Chemical Pathology JC131: Paediatric Chemical Pathology Flashcards

1
Q

Children are not small adults

A

Different:

  1. ***Reference intervals
  2. ***DDx
  3. Tests
  4. Sample requirement + considerations
  5. Treatment + monitoring
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2
Q
  1. Reference intervals (RI)
A

Need to apply ***age-specific RI

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3
Q

Paediatric biochemical problems

A
  1. Neonatal jaundice (Cholestasis)
  2. Hyperlactatemia
  3. Hyperammonaemia
  4. Hypoglycaemia
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4
Q
  1. Neonatal jaundice (Cholestasis)
A

Causes:
1. Surgical
- Bile duct abnormalities
—> Need to exclude ***Biliary atresia (need to undergo surgery ASAP before <60 days)

  1. Medical
    - **Infections
    - **
    Toxins / drugs
    - Endocrine diseases
    - ***Inborn errors of metabolism (IEM)
    - Chromosomal abnormalities

Investigations:

  1. CBC
  2. Blood + Urine culture
  3. PT
  4. U+E, glucose
  5. ***Total + Unconjugated bilirubin
  6. Urinalysis (for reducing substances)
  7. ***Metabolic screening (if acutely unwell)
    - plasma NH3, glucose, lactate, acid-base, urinary pH, ketones, CXR
    - freeze plasma / urine for future analysis
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5
Q
  1. Hyperlactatemia
A
  1. Type A lactic acidosis
    - with hypoxia
  2. Type B lactic acidosis
    - without hypoxia
Acquired / Genetic causes
Acquired causes:
- ***Hypoxia
- Exercise
- Seizure
- Severe dehydration
- ***Infections
- Severe catabolic state
- Poisoning

Genetic causes:

  • Disorders of lactate-pyruvate oxidation
  • ***TCA cycle deficiencies
  • Respiratory chain defects
  • ***Mitochondrial diseases
  • Disorders of gluconeogenesis
  • Disorders of glycogen metabolism

Investigations:
1. ***Pyruvate

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6
Q

Pyruvate

A
  • Calculate ***Lactate-to-pyruvate ratio
  • Differentiate genetic causes from acquired causes
  • No need to test for pyruvate when ***lactate is normal
  • Must add accurate volume of blood into special bottle with ***perchloric acid immediately after blood taking for accurate measurement of pyruvate
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7
Q

***4. Hypoglycaemia

A
  • Low glucose
  • +/- Ketone
Also check:
1. Ketone
- Urine dipstix vs Quantitative measurement of ketone
- 2 types of Ketone:
—> ***Acetoacetate
—> ***Beta-hydroxybutyrate
  1. Insulin
    - make sure no haemolysis in the sample
  2. Glucose transfusion rate
    - mark on request form

Algorithm for evaluation of hypoglycaemia:
Hypoglycaemia confirmed —>
1. Urine ketones ++ to +++ (
Ketosis appropriate —> fatty acid oxidation ↑)
—> Urine organic acids (by GCMS)
—> **Excess urine organic acids —> **Maple syrup urine disease, Proprionic acidaemia, Methylmalonic acidaemia etc.
—> Non-diagnostic pattern
——> Large liver (Glycogen storage disease, Fructose-1, 6-bisphosphatase deficiency)
——> Normal liver (Accelerated starvation, GH / cortisol deficiency, Glycogen synthetase deficiency)

  1. Urine ketones 0 to + (**Hypoketosis: considered **inappropriate)
    - Measure Serum insulin
    —> Suppressed (i.e. normal response) —> **Fatty acid oxidation defect (Urine organic acids, Plasma acylcarnitines, Urine acylglycines)
    —> High —> **
    Hyperinsulinism, PHHI, Insulinoma —> Factitious causes: insulin >100, C-peptide low (∵ insulin is not endogenous)

簡單而言:
Hypoglycaemia —> 睇有無Ketosis (應該要有)
—> 有Ketosis —> Maple syrup urine disease / Glyocogen storage disease / Accelerated starvation
—> 無Ketosis —> Fatty acid oxidation defect / 太多Insulin令Fatty acid oxidation suppressed

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8
Q
  1. Hyperammonaemia
A

***UCD due to IEM

Causes:

  • Ornithine transcarbamylase deficiency —> p.R277Q: ***Orotic aciduria: High increase in orotic acid in urine
  • Arginase deficiency
  • Argininosuccinate lyase deficiency
  • Argininosuccinate synthetase deficiency
  • Rett syndrome

Typical presentations for ***Urea cycle defect (UCD):

  1. ***Low plasma urea
  2. ***High ammonia
  3. ***Low arginine, High glutamine (記: LAHG)
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9
Q

Inborn errors of metabolism (IEM)

A

Cyclic metabolic pathways:

  1. TCA cycle
  2. Urea cycle

Linear metabolic pathways:

  1. Glycolytic pathway
  2. Gluconeogenesis pathway
  3. Glycogenolysis pathway

IEM:
- Phenotypically + Genetically heterogeneous group of disorders
- Causes: **Defective enzyme / transporter in metabolic pathways
—> **
metabolic malfunction / accumulation of ***toxic intermediate metabolites

15 groups of IEM (SSIEM)
Disorders of:
1. AA + peptide metabolism
2. Carbohydrate metabolism
3. Fatty acid, Ketone body metabolism
4. Energy metabolism
5. Metabolism of purines, pyrimidines, nucleotides
Etc.

