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Hyperammonemia

Hyperammonaemia

Hyperammonemia is defined as increased values of ammonia in the blood, and it is considered a medical emergency, as in severe cases it may lead to a fatal outcome. Causes are numerous, including enzyme deficiencies, liver and kidney disease, and it can be drug-induced. Severe cases include major neurological damage and encephalopathy, and the diagnosis is obtained by evaluation of liver function and levels of ammonia in serum. Treatment is targeted at the underlying cause and adjunctive therapy.


Presentation

Clinical presentation of hyperammonemia may be divided into two entities:

  • Early-onset hyperammonemia occurs in neonates in their first few days of life, which can be characterized by lethargy, poor feeding, irritability, and vomiting in some cases. In neonates with a more chronic course, failure to thrive, frequent vomiting, sleep disturbances, cognitive and intellectual deficits may all be observed in children. In more severe cases, hyperventilation, grunting, and seizures may occur, and rare cases may result in sudden unexpected death.
  • Late-onset hyperammonemia occurs in adults with underlying illnesses that result in impaired ammonia metabolism. Although some symptoms may vary depending on the underlying disease, symptoms of CNS toxicity such as lethargy, behavioral disturbances, psychosis, irritability, and epilepsy may be present.

Other symptoms, such as tachypnea, hypotonia, bulging fontanelles in neonates as a result of increased intracranial pressure, or dehydration secondary to vomiting, may be observed during a physical examination.

Transient Blindness
  • Transient blindness can also occur. Congenital hyperammonemia is usually due to genetic defects in one of the enzymes of the urea cycle, such as ornithine transcarbamylase deficiency, which leads to lower production of urea from ammonia.[en.wikipedia.org]
Psychiatric Manifestation
  • Despite the severe nature of the epilepsy, presence of concomitant psychiatric manifestations, and frequent need for poly-pharmacy associated with juvenile ceroid lipofuscinosis (JNCL, Batten disease) neither this disorder nor other subtypes of neuronal[ncbi.nlm.nih.gov]
Headache
  • Abstract Valproic acid (VPA) has successfully been used in the therapy of a number of conditions including absence seizures, partial seizures, tonic-clonic seizures, bipolar disorder, schizoaffective disorder, social phobias, neuropathic pain and migraine headaches[ncbi.nlm.nih.gov]
  • Signs and symptoms of hyperammonemia may include: Confusion Headache Dizziness Seizures Vomiting Feeling more tired than usual Not being hungry Avoiding protein Growth problems Behavior changes Coma Any of these signs and symptoms could mean that you[ravicti.com]
  • Chronic features include cognitive and learning deficits, intermittent headaches, intermittent visual disturbances, and focal neurologic signs. There may also be a lifelong aversion to dietary protein.[mhmedical.com]
  • Citation: Consultant. 2015;55(1):29-30 A 51-year-old white male with mental disability and known seizure disorder presented to his neurologist with a new onset of headache, dizziness, confusion, weakness, lethargy, and hand tremors. History.[consultant360.com]
  • Our patient developed emesis, headache, hallucinations and somnolence progressing to coma 6 hours after administration of the last L-Asp dose.[omicsonline.org]

Workup

Patients with suspected hyperammonemia should be thoroughly evaluated, to identify the underlying cause. Initial tests should include arterial blood gasses, to assess the pH status, as well as the examination of liver and kidney functions, including levels of urea, creatinine, aspartate transaminase (AST) and alanine transaminase (ALT). Serum ammonia levels can, and should be measured immediately on admission, especially for patients who are exhibiting encephalopathy or are comatose.

Evaluation of UCDs should be performed if the underlying disease is not identified, including urinary ketone tests, enzyme assays, and genetic testing including DNA mutation analysis as the gold standard. Genetic testing for all enzyme deficiencies of the urea cycle are available and can be performed.

In addition to blood tests, imaging studies including CT scan or MRI of the endocranium should be performed to determine possible brain edema.

Generalized Slowing
  • Venous serum ammonia level was determined ranging 62,1 μmol/L (normal reference: 5–32 μmol/L) and a repeat EEG showed a generalized slowing with frequent frontocentral diphasic sharp waves, suggesting a metabolic encephalopathy.[springerplus.springeropen.com]

Treatment

Therapy of hyperammonemia is aimed at limiting the intake of ammonia, as well as increasing the rate of excretion.

