It is a metabolic disorder characterized by an excess of ammonia in the blood.
It is a dangerous condition that can lead to brain damage and death. It can be primary school or high school.
The increased inflow of ammonia brain is a primary cause of neurological disorders such as congenital deficiencies of enzymes of the urea cycle, liver encephalopathy, Reye’s syndrome, several other metabolic disorders and some toxic encephalopathies.
Ammonia is an important source of nitrogen and is required for the synthesis of amino acids. It is also necessary for a normal acid-base balance. When present in high concentrations, ammonia is toxic.
It is a product of protein catabolism. It becomes the least toxic substance urea before excretion in the urine by the kidneys. Endogenous ammonia poisoning can occur when there is a limited ability of the body to excrete nitrogenous wastes, as seen in congenital enzymatic deficiencies.
Metabolic pathways that synthesize urea involve reactions that start in the mitochondria and then move to the cytosol. The process is known as the urea cycle, which comprises several enzymes that act in sequence.
A variety of environmental causes and medications can also lead to ammonia toxicity. Hyperammonemia refers to a clinical condition associated with elevated levels of ammonia manifested by a variety of symptoms and signs, including significant central nervous system abnormalities .
Appropriate and timely management requires a solid understanding of the fundamental pathophysiology, differential diagnosis and treatment approaches available. The following review discusses the etiology, pathogenesis, differential diagnosis and treatment of hyperammonaemia.
Signs and symptoms of hyperammonaemia
Acute hyperammonemia is defined as elevated levels of plasma ammonia associated with muscle hypotonia , seizures, vomiting and altered consciousness.
It is a potentially life-threatening event, the signs and symptoms of hyperammonaemia can appear and vary according to age, but are non-specific in all age groups. If the first symptoms are treated in all age groups, they could be reversible.
If left untreated, hyperammonemia could be toxic and cause irreversible brain damage to the developing brain.
The first symptoms in all age groups are loss of appetite and vomiting, which could be reversible if they are recognized and treated early.
In newborns, the first common symptoms are poor nutrition, vomiting, lethargy; it can progress to central hyperventilation that often results in respiratory alkalosis and irritability that progresses rapidly to convulsions, deep coma and even death if not treated urgently.
In babies, vomiting mimics pyloric stenosis , intolerance to cow’s milk or gastroenteritis. In older children and adults, vomiting, protein aversion, ataxia, confusion, disorientation, hallucinations, or abnormal behavior point to the central nervous system or psychiatric disorders.
If left untreated, severe hyperammonemia will be neurotoxic and will cause irreversible brain damage to both the developing and mature brain. Hyperammonemic encephalopathy is associated with high mortality rates.
Chronically, hyperammonemia can present as recurrent vomiting, headache, ataxia, strange behavior, especially if it occurs episodically, delayed development and aversion to proteins.
The total duration of a hyperammonemic coma and the degree of hyperammonemia are the most relevant prognostic factors and are negatively correlated with the neurological outcome of the patient.
Therefore, rapid identification and treatment of hyperammonemia are vital to optimize the outcome.
Hyperammonemia is one of the metabolic disorders that contribute to hepatic encephalopathy, which can cause astrocyte bloating and stimulation of NMDA receptors in the brain.
Overstimulation of NMDAr or NMDAr receptors (of N-methyl-D-aspartate) induces excitotoxicity. Patients who experience acute elevations of ammonia are presented in the intensive care unit with encephalopathy, which can progress rapidly to a brain hernia .
Patient survival requires immediate treatment of intracerebral hypertension and reduction of ammonia levels. When hyperammonemia is not believed to result from liver failure, the treatment of a hidden metabolic disorder should begin before the confirmation of an etiology.
Healthy people may experience hyperammonemia in extreme circumstances, such as excessive protein intake for body building.
Total parenteral nutrition with a high nitrogen content can also cause hyperammonemia, as can a serious injury such as a bone fracture.
The protein restriction that causes massive protein catabolism can occur. Hyperammonemia has occurred after bariatric surgery .
High levels of ammonia can be caused by increased ammonia production, which can occur during infections or postoperatively, when a patient is in a catabolic state or has a decrease in ammonia removal.
The increase in ammonia production can also occur in liver disease and with inborn errors of metabolism, particularly the defects of the urea cycle.
The postpartum period is another stressful situation that can trigger a hyperammonemia that can be misdiagnosed as postpartum psychosis.
Certain medications can unmask or even worsen a known metabolic condition associated with hyperammonemia. Valproic acid is one of those medications.
Diagnosis of hyperammonaemia
Patients of all age groups with encephalopathy of unknown etiology should undergo plasma ammonia (NH3) measurements.
It is strongly recommended that the measurement of ammonia be considered in all patients with encephalopathy, especially in newborns who require a septic screen and are sick at the same time.
Anyone of any age who exhibits any of the following symptoms should undergo an early determination of plasma with ammonia:
- Unexplained acute encephalopathy.
- Acute neurological disease
- Suspicion of sepsis in a newborn.
- Delay in the development of unknown cause.
