Keywords
hypertension - citrullinemia - arginine - newborn
Case Report
Our patient is a 5-day male newborn, with no pathological clinical record and no parental
consanguinity presenting in the emergency department for low volume urine output in
the last 12 hours. Parents referred no other symptoms. On the physical examination
it stands out respiratory distress and maintained high blood pressure (BP) in the
four limbs (above 120/90 mm Hg). Heart rate, peripheral oxygen saturation (SatO2), and temperature were within normal range. Full blood count, renal and liver function,
C-reactive protein (CRP), venous blood gas, and urine sediment were examined and found
normal except for a respiratory alkalosis. Also, urine and blood culture were taken,
and empirical antibiotic treatment started. He was transferred to a tertiary care
neonatal center to continue study and support.
On arrival to our center, he was ill with continuous respiratory moan and work of
breathing. He also had an altered mental status of being lethargic. No other findings
or dysmorphic features were observed. We corroborated the high BP both in arms and
legs (respiratory rate of 50 rpm, and SatO2 98%).
Some additional tests were added, showing mild coagulopathy, an ammonia of 93 µmol/L,
and slight left ventricular hypertrophy. Cranial and abdominal ultrasound were normal
as the CRP for enterovirus, cytomegalovirus, herpes 1,2, zoster, and parechovirus.
After a few hours of admission, the metabolic screening center informs of an altered
result for the patient (sample on dry paper at 48 hours of life) with elevated citrulline
and normal arginosuccinate acid, suggesting urea cycle disorder (UCD), specifically
type I citrullinemia as we can see in [Table 1]. At that time ammonia levels had risen to 243 µmol/L. Another plasma and urine sample
were collected for amino acid analysis; (results in [Table 2]) then, treatment of type I citrullinemia-oriented case was initiated with sodium
benzoate, sodium phenylbutyrate, l-arginine, and carnitine. Calory intake was maintained with glucose and lipids, with
protein restriction. Despite the initiation of the treatment, ammonia quickly rose
to a maximum of 875 µmol/L in the first 12 hours, requiring venous hemofiltration.
After this, it was finally possible to control hyperammonemia.
Table 1
Results of metabolic screening 48 h of life
|
Amino acids
|
μmol/L
|
Reference interval for 48 h of life
|
|
Alanine
|
327
|
124.32–419.24
|
|
Arginine
|
9.53
|
2.73–41.07
|
|
Citrulline
|
1010
|
5.21–27.07
|
|
Glutamine + lysine
|
1760
|
363.83–1145.86
|
|
Glutámic acid
|
306
|
121.93–464.41
|
|
Glicine
|
409
|
227.47–752.40
|
|
Leucine + isoleucine + hydroxyproline
|
117
|
53.78–206.34
|
|
Methionine
|
46.4
|
8.52–30.73
|
|
Ornithine
|
39.6
|
33.30–180.62
|
|
Phenylalanine
|
65.5
|
25.34–75.42
|
|
Proline
|
189
|
68.10–219.03
|
|
Succinylacetone
|
0.22
|
0.07–0.54
|
|
Tyrosine
|
115
|
27.47–187.58
|
|
Valine
|
107
|
49.55–232.38
|
|
Argininosuccínic acid
|
0.12
|
0.08–0.48
|
Table 2
Amino acid profile at 5 d of age
|
Amino acids
|
μmol/L
|
Normal values
|
|
Arginine
|
9
|
61 ± 27
|
|
Citrulline
|
4,002
|
19 ± 9
|
|
Glutamine
|
2,197a
|
506 ± 135
|
|
Lysine
|
438
|
154 ± 55
|
|
Methionine
|
347a
|
27 ± 9
|
|
Ornithine
|
14
|
79 ± 37
|
The patient needed intensive care with mechanical ventilation, inotropic support,
and hemofiltration for 3 days. Blood pressure normalized within 8 hours of the treatment.
From a neurological point of view: at admission, he was hypoactive with both limited
range of movement and response to stimulus. Altered consciousness, rapidly evolved
from stupor to drowsiness. Abnormal amplitude integrated electroencephalography (aEEG)
with a burst suppression pattern. On the second day, he presented with clinical seizures
of low amplitude clonisms of the head with acute increase work of breathing. It was
necessary to provide phenobarbital and levetiracetam bolus to control seizures, maintaining
levetiracetam as a prophylactic treatment. Significant clinical improvement was noticed
on the third day of admission, with continuous pattern on the aEEG, normal awareness
level, appropriate eye tracking, adequate peripheral and axial tone, present both
osteotendinous and archaic reflexes, harmonious and symmetrical movement of the four
limbs and normal strength. He had normal EEG. Brain magnetic resonance imaging showed
altered signal on basal ganglia with hyperintensity in T1 of nucleus pallidus and
hypointensity on white matter with punctiform hyperintensity lesions. Findings in
line with UCD[1] are shown in [Figs. 1] to [5].
Fig. 1 Axial T2-weighted image showing high intensity alteration on white matter with smaller
low intensity signals.
Fig. 2 T1-weighted low intensity signal on white matter and focal high intensity signal.
Fig. 3 (A and B) Axial and coronal, T2-weighted image showing low intensity of globi pallidi.
Fig. 4 (A and B) Axial and sagittal, T1-weighted high intensity signal of globi pallidi.
Fig. 5 (A and B) Normal MR spectroscopy. MR, magnetic resonance.
After control of HA, low protein intake (0.3 g/kg/d) was started with progressive
increase of dose up to 1.6 g/kg/d. Well-tolerated and daily ammonia check was normal.
Intravenous medication was changed to enteral l-arginine (350 mg/kg/d), carnitine (30 mg/kg/d), and glycerol phenylbutyrate. He was
discharged home with multidisciplinary follow-up with pending results of the genetic
study.
