Red Flags Part II

Lab Testing in
Metabolic Disease:
Spotting the Red Flags, Part II
Mark Korson, MD
VMP Genetics, LLC

Disclosures
MARK KORSON does not have anything to disclose.

1. Review how simple biochemical tests
indicate important pathophysiologic
scenarios.
2. Describe patterns of routine biochemical
testing that can increase suspicion about an
underlying metabolic disease
3. Recognize the uncommon physiological
significance of certain chemistry tests
OBJECTIVES
© Copyright 2020. VMP Genetics. All rights reserved

© Copyright 2019 VMP Genetics. All rights reserved
Urinalysis - blood

An otherwise healthy athletic teenager complains
of his muscles aching after football work-outs.
He says that his arms and shoulders feel less
strong than they did during last year’s season.
After one strenuous practice (a lot of tackling), he
develops intense pain in his shoulders and upper
arms and thighs.
CASE #1

Two hours later, he voids a painless “bloody”
urine. Upon direct questioning, the color is more
cola-colored than red blood.
A urinalysis shows large blood and protein.
Case 1

• Think RENAL
BLOOD ON A URINALYSIS
U/A – blood
Micro - RBCs

• Think RENAL
BLOOD ON A URINALYSIS
U/A – blood
Micro - RBCs
U/A – blood
Micro – no RBCs
Think…
A. Heart
B. Muscle
C. Liver
D. Bladder

Two hours later, he voids a painless “bloody”
urine. Upon direct questioning, the color is more
cola-colored than red blood.
A urinalysis shows large blood and protein.
Diagnosis – carnitine palmitoyltransferase (CPT) II
deficiency, a defect in fatty acid oxidation
Case 1

CARNITINE PALMITOYLTRANSFERASE (CPT) II DEF’Y
• Muscles convert fat to energy
during prolonged exercise
Physiology
• With exercise:
• Muscle pain, weakness
• Myoglobinuria
• Cardiomyopathy
Symptoms

SUMMARY POINT
• Blood on a dipstick should be confirmed
by checking for RBCs in a microscopic
examination
• If none are seen, it is not “blood”
• Think myoglobin, not hemoglobin

Transaminases
(AST, ALT)

Lab tests:
• CBC: Hgb=13.3, WBC=10.5, Plts=238
• Lytes: Na=139, K=4.5, Cl=92, HCO3=29
• BUN=10.6, creatinine=8.8
• AST=4580 (NL=5-40), ALT=1200 (NL=5-40)
• Bilirubin: Total=0.9, direct=0.1
• Alkaline phosphatase=140 (NL=44-147)
Cairns AP, et al.Nephrol Dial Transpl.2000.

Lab tests:
• CBC: Hgb=13.3, WBC=10.5, Plts=238
• Lytes: Na=139, K=4.5, Cl=92, HCO3=29
• AST=4580 (NL=5-40), ALT=1200 (NL=5-40)
Based on these lab
data, which organ
system worries you
the most?
A. Liver
B. Kidneys
C. Bone
D. Heart
E. Muscle

Lab tests:
• CBC: Hgb=13.3, WBC=10.5, Plts=238
• Lytes: Na=139, K=4.5, Cl=92, HCO3=29
• AST=4580 (NL=5-40), ALT=1200 (NL=5-40)
Based on these lab
data, which organ
system worries you
the most?
A. Liver?
B. Kidneys
C. Bone
D. Heart
E. Muscle

A 41 year old man experiences dark urine for
three days, associated with extreme fatigue, pain
and heaviness in his legs. The symptoms were
triggered after a significant amount of heavy work
while moving house the previous week.
There is a history of similar symptoms following
moderate exercise during the previous 20 years.
CASE #2

Past medical history significant for two acute
episodes of gout. On no medications. Ex-smoker
(5 years). Drank ~10 units of alcohol per week.
Examination:
• HR=80/min, BP=160/82
• Normal muscle tone, power. Normal
sensation. Normal reflexes.
Case 2