- Recurrent vomiting
- Acute liver failure, elevated transaminases of unknown cause.
- Headache, especially if it is episodic in women.
- Eat or stupor
- Psychiatric symptoms
- Aversion to protein
What ammonia levels require immediate action?
The normal level of ammonia varies according to the age of the patient. There is no scientifically sound consensus on the upper normal limit for each age group.
However, it is generally considered hyperammonemia if plasma ammonia is> 50 μmol / L in infants, children and adults and> 100 μmol / L in newborns.
Other authors have described the normal reference range in the following way:
- Up to 7 days: 94 μmol / L.
- 8-30 días: 80 μmol/L.
- 1 month to 15 years: 48 μmol / L.
- >15 años: 26 μmol/L.
It should be noted that the normal reference ranges of individual laboratories should be used for clinical interpretation.
A warning system for nurses and doctors should be active in the laboratory in case the ammonia is above the reference range and this should be immediately reported to the health professional in charge of the patient.
What precaution should be taken to test ammonia?
False positive hyperammonemia is not uncommon; therefore, several precautions should be taken into account when collecting blood samples to measure ammonia.
A sample of free-flowing venous (or arterial) blood without a tourniquet should be taken in a tube containing an anticoagulant (eg, lithium or heparin).
The sample should be placed in ice water, transported to the laboratory and analyzed immediately. The results must be available within 60 minutes after the extraction of the samples.
Primary vs. High school
Primary hyperammonemia is caused by several inborn errors of metabolism that are characterized by reduced activity of any of the enzymes in the urea cycle.
The most common example is the deficiency of ornithine transcarbamylase, which is inherited in an X-linked manner.
Secondary hyperammonemia is caused by congenital errors of the intermediary metabolism, which are characterized by a reduced activity of enzymes that are not part of the urea cycle or the dysfunction of the cells that make an important contribution to metabolism.
Examples of the former are propionic acidemia and methylmalonic acidemia, and examples of the latter are acute liver failure and liver cirrhosis with liver failure.
Acquired vs. congenital
Acquired hyperammonemia is usually caused by diseases that cause acute liver failure, such as overwhelming hepatitis B or exposure to hepatoxins, or liver cirrhosis with chronic liver failure.
Chronic hepatitis B, chronic hepatitis C, and excessive alcohol consumption are common causes of cirrhosis. The physiological consequences of cirrhosis include the derivation of blood from the liver to the inferior vena cava, which produces a decrease in blood filtration and the elimination of nitrogen-containing toxins in the liver and then hyperammonaemia.
This type of hyperammonemia can be treated with antibiotics to kill the bacteria that initially produce ammonia, although this does not work as well as eliminating proteins from the colon before digestion to ammonia, which is achieved by administering lactulose for administration frequent (3-4 per day) bowel movements.
The medication-induced hyperammonemia can occur with an overdose of valproic acid and is due to a carnitine deficiency. Its treatment is the replacement of carnitine.
Severe dehydration and bacterial overgrowth of the small intestine can also lead to acquired hyperammonemia.
Congenital hyperammonemia is usually due to genetic defects in one of the enzymes in the urea cycle, such as ornithine transcarbamylase deficiency, which leads to a lower production of urea from ammonia.
The following list includes such examples:
- Mendelian inheritance online in man (OMIM) 311250 – hyperammonemia due to deficiency of ornithine transcarbamylase.
- Mendelian inheritance online in man (OMIM) 606762 – hyperinsulinism-hyperammonemia syndrome (glutamate dehydrogenase 1).
- Mendelian inheritance online in man (OMIM) 238970 – hyperornitinemia-hyperammonemia-homocitrulinuria.
- Mendelian inheritance online in man (OMIM) 237310 – hyperammonemia due to N-acetylglutamate synthetase deficiency.
- Online Mendelian inheritance in man (OMIM) 237300 – Hyperammonemia due to deficiency of carbamoyl phosphate synthetase I (carbamoyl phosphate synthetase I).
- Mendelian inheritance online in man (OMIM) 238750 – hyperilisinuria with hyperammonemia (unknown genetics).
- Acidemia metilmalónica.
- Acidemia isovalérica.
- Propionic acidemia.
- Carnitine palmitoyltransferase II deficiency.
- Transient hyperammonemia of the newborn, specifically in the premature.
Once hyperammonemia is suspected, immediate treatment is crucial to prevent neurological damage and avoid associated morbidity and mortality.
The cognitive result is inversely related to the number of days of neonatal coma in the disorders of the urea cycle. Rapid control of hyperammonemia is crucial to prevent or decrease the degree of mental retardation.
The patient must be managed in a hospital with access to basic metabolic tests, first-line hyperammonemia medications, dialysis facilities and metabolic specialists.
If any of these elements is not available, the patient should be transferred without delay to a specialized center after stabilization according to basic life support (circulation, airway and respiration), addressing the vital signs as with any critical patient and including the blood glucose monitoring. In addition, the following should be done:
- Insert the intravenous lines, if possible as central venous access. If this can not be achieved, intraosseous access could be an alternative.
