Transcript Pediatric Puzzler - LSU School of Medicine

October 2007



CC: “I keep vomiting”
HPI: 9 yo male presents with one week history
of intermittent vomiting. He was punched in
the head one week prior but had no outward
signs of injury, though he did have emesis on
the day of the injury.
Since then he has vomited on and off. The
emesis was NB NB.

Three days prior to this visit he stayed home
from school because of decreased appetite
and malaise.

He went to school the next day but was sent
home because of nausea.

That evening he was well until after dinner
when he had multiple episodes of emesis.

Of note… no headaches and no visual
changes



Mom finally called the pediatrician and was
sent to the ER.
The patient had a head CT done and was
given IVF. The CT was read as normal.
He was discharged home.

During your shift in the CHER, the patient is
brought in by his mom for lethargy.

She said he was watching cartoons and was
slow to answer questions.

He became listless and lethargic. He required
lots of stimulation to answer questions.

He was noted to have one (small) episode of
bilious emesis as well.







PMH: mild intermittent asthma. No recent
illnesses
Meds: Albuterol PRN, last use 1 month ago
Imm: UTD
Dev: Normal, does well in school
Fam Hx: noncontributory
Social: Lives with mom, dad and brother in
Metairie.
Travel Hx: none, occasionally goes camping
with sibling.








Ht: 143 cm (95%) Wt: 27 kg (50%)
T 98.9 HR 86 RR 22 BP 100/70
Gen: pale, thin, does not open his eyes when you
ask him to but follows other motor commands
“raise your leg”
HEENT: no nuchal rigidity or meningeal signs
CV: rrr no murmur
Chest: CTAB
Abd: benign
Skin: no rash, icterus, track marks, petechiae, etc

Neuro:
◦ MS: responds to painful stimuli, nonverbal,
follows some commands
◦ CN: PERRL, no photophobia, EOMi, symmetrical
face, tongue midline
◦ Tone: normal
◦ Motor: 5/5 in all extremities when pt would
cooperate
◦ Sensory: Appeared intact
◦ DTR: 2+ everywhere except 3+ patellar B and 4-5
beats of ankle clonus B
Top 3 Differentials
&
Top 3 Tests
Intermittent Vomiting x 1 wk
Acute Mental Status Changes
In an otherwise well child

Encephalopathy
◦
◦
◦
◦
◦
Hypoxic ischemia
Hypoglycemia
Cerebral Edema
Increased ICP
Toxins

Acute CNS infection

Postinfectious

◦ Exogenous
◦ Endogenous
 Renal failure?
 Liver failure?

◦ Bacterial
◦ Viral
◦ Mycoplasma
◦ Varicella
◦ Etc
Toxins



IEM
◦ Urea metabolism
◦ Inherited Organic
acidemias
Reye Syndrome
Complex migraine
Temporal lobe
epilepsy

ER visit day prior:
◦ BUN 17, Cr 0.7
◦ HCO3 20
◦ Other electrolytes, LFTs,
Amylase, Lipase, CBC was
normal
◦ UA: SG 1.030,1+ ketones
◦ KUB: wnl
◦ Head CT: wnl
Bolus given. Sent Home

Today:
◦ All the same labs were
repeated
 Results were the same!
◦ Utox: negative
◦ LP:
 CSF was normal
Bolus given. Admitted.



Patient becomes more alert after bolus.
He asks for food and is loving the Children’s
Hospital TV channels.
Speech is dysarthric
◦ Mom says that this is NOT his normal speech
◦ BUT she is happy that he is acting more like himself



You’re called because the patient becomes
agitated.
He is kicking, screaming, and pulling at his
IV.
Why this acute decompensation???
What do you do?
Any further tests?
Has anything entered into your
index of suspicion?

CMP
◦ normal

Ammonia
◦ 220 umol/L (nl <30)
◦ This level was repeated and confirmed
9 yo male with acute mental
status changes, vomiting and
hyperammonemia.

Ammonia released from catabolism of amino
acids
◦ Cell breakdown
◦ Excess dietary protein


Excreted as urea (kidney) via urea cycle as
conversion of glutamate to glutamine (liver)
Increased ammonia almost exclusively toxic
to the brain

NH3 must be measured in every sick child who is
encephalopathic for an apparently unknown
cause

Otherwise hyperammonemia may be missed and
the child deprived of treatment.

Signs and Symptoms (>100-200 umol/L)
◦
◦
◦
◦
◦
◦
Lethargy
Confusion
Vomiting
Acute ataxia
Hyperactivity
Coma (>300)

In healthy neonates, NH3 is <100
◦ If sick can be up to 180umol/L
◦ Suspect IEM in neonates if >200umol/L

In older children, NH3 is <80umol/L
(nl=<35)
◦ Think IEM if >100umol/L



Blood sample must be taken as uncuffed
venous or arterial, kept on ice, and
analyzed immediately.
It’s put in a green or purple top tube
False elevations are common
◦ Hemolysis
◦ Delay in processing
◦ Exposure to room temp
Any guesses?