Patients who are suffering from enzyme deficiencies are often on intravenous adjunctive therapy. Drugs that are used include arginine (for argininosuccinase deficiency), sodium phenylbutyrate and sodium benzoate (OTC deficiency). High protein intake can be a source of excess ammonia, and reduction in protein intake through diet may reduce serum levels of hyperammonemia. Some of these agents can be used in patients to stimulate excretion of nitrogen, such as sodium benzoate, while phenylbutyrate is also used as a drug which facilitates excretion of nitrogen compounds and glutamine.

In cases of hepatic encephalopathy and hyperammonemia, stool acidification can aid in trapping ammonia in the stool through the use of lactulose. In patients who require severe metabolic corrections, hemodialysis may be recommended, while liver transplantation is discussed as a treatment option for patients with irreversible liver disease [9] [10].

Prognosis

The prognosis of hyperammonemia depends on the severity of illness and the status of the underlying disease responsible for the development of this metabolic phenomenon. Survival rates significantly vary, but neonatal forms of hyperammonemia are much more severe, with 5-year survival rates ranging from 22-35% in some studies. On the other hand, hyperammonemia in adults has much better outcomes, ranging from 41%-87% in certain studies. Several factors, such as peak ammonia levels, duration, and the onset of coma have been proposed as outcome predictors.

Etiology

Hyperammonemia can be caused by numerous diseases which either accelerate the production rate or reduce its excretion. Causes include:

  • Enzyme deficiencies - Neonatal forms of hyperammonemia are caused by urea cycle disorders (UCDs), which include partial or total deficiency of key enzymes involved in the principal metabolic pathway of ammonia. Enzymes that may be deficient include carbamoyl phosphate synthetase I (CPS-I); ornithine transcarbamylase (OTC); argininosuccinate synthetase (AS); and argininosuccinate lyase (AL). Reduced activity of these enzymes results in impaired ammonia metabolism, and it's subsequent buildup. These deficiencies are transmitted by autosomal recessive pattern, while OTC deficiency is X-linked.
  • Liver disease - Virtually all ammonia is metabolized in the liver through the urea cycle, and liver diseases such as cirrhosis, chronic viral hepatitis, portal hypertension, and hepatic coma impair the synthetic functions of the liver, thus reducing the capacity of this organ to efficiently metabolize ammonia.
  • Renal disease - Reduced ability of the kidneys to excrete urea consequently leads to accumulation of ammonia, which may occur in tubular necrosis, glomerulonephritis, and renal failure.
  • Gastrointestinal diseases - Severe infections of the alimentary tract accompanied with stasis or hemorrhage may lead to increased levels of ammonia, as the intestinal flora increases its rate of production.
  • Reye's syndrome - This pediatric disease in which aspirin use leads to potentially fatal hepatic damage and encephalopathy is characterized by hyperammonemia, due to severe damage to the liver.
  • Drug-induced - Several drugs that are metabolized by the liver, and can cause hepatotoxicity, can induce an increase in serum levels of ammonia, including antimicrobial agents (such as isoniazid and tetracycline), antiepileptics (such as valproic acid), while loop and thiazide diuretics may also induce hyperammonemia.

Epidemiology

The exact prevalence rates of hyperammonemia are not known, but the prevalence of urea cycle disorders, which are one of the main causes of neonatal hyperammonemia, is estimated to be 1 in 25,000 live births in the United States, while prevalence rates vary over the world, ranging from 1 in 8,000 to 1 in 44,000 live births [2]. However, these rates may be underestimated, primarily because of underdiagnosis of both fatal and surviving cases. This metabolic disorder has no gender predilections, and as mentioned previously, patients with liver, kidney, and gastrointestinal disease have a significantly increased risk for developing hyperammonemia.

Sex distribution
Age distribution

Pathophysiology

Ammonia accumulation in the body occurs due to the fact that it is the end-product of protein catabolism, and it is synthesized by bacterial flora of the gastrointestinal tract. In minor concentrations, the body utilizes ammonia in the form of ammonium ion (NH4+) as a pH buffer, which is derived from glutamine synthesis in the kidneys.

