Urea cycle defect

Classification according to ICD-10
E72.2	Urea cycle disorders
E72.4	Disorders of the ornithine metabolism (ornithinaemia)
ICD-10 online (WHO version 2019)

Urea cycle defects are metabolic diseases that are associated with a disturbance in nitrogen excretion . They lead to hyperammonaemia , i.e. an abnormally high level of ammonia in the blood. Ammonia is a metabolic toxin and, in high concentrations, can damage nerve cells , especially the brain. These are hereditary diseases that can lead to death if left untreated, but can also be benign if detected and treated early.

Urea cycle

Main article: urea cycle

The urea cycle takes place in the cells of the liver ( hepatocytes ). Nitrogen is absorbed with food or protein and transported from the intestine via the portal vein to the liver. Ammonia is a chemical compound of nitrogen and hydrogen . Ammonia (NH ₃ ), which is toxic to humans , is converted into harmless urea in the urea cycle through a series of metabolic processes. The urea is then excreted in the urine through the kidneys.

Diseases based on urea cycle defects

Six different urea cycle enzyme defects of importance to humans are known:

• Carbamoyl phosphate synthetase I (CPS) deficiency
• N- acetyl glutamate synthetase (NAGS) deficiency
• Ornithine transcarbamylase (OTC) deficiency
• Argininosuccinate synthase (ASA) deficiency ( citrullinemia type I )
• Argininosuccinate Lyase (ASL) deficiency ( arginine succinic acid disease )
• Arginase-1 deficiency ( hyperargininemia )

The main symptom is hyperammonaemia . All urea cycle defects are autosomal - recessive inherited only exception is the OTC deficiency, which X-linked inherited recessive. A urea cycle defect can manifest itself for the first time in any phase of life .

frequency

The annual incidence in the United States is roughly:

• Total: 1: 8,200
  • OTC deficiency (ornithine transcarbamylase deficiency) 1: 14,000
  • ASA deficiency 1: 57,000
  • CPS deficiency 1: 62,000
  • ASL deficiency 1: 70,000
  • Arginase deficiency 1: 363,000
  • NAGS deficiency: no reliable data known

Predilection times

Most urea cycle defects manifest themselves in infancy or childhood, but they can ultimately manifest for the first time at any age. However, there are certain phases in life in which the disease often breaks out.

• Neonatal period : late infancy with the switch to relatively protein-rich food and the beginning of a period with frequent infections
• Puberty with changing growth and psychosocial factors as a trigger
• Start treatment with valproate
• Women during pregnancy
• with increased protein supply in the diet or artificial intravenous nutrition , for example as part of a major operation

Age of manifestation

A urea cycle defect manifested itself for the first time in a study from 1996 at the following age:

In infancy: 41.5%

Later onset of illness: 58.5%

male

<18 years: 18.9%

> 18 years: 1.5%

Female

<18 years: 31.6%

> 18 years: 6.5%

Symptoms

Depending on the age at which the disease first appeared, the symptoms are different:

• Symptoms in infancy: lethargy , poor drinking, vomiting, tachypnea , seizures , encephalopathy , coma , in the worst case death.

• Symptoms in early childhood : Often far less dramatic than in newborns: failure to thrive, refusal to eat, ataxia , irritability , behavioral problems, seizures , often unrecognized, fatal coma .

• Symptoms in adolescents and adults : Progressive psychiatric or neurological symptoms, recurrent acute symptoms with inappetence , lethargy , irritability, agitation , confusion, vomiting, headache and ataxia due to metabolic stress situations, episodic metabolic encephalopathies ( most severe hepatic encephalopathy , coma ), death .

A very high concentration of ammonia in the blood can cause permanent damage to the brain and thus lead to mental retardation .

Differential diagnosis

The following diseases can resemble urea cycle defects , but should be differentiated from them: disorders of fatty acid oxidation, hyperammonaemia as a result of genetic defects in amino acid transport ( hyperammonaemia-hyperornithinaemia-homocitrullinuria HHH syndrome ); Lysinuric protein intolerance (LPI), variant of glutamate dehydrogenase ( hyperinsulinism-hyperammonaemia syndrome ), citrullinaemia type II , temporary hyperammonaemia in premature infants due to a persistent ductus venosus (Arantii) , organoacidemias .

therapy

Acute therapy

The primary goal of acute therapy is the rapid lowering of the ammonia concentration in the blood. The principles of acute treatment are:

• Stop the supply of proteins (for a maximum of two days) or intravenous administration of amino acids
• Intravenous supply of glucose via a central venous catheter and continuous infusion of insulin (reversal of the catabolic metabolic situation and restoration of an anabolic metabolic situation)
• Medicinal lowering of the ammonia level (through sodium benzoate , sodium phenylbutyrate and carbamyl glutamate , use of alternative ways of nitrogen elimination)
• Infusion of arginine hydrochloride (to optimize the remaining function of the urea cycle)
• Forced diuresis
• Balance of the acid-base status and the electrolyte balance
• Hemodiafiltration for detoxification (if necessary)
• Avoiding increased ammonia production by intestinal bacteria can be from by temporary antibiotic gut renovation and administration of lactulose done

Long term therapy

In long-term treatment, the aim is to design the nitrogen uptake in a carefully prepared therapy scheme in such a way that the ammonia and glutamine concentrations in the blood are kept within the normal range as far as possible when optimal growth is achieved. This is achieved in particular by restricting the amount of protein in the diet, which must be strictly calculated on the basis of a so-called balanced diet .

