and brain magnetic resonance imaging showed a decrease in subcortical lesions.CONCLUSION LT can significantly improve partial neurological impairment caused by late-onset OTCD hyperammonemic encephalopathy,and LT can be actively considered when early drug therapy is ineffective.