Lab tests:
• CBC: Hgb=13.3, WBC=10.5, Plts=238
• Lytes: Na=139, K=4.5, Cl=92, HCO3=29
• AST=4580 (NL=5-40), ALT=1200 (NL=5-40)
Case 2

Lab tests:
• CBC: Hgb=13.3, WBC=10.5, Plts=238
• Lytes: Na=139, K=4.5, Cl=92, HCO3=29
• AST=4580 (NL=5-40), ALT=1200 (NL=5-40)
• CK=600 (NL=25-180)
• Aldolase=22.2 (NL=1.2-7.6)
Case 2

Diagnosis:
• Very long chain acyl CoA dehydrogenase (VLCAD)
deficiency
Case 2

VERY LONG CHAIN ACYL CoA DEHYDROGENASE (VLCAD) DEF’Y
• A defect in fatty acid oxidation
(conversion of fat to ketones)
VLCAD def’y
• The liver converts fat to ketones
during fasting or poor calorie intake
• Muscles convert fat to energy
during prolonged exercise
Physiology

VERY LONG CHAIN ACYL CoA DEHYDROGENASE (VLCAD) DEF’Y
• Reduced fasting tolerance
• Hypoglycemia, altered mental
status with prolonged fasting/poor
fat intake
• With exercise:
• Muscle pain, weakness
• Myoglobinuria
• Cardiomyopathy
Symptoms

TRANSAMINASES
• Indicators of hepatocyte integrity
• If abNL, may reflect hepatoxicity
• Abnormal in many (metabolic) diseases
Significance

TRANSAMINASES
• Indicators of hepatocyte integrity
• If abNL, may reflect hepatoxicity
• Abnormal in many (metabolic) diseases
Significance
• Concentrated in the liver but are
also found in:
• Skeletal muscle
• Myocardium
• Kidney
Not necessarily
liver-specific

A neonate is admitted to the NICU on day 3 of
life in severe congestive heart failure. On
examination, he is non-dysmorphic and
lethargic. Weight=2.2 kg.
Echocardiogram identifies a
dilated cardiomyopathy with
an ejection fraction of 20%.
CASE #3
Courtesy SIMD-NAMA 2019

Lab findings:
• Venous gas: pH=7.2, HCO3=17
• Glucose=25
• AST=230, ALT=200
• CK>500
Metabolic testing – VLCAD deficiency (a defect
in long chain fatty acid oxidation)
Courtesy SIMD-NAMA 2019
Case 3

A newborn is born at term to consanguineous
parents. Apgar score: 91 and 105. Weight=2.93
kg. On day 2, he developed lethargy and apathy.
Katz.MolecGeneticsMetabolism.2017
Lab findings:
• Glucose=normal
• AST=240, ALT=58
• CK=13,445
CASE #4

He later developed left ventricular hypertrophy
and a pericardial effusion.
Metabolic testing – VLCAD deficiency
Katz.MolecGeneticsMetabolism.2017
Case 4

SUMMARY POINT
• When AST and ALT are high, look carefully
at other markers of liver disease.
• If AST and ALT are the only ones elevated,
and/or if there are concerns about
muscle symptoms, order a CK

Bilirubin

CASE #5
A female is born to consanguineous parents (first
cousins) at term following an unremarkable
pregnancy. Normal Apgar scores. Birth
weight=3300 gm.
Develops jaundice on day 2 and starts having
feeding problems. Admitted to hospital on day 3
because of fever and jaundice. On examination,
she is lethargic and has a weak suck.
Kundak.Turk J Hemat.2012

Lab tests:
• CBC: Hgb=15.7, WBC=10.3, Plts=233
• Electrolytes: Na=147, K=4.5
• Total bilirubin=15.6, direct=1.0
• AST=1367, ALT=504
Case 5

Lab tests:
• CBC: Hgb=15.7, WBC=10.3, Plts=233
• AST=1367, ALT=504
Case 5
Based on the nature of
the hyperbilirubinemia,
this baby is not likely to
have galactosemia.
A. True
B. False