Under physiological conditions, excess concentrations of ammonia are metabolized by the liver through the urea cycle, which comprises both mitochondrial and cytosolic enzymatic reactions which eventually lead to formation of urea, which is then excreted by the kidneys. However, when ammonia concentrations exceed the capacity of the liver to metabolize it, or when certain diseases reduce the metabolic functions of the liver, toxic accumulation of ammonia in the body occurs. Ammonia can cause significant damage to virtually all cell lineages, but the the principal site of ammonia toxicity is the central nervous system, where ammonia binds to glutamic acid, forming glutamate. Glutamate, through its excitatory properties as a neurotransmitter, activates N-methyl-D-aspartate (NMDA) receptors, which ultimately leads to depletion of ATP and cell death, and is hypothesized as the cause of seizures in hyperammonemia. This mode of toxicity implicated that NMDA antagonists may be targeted with therapy, with animal models showing increased survival rates [3]. Apart from NMDA activation, ammonia directly inhibits the Krebs cycle through binding to alpha-ketoglutaric acid, and inhibits the process of aerobic glycolysis. By preventing oxygen and energy supply to the brain through this mechanism, it is one of the main causes of coma in patients.

In addition to NMDA activation, other properties have been investigated, including abnormal astrocyte morphology. Namely, it was observed that junctions between astrocytes, as well as potassium and aquaporin channels, are downregulated in the setting of hyperammonemia, which hypothesizes that disrupted water and potassium equilibrium may be the cause of brain edema that is encountered in patients suffering from increased levels of ammonia [4]. Tumor suppressor proteins, such as p53, were also shown to be involved in astrocyte swelling and inhibition of glutamate uptake [5].

In addition to organic changes that occur as a result of hyperammonemia, changes in mental behavior are observed, and the pathogenesis involves several factors. As a result of excessive glutamate stimulation of NMDA receptors, and alterations in receptor regulation, changes in learning and cognitive skills are attributable to this phenomenon [6]. In addition, overstimulation of benzodiazepine receptors and increased GABAergic tone have been proposed as factors which result in altered consciousness and coma, as well as decline in intellectual function. The glutamate-nitric oxide-cGMP pathway has been a target for therapy in animal models, through administration of phosphodiesterase which restored the levels of cGMP [7].

Damage to genetic material, including oxidation of RNA, has been observed in patients with hyperammonemia as well, which results in impaired gene expression, through reduced capacities for transcription and translation, but also an intracellular accumulation of zinc and reactive oxygen species. These events lead to cell damage, and eventual death and such changes have been implicated in the pathogenesis of memory loss and learning difficulties [8].

Prevention

Prevention of hyperammonemia can be achieved in patients with underlying illnesses that predispose them to this metabolic disease by proper management of their conditions, through regular therapy, but also by proper dietary habits. If patients are at risk of developing hyperammonemia, protein intake should be reduced and monitored. Antenatal screening for urea cycle disorders and enzyme deficiencies can provide valuable data for therapeutic strategies of neonates, and significantly improve survival rates.

Summary

Hyperammonemia is a potentially life-threatening metabolic disturbance that occurs as a result of an accumulation of ammonia, which is a degradation product of amino acid metabolism and is also released from intestinal flora. Under physiological circumstances, ammonia is found in minor concentrations in the blood, and one of the most important functions include pH buffering. The vast majority of ammonia is produced as an end-product of protein metabolism (including deamination of amino acids, glutamine hydrolysis), and excessive amounts are metabolized in the liver through the urea cycle and excreted via the kidneys and urine, but numerous conditions and illnesses impair normal ammonia metabolism, or induce higher rate of ammonia production [1]. Causes include urea cycle disorder (UCD), such as severe or total deficiency of enzymes involved in the urea cycle, liver diseases such as cirrhosis, hepatic encephalopathy, renal and gastrointestinal diseases, Reye's syndrome, while hyperammonemia can also be drug-induced (examples include isoniazid, thiazide and loop diuretics, valproic acid, and many other). This condition may appear during the neonatal period, in the case of deficiencies of enzymes of the urea cycle, in which case the disease is severe, or it can appear in children and adults with diseases that disturb normal ammonia metabolism. Hallmarks of hyperammonemia include neurological disease, as ammonia readily crosses the blood brain barrier and rapidly causes severe damage to the central nervous system, which may lead to encephalopathy, coma, and even fatal outcomes. Other symptoms include lethargy, vomiting, muscle wasting, and changes in the mental status. The diagnosis of hyperammonemia is made by evaluating liver and kidney function (levels of transaminases, urea, creatinine, proteinuria), as well as measuring serum ammonia values. Treatment of hyperammonemia is directed at reducing the intake of ammonia through reduced protein intake, and accelerate its excretion through the use of several nitrogen-binding pharmacologic agents such as sodium phenylbutyrate, carglumic acid, and other, while in severe cases, hemodialysis is considered as a therapeutic measure in severe hyperammonemia that cannot be corrected by standard therapy. Liver transplantation has been proposed in patients with a terminal liver disease, and proper management of possible underlying diseases is vital in restoring metabolic equilibrium in terms of ammonia metabolism. Because of its prognosis, which may be fatal, immediate treatment is necessary for establishing better patient outcomes.