- Maintain the airway: intubate and ventilate if necessary.
- Adequate rehydration with a minimum of 10% glucose dextrose and high caloric intake, maintain normal blood pressure and add vasopressors if necessary.
- Take samples of blood and urine.
- Stop all protein intake (but do not retain the protein for more than 36-48 hours, as it may promote the breakdown of endogenous proteins and hinder metabolic control).
- Prepare for probable hemodialysis by contacting the relevant renal and surgical specialists in anticipation of an imminent need.
The treatment focuses on limiting the intake of ammonia and increasing its excretion. Dietary protein, a metabolic source of ammonium, is restricted and caloric intake is provided by glucose and fat.
Intravenous arginine (argininosuccinase deficiency) sodium phenylbutyrate and sodium benzoate (deficiency of ornithine transcarbamoylase) are pharmacological agents commonly used as adjuvant therapy to treat hyperammonemia in patients with enzyme deficiencies of the urea cycle.
Sodium phenylbutyrate and sodium benzoate can serve as alternatives to urea for the excretion of residual nitrogen. Phenylbutyrate, which is the product of phenylacetate, is conjugated with glutamine to form phenylacetylglutamine, which is excreted by the kidneys.
Similarly, sodium benzoate reduces the ammonia content in the blood by conjugating with glycine to form hippuric acid, which is rapidly excreted by the kidneys.
A preparation containing sodium phenylacetate and sodium benzoate is available under the trade name Ammonul.
Acidification of the intestinal lumen with lactulose can decrease ammonia levels by protonating ammonia and trapping it in the stool. This is a treatment for hepatic encephalopathy.
In case of acute hyperammonemia, dialysis should be initiated as soon as possible when the ammonia exceeds 200μmol / L.17.
Treatment of severe hyperammonaemia (serum ammonia concentrations greater than 1000μmol / l) should begin with hemodialysis if medically appropriate and tolerated.
Hemodialysis is the most effective way to quickly get rid of excess ammonia and is far superior to other dialysis methods (hemofiltration, peritoneal dialysis).
Hemodialysis has the added benefit of eliminating amino acids such as glutamine and, in this way, eliminating additional waste nitrogen from the body.
A newborn or small child with plasma ammonia greater than 300μmol / l should receive hemodialysis as soon as possible and administer Ammonul intravenously until hemodialysis is instituted.
Central venous catheters should be placed in a critical patient in hyperammonemic crisis in anticipation of the potential of hemodialysis and appropriate nephrology and surgery specialists should be alerted in advance of this possible need.
The decision to hemodialyze is essential to prevent or minimize irreversible damage to the central nervous system; in case of doubt in the presence of a markedly elevated ammonia level, the decision should be to hemodialyze as soon as possible.
Treatment of hyperammonemia in the newborn
Of course, basic support for the airway and circulation is provided, whichever is necessary. Sometimes, the baby will have an acid imbalance or an electrolyte imbalance that must be corrected. Hypoglycaemia, of course, must be treated as well.
The most important action is to prevent catabolism. Most of these neonatal cases involve children who have not fed well and who are catabolic, and the body of the newborn destroys the muscle reserves, releasing proteins and amino acids that try to be metabolized, but the defect of the urea cycle increases the level of ammonia .
Simply starting an intravenous (IV) line and administering fluids with dextrose and the proper electrolytes is important and could save lives.
In some cases, we use intravenous nitrogen scavenging medications. Sometimes, these medications are not effective, however, and we could even perform hemodialysis.
Hyperammonemia in disorders of the urea cycle: role of the nephrologist
Hyperammonemia associated with inherited disorders of the metabolism of amino acids and organic acids is usually manifested by irritability, drowsiness, vomiting, convulsions and coma.
Although most of these patients present in the newborn period, they can also occur in childhood, adolescence and adulthood with growth retardation, persistent vomiting, developmental delay or changes in behavior.
Persistent hyperammonemia, if not treated quickly, can cause irreversible neuronal damage.
After establishing the diagnosis of hyperammonemia in a severely ill patient, certain diagnostic tests must be performed to differentiate between urea cycle defects and other causes of hyperammonemic encephalopathy.
In a patient with a presumed hereditary metabolic disorder, the goal of therapy should be to normalize ammonia levels in the blood.
Recent experience has provided treatment guidelines that include minimizing endogenous ammonia production and protein catabolism, restricting nitrogen intake, administering substrates of the urea cycle, administering compounds that facilitate the removal of ammonia through alternative routes and, in severe cases, dialysis therapy.
The initiation of dialysis in the patient with encephalopathy with hyperammonemia is indicated if the level of ammonia in the blood is greater than three to four times the upper limit of normal. Hemodialysis is the most effective treatment for rapidly reducing ammonia levels in the blood.
Continuous hemofiltration and peritoneal dialysis are also effective ways to reduce ammonia levels in the blood.
A better understanding of ammonia metabolism and the neurological consequences of hyperammonemia will help the nephrologist to provide optimal care for this population of high-risk patients.