Inheritance:
- ***AR (mostly)
—> both copies of defective gene in parent (both carriers)
—> 25% inheriting both defective genes

Epidemiology:

  • Individually rare, collectively common
  • substantial patient burden, present in all ethnic groups
  • 1:4000 newborns
  • 1:4122-7580 in HK

Presentation:

  • Early (at birth, early infancy, childhood) (but some can present in adulthood)
  • **Non-specific clinical symptoms (esp. in neonatal period) (e.g. appetite problems, vomiting, acute / chronic encephalopathy, myopathy, hypoglycaemia, hepatic syndromes) —> **rule out sepsis pattern
  • Benefit from prompt recognition, diagnosis, treatment
  • **Newborn screening becoming **gold standard worldwide for detecting IEM
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10
Q

Screening methods of IEM

A
  1. Conventional screening test
    - one analysis of one metabolite (e.g. PKU)
  2. Current screening test: **Profile test
    - many metabolites for different diseases in 1 analysis
    - by **
    Tandem mass spectrometry (MS/MS) —> more cost effective
    - Dried blood spot broad spectrum metabolic screening
    —> clinical indications:
    —> expanded newborn screening, **failure to thrive, **neurological abnormalities e.g. **developmental delay, hearing / visual impairment, **dysmorphism etc.
    —> need to be highly suspicious of IEM if a case cannot be explained by other clinical features

Major metabolic investigations:

  1. ***Plasma amino acids (PAA)
  2. Plasma acylcarnitines (PAC)
  3. ***Urine organic acids (UOA)
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11
Q

Diagnosis + Management of IEM

A

Diagnosis:
Confirmatory test
- ***Biochemical test (mainly)
- Genetic testing (supplemental)

Management:

  1. ***Dietary control
  2. ***Enzyme replacement therapy
  3. Steroid treatment
  4. Surgical: Liver + Kidney transplantation
  5. Genetic counselling
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12
Q

General guidelines to approach patient suspected of IEM

A
  1. Consider IEM in parallel with more common conditions
  2. Aware of symptoms that persistent / remained unexplained after initial treatment and usual investigations performed
  3. Suspect any ***neonatal death many possibly due to IEM esp. those attributed to sepsis
  4. Carefully review all autopsy findings
  5. Not to confuse a symptom / a syndrome with etiology
  6. Remember that IEM can present at ***any age
  7. Know that most are hereditary + transmitted as recessive disorder, majority appear as sporadic because of small size in sibships in developed countries
  8. Initially consider inborn errors amenable to treatment (those that cause intoxication)
  9. Undertake only those investigations that are able to diagnose treatable IEM in acute / emergency situation
  10. Obtain help from specialised centres
  11. Do not miss a treatable disorder
  12. First take care of patient (emergency treatment) —> then family (genetic counselling)
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13
Q

3 major IEM groups

A

Based on pathophysiological features:
Group 1: Leading to **intoxication
Group 2: **
Energy metabolism defects
Group 3: Involving ***complex molecules

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14
Q

Expanded newborn screening

A

Classic screening criteria:
- Wilson and Jungner criteria

Revisited emerging screening criteria:

  1. Screening programme should respond to a recognised need
  2. Objectives of screening should be defined at the outset
  3. Defined target population
  4. Scientific evidence of screening programme effectiveness
  5. Integrate education, testing, clinical services and programme management
  6. Quality assurance, with mechanisms to minimise potential risks of screening
  7. Ensure informed choice, confidentiality, respect for autonomy
  8. Promote equity + access to screening for entire target population
  9. Programme evaluation should be planned from the outset
  10. Overall benefits should outweigh harm

Screening programme in HK:

  1. ***Congenital hypothyroidism
  2. ***G6PD
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15
Q

Preventable morbidities + mortalities

A
  1. ***Tyrosinaemia type 1
    - delay in diagnosis —> need liver transplantation
    - effective drugs available to avoid liver transplantation
  2. ***Very long chain Acyl-CoA dehydrogenase deficiency
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16
Q

Screening workflow of Newborn screening programme

A
  1. Parental education
    - Information delivery + education about NBS
  2. Obtain consent
  3. ***Blood spot sampling
  4. Transportation of blood samples to lab
  5. Dried blood samples preparation + testing in expanded NBS lab
  6. Results interpreted + reported by chemical pathologist
  7. Recalling screening positive cases + taking blood for ***repeat testing
  8. Diagnostic confirmatory testing
  9. Continuous management + monitoring
  10. Assess outcomes + result of NBS programme
17
Q

Summary

A
  1. Neonatal jaundice (Cholestasis) —> Rule out Biliary atresia
  2. Hyperlactatemia —> 睇Pyruvate
  3. Hyperammonaemia —> 睇Urea, Arginine, Glutamine
  4. Hypoglycaemia —> 睇Ketone (Acetoacetate, Beta-hydroxybutyrate), Insulin