Chemical Pathology JC131: Paediatric Chemical Pathology Flashcards
Children are not small adults
Different:
- ***Reference intervals
- ***DDx
- Tests
- Sample requirement + considerations
- Treatment + monitoring
- Reference intervals (RI)
Need to apply ***age-specific RI
Paediatric biochemical problems
- Neonatal jaundice (Cholestasis)
- Hyperlactatemia
- Hyperammonaemia
- Hypoglycaemia
- Neonatal jaundice (Cholestasis)
Causes:
1. Surgical
- Bile duct abnormalities
—> Need to exclude ***Biliary atresia (need to undergo surgery ASAP before <60 days)
- Medical
- **Infections
- **Toxins / drugs
- Endocrine diseases
- ***Inborn errors of metabolism (IEM)
- Chromosomal abnormalities
Investigations:
- CBC
- Blood + Urine culture
- PT
- U+E, glucose
- ***Total + Unconjugated bilirubin
- Urinalysis (for reducing substances)
- ***Metabolic screening (if acutely unwell)
- plasma NH3, glucose, lactate, acid-base, urinary pH, ketones, CXR
- freeze plasma / urine for future analysis
- Hyperlactatemia
- Type A lactic acidosis
- with hypoxia - 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
Pyruvate
- 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
***4. Hypoglycaemia
- Low glucose
- +/- Ketone
Also check: 1. Ketone - Urine dipstix vs Quantitative measurement of ketone - 2 types of Ketone: —> ***Acetoacetate —> ***Beta-hydroxybutyrate
- Insulin
- make sure no haemolysis in the sample - 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)
- 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
- Hyperammonaemia
***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):
- ***Low plasma urea
- ***High ammonia
- ***Low arginine, High glutamine (記: LAHG)
Inborn errors of metabolism (IEM)
Cyclic metabolic pathways:
- TCA cycle
- Urea cycle
Linear metabolic pathways:
- Glycolytic pathway
- Gluconeogenesis pathway
- 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
Screening methods of IEM
- Conventional screening test
- one analysis of one metabolite (e.g. PKU) - 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:
- ***Plasma amino acids (PAA)
- Plasma acylcarnitines (PAC)
- ***Urine organic acids (UOA)
Diagnosis + Management of IEM
Diagnosis:
Confirmatory test
- ***Biochemical test (mainly)
- Genetic testing (supplemental)
Management:
- ***Dietary control
- ***Enzyme replacement therapy
- Steroid treatment
- Surgical: Liver + Kidney transplantation
- Genetic counselling
General guidelines to approach patient suspected of IEM
- Consider IEM in parallel with more common conditions
- Aware of symptoms that persistent / remained unexplained after initial treatment and usual investigations performed
- Suspect any ***neonatal death many possibly due to IEM esp. those attributed to sepsis
- Carefully review all autopsy findings
- Not to confuse a symptom / a syndrome with etiology
- Remember that IEM can present at ***any age
- Know that most are hereditary + transmitted as recessive disorder, majority appear as sporadic because of small size in sibships in developed countries
- Initially consider inborn errors amenable to treatment (those that cause intoxication)
- Undertake only those investigations that are able to diagnose treatable IEM in acute / emergency situation
- Obtain help from specialised centres
- Do not miss a treatable disorder
- First take care of patient (emergency treatment) —> then family (genetic counselling)
3 major IEM groups
Based on pathophysiological features:
Group 1: Leading to **intoxication
Group 2: **Energy metabolism defects
Group 3: Involving ***complex molecules
Expanded newborn screening
Classic screening criteria:
- Wilson and Jungner criteria
Revisited emerging screening criteria:
- Screening programme should respond to a recognised need
- Objectives of screening should be defined at the outset
- Defined target population
- Scientific evidence of screening programme effectiveness
- Integrate education, testing, clinical services and programme management
- Quality assurance, with mechanisms to minimise potential risks of screening
- Ensure informed choice, confidentiality, respect for autonomy
- Promote equity + access to screening for entire target population
- Programme evaluation should be planned from the outset
- Overall benefits should outweigh harm
Screening programme in HK:
- ***Congenital hypothyroidism
- ***G6PD
Preventable morbidities + mortalities
- ***Tyrosinaemia type 1
- delay in diagnosis —> need liver transplantation
- effective drugs available to avoid liver transplantation - ***Very long chain Acyl-CoA dehydrogenase deficiency
