Primary hyperammonaemia: Current diagnostic and therapeutic strategies

All UCDs can manifest at all ages. Nevertheless, about half of the patients present early in life during the neonatal period (16, 17). These patients are classified as ‘early-onset UCDs’. Another about 50% of the patients present outside the neonatal period, that is, later than the first 28 days in life and are called ‘late-onset UCD patients’. It is generally accepted that a complete loss of enzyme or transporter function very likely leads to the neonatal onset and severe disease. However, there is also significant morbidity and mortality in late-onset patients (18, 19, 20). In particular, there is a relevant risk of death during the first presentation both for neonatal and late-onset forms. Early identification of the affected patients and the immediate start of therapy are of utmost importance to treat UCDs.

The symptoms in both forms are mainly neurological and in most patients not very specific (4). Lethargy, progressing to somnolence and later coma, vomiting and refusal to feed, hypothermia, and seizures are common symptoms in neonates. Very often, the clinical situation is initially interpreted and treated as bacterial sepsis, which contributes to a significant delay in establishing the diagnosis if differential diagnoses are only considered after the failure of (in a day or two of) antibacterial treatment.

Outside the neonatal period, signs and symptoms become more variable but the neurological character remains. The reader is referred here to a comprehensive list of neonatal and late-onset signs and symptoms in the recently revised guideline paper (4).

The most relevant complication is brain damage, which can become irreversible already within a few hours after the occurrence of severe hyperammonaemia (21, 22). Although there is no clear threshold for plasma ammonia to cause irreversible brain damage, an elevation of ammonia exceeding 1,000 μmol/L for more than 24 h is in most cases associated with a poor prognosis and even early death of the patient (4). Making the clinical management of these patients very challenging, there are reports of single patients that survive such an episode without obvious neurological sequelae (23).

The most important diagnostic key is in the hands of those who first treat these patients. Doctors in the emergency departments or the neonatal intensive care units will be the first to manage a yet unknown neonatal patient with the first manifestation of hyperammonaemia. In the late-onset cases, doctors with different specialities, such as general physicians, neurologists, psychiatrists, gastroenterologists and also doctors in the emergency wards may see such patients first. These doctors are key to raise an early suspicion of an underlying metabolic defect and thereby recommend the analysis of plasma ammonia. It has been shown that neonates suffering from hyperammonaemia are much more likely to be tested for elevated blood lactate than for hyperammonaemia (24). This diagnostic algorithm must be improved giving the same importance to ammonia determination as to metabolites that can be tested applying point-of-care device such as lactate as a frequent part of standard blood gas analysis. Ideally, ammonia determination should be available to all units that are involved in the emergency management of patients of all ages.

If ammonia is found to be elevated, contact should be made to the next metabolic centre to discuss and plan the next diagnostic steps and initial therapy, and, depending on the clinical situation, the transfer of the patient for further management (4). In any patient with severe hyperammonaemia and indicative of significant neurological impairment with seizures or (pre) coma, an immediate transfer to a metabolic centre for further management including (the likely necessary) extrarenal ammonia detoxification using haemodialysis or haemodiafiltration should be considered and planned without delay.

If hyperammonaemia is found, then relevant laboratory analyses to understand its aetiology include the profiles of amino acids in plasma, organic acids in urine including the determination of orotic acid and acylcarnitines in the blood (25). With these ‘metabolic screening tests’, the majority of patients with symptomatic hyperammonaemia can be defined as a specific disorder, yet of course pending further confirmatory testing. For the group of primary hyperammonaemias, which is the focus of this manuscript, urinary organic acids (apart from increased urinary orotic acid in OTC deficiency and the distal UCDs) and blood acylcarnitines are mainly normal, while plasma amino acids frequently show specific changes. A summary of characteristic biochemical findings is listed in Table 1.

For confirmation of the diagnosis, mutation analysis is the preferred method, as it offers the additional advantage of specific testing of other family members (especially important in OTC deficiency) and prenatal testing in future pregnancies (4, 26). In addition to mutation analysis, functional tests can be done, mainly enzymatic analyses, but these require invasive samplings such as skin or liver biopsies and still lack the aforementioned additional advantages. Nevertheless, functional assays can be of high value in patients with inconclusive molecular genetic analysis (27).

Another diagnostic tool that was introduced more than 20 years ago is the use of stable isotopes for a flux study of the entire urea cycle (28, 29). This method was used in the past almost exclusively as part of the experimental studies involving novel therapy developments such as hepatocyte transplantation or gene therapy approaches (30), and these novel methods may facilitate future use of this approach (31). Establishing the ureagenesis capacity may also be useful in testing the relevance of the existing medications in new indications, for instance, the use of carglumic acid in UCDs other than NAGS deficiency. It has been proposed several times that stimulation of the urea cycle may also be beneficial for CPS1 deficiency, for example, but there is only preliminary experimental or clinical proof for such claims (32). The comparison of the urea cycle flux before and after the introduction of carglumic acid could help in identifying patients that benefit from this additional therapy.

Therapy of primary hyperammonaemia is discussed below separately for acute and chronic management.

Acute management is based on two principles: the rapid detoxification of ammonia and the establishment of anabolism to prevent any further protein breakdown (33). Detoxification of ammonia should be achieved as fast as possible to prevent (further) brain damage. The most powerful method for this is the extracorporeal removal of ammonia from the blood and organism by haemodialysis or haemodiafiltration (34, 35). The choice of the method will mainly depend on the local availabilities and experience. Drawbacks of any dialysis method are the time needed to start this procedure, potential adverse events associated with the insertion of vascular catheters, the necessary anticoagulation and disturbances of electrolytes and blood gas homoeostasis during the procedure. Therefore, any attempt should be made to identify patients early enough during metabolic decompensation(s) to avoid (or at least reduce) the need for such drastic therapies. However, patients identified with clinical signs of encephalopathy should be kept prepared for dialysis without any further delay. It has been shown that the majority of newborns with a presentation of any UCD will have to be subjected to dialysis (23). It is therefore not justified to first try a ‘conservative’ approach using only high glucose infusions ± insulin, nitrogen scavengers, and infusions of L-arginine to treat symptomatic hyperammonaemia.

Chronic management of primary hyperammonaemias is for most patients based on a combination of low protein diet plus the supplementation of essential amino acids, vitamins and trace elements to prevent their respective deficiencies, together with nitrogen scavengers and few other medications (4, 36). The list of medications, their usual dosages and the rationale are summarised in Table 2.