…causes a direct
hyperbilirubinemia”
“Metabolic
liver disease…
ASSESSMENT OF LIVER DISEASE / DYSFUNCTION

• …causes a direct
hyperbilirubinemia”
“Metabolic
liver disease…
• True but it starts as an
unconjugated hyperbilirubinemia

Age (days of life)
Direct/
Total
Bilirubin
Ratio
0 4 102 8
0.2
0.4
0.6
0.8
1.0
Galactosemia:
Direct / Total Bilirubin (n=27)

Lab tests:
• CBC: Hgb=15.7, WBC=10.3, Plts=233
• AST=1367, ALT=504
• Urine reducing substances positive
Confirmation – Galactose-1-phosphate
uridyltransferase low
Diagnosis - galactosemia
Case 5

SUMMARY POINT
• Don’t rule out a metabolic disease just
because the patient presents with
primarily an unconjugated
hyperbilirubinemia…

GALACTOSEMIA
• A defect in metabolizing galactose,
a component of milk sugar (lactose)
GALT def’y
• Poor feeding, failure to thrive
• Liver disease  failure
• Cataracts
• Sepsis risk in the newborn period
Symptoms

There is a concern for a diagnosis of
galactosemia. Cow’s milk feedings are held.
Which ONE of the following actions would be
your next move?
A. Molecular DNA testing to confirm the diagnosis
B. Complete sepsis work-up
C. Eye examination for cataracts
D. Assess for coagulopathy
CASE #6

There is a concern for a diagnosis of
galactosemia. Cow’s milk feedings are held.
Which ONE of the following actions would be
your next move?
A. Molecular DNA testing to confirm the diagnosis
B. Complete sepsis work-up
C. Eye examination for cataracts
D. Assess for coagulopathy
Case 6

Lab tests:
• CBC: Hgb=15.7, WBC=10.3, Plts=233
• AST=1367, ALT=504
• Urine reducing substances positive
• PT>60 sec; INR>6; aPTT=88 sec
Diagnosis – classical galactosemia Kundak.Turk J Hemat.2012
Case 6

COAGULATION MEASUREMENTS
• An important indicator of
hepatic synthetic function
Significance
• Transaminase and bilirubin levels
do not predict and do not
correlate with PT, INR, PTT
Caution!

A male infant presents with lethargy. His belly is
distended due to ascites and his liver edge is
irregular and firm at 5 cm below the right costal
margin.
• AST=65
• Bilirubin: total=2.1, direct=0.99
• PT=26.8 sec, INR=61.1 sec
Case #7 - TYROSINEMIA TYPE I
Rashad.SudJPediatr.2011

REMINDER
• When assessing a patient for possible
metabolic liver disease, always assess all
aspects of liver function.

• AST, ALT
• Alkaline phosphatase
(5’-nucleotidase and GGTP)
• Bilirubin, total and direct
• PT, INR, PTT
• Albumin
Tests

• AST, ALT
• Alkaline phosphatase
(5’-nucleotidase and GGTP)
• Bilirubin, total and direct
• PT, INR, PTT
• Albumin
• ⍺-fetoprotein
• Glucose, NH3
Tests

The anion gap (electrolytes)
Urinalysis - pH

What is the most common cause
of a metabolic acidosis?

PRIMARY METABOLIC
ACIDOSIS
INCREASED ANION GAP NORMAL ANION GAP
- GI disease

PRIMARY METABOLIC
ACIDOSIS
- GI disease
- Renal disease
- Metabolic disease

PRIMARY METABOLIC
ACIDOSIS
- GI disease
- Renal disease
- Metabolic disease
- Shock, dehydration
- Starvation
- Poisons, toxins
- Metabolic disease

PRIMARY METABOLIC
ACIDOSIS
INCREASED ANION GAPINCREASED ANION GAP
- Shock, dehydration
- Starvation
- Poisons, toxins
- Metabolic disease
ORGANIC ACIDEMIAS
CONGENITAL LACTIC ACIDEMIAS