In some cases, mixtures of high-quality essential amino acids can be used as partial substitutes for natural protein. In special cases, feeding using a nasogastric tube or a PEG tube is possible.

In terms of drugs , the remaining function of the urea cycle can be optimized by taking L-arginine or L-citrulline . Alternative ways of eliminating nitrogen “bypassing the urea cycle” can be used with sodium benzoate or sodium phenylbutyrate . Other substances such as citrate , carnitine , vitamins and trace elements can be supplemented individually as required .

In certain cases, a liver transplant may be necessary, which is the only possibility of healing the urea cycle defect for the person concerned, but is associated with not inconsiderable risks.

On the one hand, the availability of suitable donor organs is problematic, so that livers from adult donors have to be used. Due to the limited space available in the abdomen of a newborn / toddler, only a lobe of the liver (split liver), which is the smallest unit that can be transplanted due to the blood vessel structure of the liver, is transplanted. Often, however, this also causes a space problem (large-for-size situation). As a result of the transplantation of organs / liver lobes that are too large, a subsequent closure of the abdominal wall can be difficult or even impossible; Other typical complications are severe circulatory disorders of the transplanted liver and thromboses. Despite all the advances in transplant medicine, liver or split liver transplants are risky in newborns. Various scientific publications suggest a connection between the success of a liver transplant and the weight or age of the child. However, since the ammonia levels in the first few days after birth can already increase significantly, the course of which ranges from severe neurological damage to coma or death, metabolic stabilization is essential for newborns and small children with urea cycle defects.

A method of infusing metabolically competent liver cells appears to be very promising. This approach is pursued in various forms by several university institutions as well as by the pharmaceutical industry in large-scale clinical studies worldwide. At the end of 2013, Cytonet submitted an application for (market) approval for a liver cell product with adult liver cells to the European Medicines Agency (EMA).

Mechanism of action and possible uses of liver cell therapy: In the most common variant of liver cell therapy, liver cells that are obtained from non-transplantable donor livers are infused into the patient's liver in several passages via a portal vein catheter. There they should settle and take over the breakdown of ammonia to urea instead of the defective body's own liver cells. So that there is no rejection reaction, the patients are immunosuppressed after liver cell therapy.

literature

• S3 guideline for the diagnosis and therapy of urea cycle disorders of the specialist society. In: AWMF online (as of 2012)
• Eberhard Mönch: Defects in the urea cycle. Clinical Significance and Therapy; UNI-MED Science-Verlag, 2000, ISBN 3-89599-514-2 .

Web links

Wikibooks: Urea Cycle  - Learning and Teaching Materials

Individual evidence

1. ↑ JE Wraith: Ornithine Carbamoyltransferase deficiency. In: Arch Dis Child . 2001 Jan; 84 (1), pp. 84-88. Review. PMID 11124797
2. ^ Orphanet, an EU-funded portal on rare diseases
3. ^ ^{A b} S. W. Brusilow, NE Maestri: Urea cycle disorders: diagnosis, pathophysiology, and therapy. In: Advances in Pediatrics. Vol. 43, 1996; 43, pp. 127-170.
4. ↑ DocCheck Medical Services GmbH: Ornithine transcarbamylase deficiency - DocCheck Flexikon. Retrieved June 1, 2017 . 
5. ↑ ^{a b c d} AWMF guidelines on urea cycle defects from May 2002.
6. ↑ Christoph Werner: Aspects of the drug therapy of urea cycle defects with special consideration of the arginine succinic acid disease. Dissertation . TU Munich 2007.
7. ↑ H. Noujaim et al: Techniques for and Outcome of Liver Transplantation in Neonates and Infants Weighing Up to 5 Kilograms. In: J PediatrSurg. 2002, 37, pp. 159-164; Perito E Pediatric: Liver Transplantation for Urea Cycle Disorders and Organic Acidemias: United Network for Organ Sharing Data for 2002–2012. In: Liver Transpl. 2014, 20, pp. 89-99.
8. ^ European Medicines Agency. Applications for new human medicines under evaluation by the Committee for Medicinal Products for Human Use.
9. ↑ J. Meyburg et al: One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. In: transplant. 2009; 87 (5), pp. 636-641; H. Kriegbaum, J. Meyburg: Liver Cell Infusion - A new therapy option in children with urea cycle defects. In: European Pediatrics. 2009; Vol 3 Extract, pp. 3-7; J. Meyburg et al .: Monitoring of intraportal liver cell application in children. In: Cell Transplant. 2010, 19 (5), pp. 629-638; J. Meyburg, F. Hoerster, J. Weitz, G. Hoffmann, J. Schmidt: Use of the middle colic vein for liver cell transplantation in infants and small children. In: Transplantation Proceedings. 2008; 40, pp. 936-937; J. Meyburg et al. Liver cell transplantation: basic investigations for safe application in Infants and small children. In: Cell Transplant. 2009; Vol 18, pp. 777-786.

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