Inadequate function of urea cycle
◦ Hepatocellular dysfunction
◦ Deficient urea cycle enzymes
 Acquired
 Reye
 Drugs (valproate, chemotherapy)
 Inherited
 Urea cycle enzyme deficiency
 Organic acidemia
 Fatty acid oxidation defects


UTI from urease-producing organisms
Increased muscle activity
◦ Respiratory distress and seizures (not >180umol/L)

Blood gas

Urine

BMP
◦ Respiratory alkalosis as NH3 stimulates resp center
◦ Metabolic acidosis think organic acidemia vs FAO d/o
◦ Ketones- organic acidemia
◦ Anion gap

Liver function tests
Plasma and urinary amino acids
Urine organic acids
Acylcarnitine profile

Plasma carnitine level



◦ Fatty acid oxidation defects
Urine OA came back
Elevated orotic acid
Plasma AA
Elevated glutamine level
Low/Absent citrulline



Most common urea cycle disorder
The ammonia that is not detoxified by the
urea cycle is converted to glutamine and
glutamate.
Increased glutamine in astrocytes  osmotic
shift of fluid into astrocytes 
swelling/cerebral edema

The goal of the urea cycle is to breakdown
ammonia into urea.

This process takes place in the hepatocytes.

It’s that simple!

Is an x-linked disorder (1/30,000)
◦ The other urea cycle defects are AR
◦ Does rarely occur in girls! 10% of female carriers
become symptomatic

Typical presentation
◦ Males in first week of life with lethargy, vomiting,
hypothermia (looks like sepsis)
◦ Respiratory Alkalosis

Late Onset Disease
◦ Typically females with vomiting, lethargy and
behavioral changes




Symptoms can occur following viral illness,
childbirth and use of VPA.
Onset of symptoms frequent at the time of
weaning from breast milk
CT/MRI can show evidence of acute ischemia.
Generalized high intensity in white matter,
brainstem, basal ganglia and bilateral frontal
lobes.
EEG- slowing, can show triphasic waves





Triad of encephalopathy, respiratory alkalosis
and hyperammonemia.
NH3 levels (> 500 uM hemizygotes), > 100 uM
heterozygotes.
Normal anion gap respiratory alkalosis
Serum amino acids: low citrulline, arginine,
increased glutamine. Urine: high orotic acid.
DNA diagnosis available




Stop protein intake!
Provide adequate calories to prevent
catabolism (10% dextrose)
Only use lipids if fatty acid oxidation ruled out
Generous amounts of fluids to promote
ammonia excretion




Sodium benzoate and sodium phenylacetate
to promote ammonia excretion
If NH3 >400 or no improvement in 8hrshemodialysis or hemofiltration
NO exchange transfusion, blood product
transfusion or drugs that impair liver
function
Call genetics

Plasma glutamine is useful marker for effective
therapy (<1000umol/L)

Decrease protein intake acutely during infection

Ibuprofen instead of Tylenol


Diet- low protein. Most patients can receive less
than the RDA of protein and maintain good
growth
Ensure essential amino acids and
vitamins/minerals

What triggered his presentation?
◦ Intermittent vomiting associated with increased
protein intake
◦ He was well in the mornings because of overnight
fast.
◦ Vomiting occurred later in the day because of
eating

Overall trigger was mild viral illness
◦ Not from the school bully! 



June 2007… AG a 7yo female was transferred
to the PICU with a 3 day history of lethargy
progressing to coma.
Dialysis was started for hyperammonemia
She was diagnosed with OTC deficiency
◦ Confirmed heterozygote by DNA
◦ Apparently, she lived on a vegan commune with her
mom and spent the weekend with dad chowing
down on burgers.
◦ She was also on valproic acid for epilepsy.
◦ Both factors contributed to the presentation!
Inborn Errors of Metabolism
Diagnostic Approach
•KETONES NEGATIVE
ENCEPHALOPATY < 24 HRS
•HEPATOSMEGALY
•HYPOGLYCEMIA
INFANT/CHILD WITH
SUSPECTED
METABOLIC DISEASE
NON KETOTIC
HYPERGLYCINEMIA
METABOLIC
ACIDOSIS
•HYPOGLYCEMIA
•HYPERCHLOREMIA
•METABOLIC ACIDOSIS
•HYPERBILIRUBINEMIA
•REDUCING SUBTANCE IN URINE
GALACTOSEMIA
•METABOLIC
ACIDOSIS
•KETONURIA
•+/- HYPERAMMONEMIA
•LOW KETONES
FATTY ACID
OXIDATION
DEFECT
GLYCOGEN
STORAGE
DISEASE
ORGANIC
ACIDEMIA
•RESPIRATORY ALKALOSIS
•HYPERAMMONEMIA
•NEGATIVE KETONES
UREA CYCLE
DISEASE
Thank you to Dr. Allison
Conravey and Dr. Marble for
their expertise!