Discussion
The urea cycle is a metabolic pathway that transforms ammonia into urea. The result
of the catabolism of amino acids is ammonia, a high toxic compound that cannot be
excreted unless it is processed into a high solubility substance such as urea. Genetic
defects in the enzymes involved in the cycle can occur, the result is a UCD. These
can be[2]:
-
N-Acetyl glutamate synthase deficiency (NAGS; OMIM 237310).
-
Carbamoyl phosphate synthetase deficiency (CPS-1; OMIM 237300).
-
Ornithine transcarbamoylase deficiency (OTC; OMIM 311250).
-
Citrullinemia type I (deficiency of argininosuccinate acid synthase [ASS]; OMIM 215700).
-
Argininosuccinic aciduria (deficiency of argininosuccinate acid lyase [ASL]; OMIM
207900).
-
Argininemia (deficiency of arginase [ARG]; OMIM 207800).
We can include three deficiencies of membrane transporters:
-
Hyperornithinemia, hyperammonemia, homocitrullinuria syndrome (deficiency of the mitochondrial
ornithine transporter).
-
Lysinuria with protein intolerance (due to altered transport of dibasic amino acids).
-
Citrine deficiency or citrullinemia type 2 (aspartame-glutamate mitochondrial hepatic
transporter deficit; [Fig. 6]).
Fig. 6 Urea cycle in the liver. Ammonia reacts with bicarbonate and with N-acetyl glutamate to produce carbamoyl phosphate (CPS). The CPS yields its carbamoyl
group to ornithine to form citrulline. Citrulline is released to cytoplasm. The second
amyl group from aspartate is condensed with citrulline to form arginosuccinate, which
is hydrolyzed into free arginine and fumarate. The fumarate enters the Krebs cycle
and arginine hydrolyzes to form urea (excreted in the urine) and ornithine, which
re-enters the mitochondria to restart the cycle. Mitochondrial enzymes (upper part
of the cycle): N-acetyl glutamate synthetase (NAGS) essential co-activator of CPS-1; carbamoyl phosphate
synthetase (CPS-1); Ornithine transcarbamylase (OTC). Cytoplasmatic enzymes (or lower
part of the cycle): arginosuccinate synthetase (ASS); arginosuccinate lyase (ASL);
arginase (ARG). Ornithine transporter deficit (ORNT-a) produces HHH syndrome. HHH,
hyperornithinemia, hyperammonemia, homocitrullinuria.
In this case, given the increase in citrulline and the decrease in arginosuccinate,
the diagnostic suspicion is an alteration in arginine synthetase and therefore a type
I citrullinemia. Even so, regardless of the suspected diagnosis, the main acute manifestations
of the UCD are those derived from hyperammonemia (HA). Ammonia is a highly toxic product,
especially on the central nervous system. It is considered as a potentially lethal
metabolic emergency. The clinical syndrome of the newborn (which is the form of debut
in 60% of the cases) begins at 24 to 72 hours of life, producing decrease feeds, thermic
dysregulation, vomiting, impaired level of consciousness (drowsiness that evolves
into coma), and seizures. A common sign is central hyperventilation and respiratory
alkalosis. This may evolve to respiratory and cardiac failure.
An ammonia level >110 mmol/L in the neonatal period is considered pathological. In
the case of suspicion, therapeutic measures should be initiated immediately.[3] In our case, these measures were aimed at the diagnosis of suspected type 1 citrullinemia
which does not respond to cofactors or carglumic acid (Carbaglu).
Why High Blood Pressure?
The patient debuted with arterial hypertension as a lead symptom. Hypertension screening
was performed:
-
Heart disease: there were no differences in BP or SatO2 between upper or lower limbs. Chest X-ray without cardiomegaly or acute lung edema
was obtained. An emergency echocardiogram was performed showing only a concentric
hypertrophy of the left ventricle.
-
Acute renal failure, renal stenosis: Had normal renal function. Doppler ultrasound
of the renal veins was performed without alterations.
-
Intracranial hypertension/acute bleeding: normal heart rate. Normotensive fontanelle.
-
Cranial ultrasound was normal.
-
Endogenous production of catecholamines: abdominal ultrasound without masses. Normal
urine metanephrines.
After the diagnosis of suspected type I citrullinemia, we reviewed the pathophysiology
and previous literature. This disorder involves arginine deficiency. It cannot be
synthesized and forms an essential part of amino acid, as can be seen in [Fig. 7]. l-arginine acts as a substrate for nitric oxide synthetase to form endothelial nitric
oxide and citrulline.[4]
Fig. 7
l-arginine acts as a substrate for nitric oxide synthetase (ONS) to form endothelial
nitric oxide (NO) and citrulline.
A reduction in NO production plays a major role in vascular tone and hence increase
in BP.[4]
[5] As it can be seen in [Table 1], arginine levels at 48 hours of life were in the lower reference value. At that
moment, our patient was asymptomatic. At 5 days of age, when he debuted with hypertension,
arginine was below normal range. Once treatment was started, which included arginine
supplementation, the patient's BP normalized. The connection between hypertension
and UCD had barely been described, with little representation in this specific literature.
Recently, Teufel et al[6] described a series of 17 patients in which 81% of them presented with BP >95th percentile
at debut. They also, highlighted how this clinical parameter could be useful to discern
a UCD debut from a neonatal sepsis. Although the study involves a small series of
patients, it underlines and supports what we have seen in this particular case and
the importance of having present UCD as a differential diagnosis in a newborn with
high BP.
Conclusion
Hypertension and UCD maintain a clear pathophysiological relationship, barely described
in the literature, which can prove to be very useful in daily clinical practice.