PRIMARY METABOLIC
ACIDOSIS
NORMAL ANION GAP
- GI disease
- Renal disease
- Metabolic disease
METABOLIC LIVER DISEASE
MITOCHONDRIAL DISEASE
CYSTINOSIS

THE “ANION GAP”
There is no “anion gap” really…

THE ANION GAP
• Difference between measured
anions and cations in the blood
Definition
Calculation • Anion gap = Na - (Cl + HCO3)
• Anion gap = 140 - (105 + 25)
• Anion gap = 10
• Normal anion gap = 10-15

THE NON-ANION GAP ACIDOSIS
Anion gap = Na - (Cl + HCO3)
Anion gap = 140 - (115 + 10)
Anion gap = 15
HIGH
NORMAL
LOW
 Bicarbonate loss (urine or stool)

THE ANION GAP ACIDOSIS
Anion gap = 140 - (105 + 10)
Anion gap = 25
NORMAL
HIGH
LOW
 Anion accumulation

THE ANION GAP ACIDOSIS
Anion gap = 140 - (105 + 10)
Anion gap = 25
 Anion accumulation
(lactate, ketones, organic acids,
toxins…)
NORMAL
HIGH
LOW

A 6 month old infant male, product of a healthy
pregnancy/labor/delivery, is found to have a
distended belly at 3 months. By that time, he has
lost 1 kg of weight and is failing to thrive. He
continues to feed every 3-4 hours day and night.
At 5 months of age, the liver is noted to be
enlarged. He is evaluated in the ED shortly after
that for fever and upper respiratory symptoms.
He presents to the ED, looking ill. Last feeding
~3 hours prior to arrival.
CASE #8

Lab tests:
• Glucose=39 mg/dL
• Electrolytes: Na=141, K=3.7, Cl=112,
HCO3=15
• ALT=118, AST=274
• Other liver functions normal
• Lactate=3.6 mmol/L (NL<2.2)
• Urinalysis: pH=6.5
Case 8

Lab tests:
HCO3=15
• ALT=118, AST=274
Anion gap = 14 (NL)
Case 8

Lab tests:
HCO3=15
• ALT=118, AST=274
Based on these
clinical/lab data, this
patient has liver disease.
Which other organ are
you worried about?
A. Brain
B. Kidneys
C. Eyes
D. Heart
E. Muscle
Case 8

Lab tests:
HCO3=15
• ALT=118, AST=274
Diagnosis – glycogen storage
disease type I
Based on these
clinical/lab data, this
patient has liver disease.
Which other organ are
you worried about?
A. Brain
B. Kidneys
C. Eyes
D. Heart
E. Muscle
Case 8

Glucose + Ketones

Three glucose-ketone scenarios:
A. The septic newborn:
• Blood glucose=32 mg/dL
• Urine ketones=trace
B. The 3 month old child with
gastroenteritis and dehydration:
• Urine ketones=1+
C. The septic newborn:
• Urine ketones=4+
CASE #9
All are abnormal clinical
situations but which of
the glucose-ketone
relationships are
pathological?
A. A, B, C
B. A, B
C. B, C
D. A, C
E. A

HYPOKETOTIC HYPOGLYCEMIA

HIGH Insulin
State
LOW Insulin
State

HIGH Insulin
State
FAT FATTY
ACIDS
KETONES

HIGH Insulin
State
• Insulin tumor
• Infant of DM mother
• Beckwith-Wiedemann
syndrome
• Iatrogenic

FAT FATTY
ACIDS
KETONES
LOW Insulin
State

LOW Insulin
State
• Fatty acid oxidation
defects
• Glycogen storage disease
type I

• Immaturity in fatty acid
oxidation  reduced
production
• Rapid metabolic rates 
increased
consumption/uptake
• …hypoketotic hypoglycemia
is normal
In neonates…
WHAT’S THE STORY WITH NEONATAL KETOGENESIS?

• Hypoketosis is normal
• Significant ketosis is not
normal
• Absent or inadequate ketosis
is never normal in a very
catabolic or hypoglycemic
child
In neonates…
KETONES – “THE RULES”
Beyond 2-3
months of age…

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Red Flags Part II

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