Patient Information

Hyperammonemia is a potentially life-threatening metabolic disorder that occurs due to toxic accumulation of ammonia, which is normally metabolized by the liver and excreted by the kidneys. Ammonia is normally found in small concentrations in the body and performs important functions in regulating body pH. It is formed as an end-product of protein metabolism, but it also formed by bacteria from the gut. Because it is toxic to our cells in increased amounts, it is metabolized in the liver through the "urea cycle", which leads to excretion of ammonia in urine.

The causes of hyperammonemia include genetic disorders (deficiencies of enzymes of the urea cycle), liver disease (cirrhosis, chronic viral infection), chronic kidney disease, severe gastrointestinal infection, and it can also be induced by some drugs. It can be observed in neonates, in which severe enzyme deficiencies lead to accumulation of ammonia within days, or in adults, in which the mentioned diseases can cause this disorder.

Patients with hyperammonemia present with lethargy, irritability, vomiting, altered consciousness, and in some cases coma. The central nervous system is the main site of ammonia toxicity, and numerous symptoms regarding this system including memory loss, cognitive and intellectual impairment, irritability, seizures, and many other symptoms can be observed in these patients. In neonates and children, poor feeding, failure to thrive, as well as frequent vomiting may be observed, and in severe cases, sudden death may occur.

Because hyperammonemia can result in death, immediate workup, consisting of measuring levels of ammonia in the blood, as well as evaluation of liver and kidney function and other tests, should be performed, and treatment should be rapidly initiated. Treatment includes reduction of protein intake, to reduce the levels of formed ammonia, but several drugs can be used to stimulate excretion of ammonia and associated products through urine.

References

Article

  1. Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008;97(10):1420-5.
  2. Haeberle J, Boddaert N, Burlina A, et al. Suggested Guidelines for the Diagnosis and Management of Urea Cycle Disorders. Orphanet J Rare Dis. 2012;29: 7(1):32.
  3. Rodrigo R, Cauli O, Boix J, ElMlili N, Agusti A, Felipo V. Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications. Neurochem Int. 2009;55(1-3):113-8.
  4. Lichter-Konecki U, Mangin JM, Gordish-Dressman H, Hoffman EP, Gallo V. Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Glia. 2008;56(4):365-77.
  5. Panickar KS, Jayakumar AR, Rao KV, Norenberg MD. Ammonia-induced activation of p53 in cultured astrocytes: role in cell swelling and glutamate uptake. Neurochem Int. 2009;55(1-3):98-105.
  6. Llansola M, Rodrigo R, Monfort P, et al. NMDA receptors in hyperammonemia and hepatic encephalopathy. Metab Brain Dis. 2007;22(3-4):321-35.
  7. Monfort P, Cauli O, Montoliu C, et al. Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy: therapeutical implications. Neurochem Int. 2009;55(1-3):106-12.
  8. Schliess F, Görg B, Häussinger D. RNA oxidation and zinc in hepatic encephalopathy and hyperammonemia. Metab Brain Dis. 2009;24(1):119-34.
  9. Meyburg J, Das AM, Hoerster F, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation. 2009;87(5):636-41.
  10. Meyburg J, Schmidt J, Hoffmann GF. Liver cell transplantation in children. Clin Transplant. 2009; 23(21):75-82.

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Last updated: 2018-06-22 11:23