Metabolism Flashcards
Presentation Metabolic Disorders
Unexpected severe presentation of common illness Significant metabolic acidosis Unexplained respiratory alkalosis Hypoglycaemia Cardiac failure / cardiomyopathy Hepatomegaly/hepatosplenomegaly Drowsiness, coma, irritability Early onset seizure Dysmorphic features Developmental regression or loss of skills Sudden unexplained death
First line Ix suspected metabolic disorder
Bloods:
- Aminoacids and acyl carnitines (urea cycle disorder, organic acidaemia, aminoacidopathy)
-Ammonia (urea cycle disorder)
-Beutler screning test (galactosaemia)
-Very long chain fatty acids (peroxisomal disorder)
-White cell enzymes (dysmorphism, organomegaly, learning difficult, developmental regression)
-lactate (mitochondrial, glycogen storage disorder)
Urine:
-Organic acids (organic acidaemia, fatty acid oxidation disorder)
-Amino acids (tubulopathy, cystinosis)
-Glycoaminoglycans and oligosaccharides (mucopolysaccharidoses, oligosaccharidoses)
Management principles of metabolic disorder
Symptomatic therapy .e.g. antivonvulsants, analgaesua
Specific therapy .e.g. ammonia scavengers
Enzyme replacement
Dietary manipulation principles in metabolic disorder
Supply of deficient product
Preventing toxic accumulation
Prevention of catabolism
Ketogenic diet
Newborn screening
Newborn babies on day 5-7
- cystic fibrosis
- congenital hypothyroidism
- phenylketonuria
- haemaglobinopathies
- Medium chain acyl-CoA dehydrogenase deficiency
- Glutaric aciduria type 1
- Isovaleric acidaemia
- Homocystinuria
- Maple syrup urine disease
Late presentation and Mx PKU
Learning difficulty
Seizures
Microcephaly
Mx: phenyalanine restricted diet
Late presentation and Mx MCAD
Encephalopathy (rapidly progressive)
Collapse after prolonged fast
Non-ketotic hypoglycaemia
Mx: avoidance of fasting and provision of emergency regimen
Late presentation and Mx Glutaric aciduria type 1
Macrocephaly
Encephalopathic crisis aged 6-18m
Dystonic-dyskinetic movement disorder
Mx: specialist diet, avoidance of fasting, daily carnitine
Late presentation and Mx Isovaleric acidaemia
Metabolic acidosis
Hyperammonaemia
Mx: low protein diet, carnitine, glycine
Late presentation and Mx Homocystinuria
Marfanoid appearance Learning difficulty Lens dislocation Osteoporosis Thromboembolism Mx: low protein diet, pyridoxine, folic acid
Late presentation and Mx Maple syrup urine disease
Progressive encephalopathy within weeks
Mx: Low protein diet
Define anion gap
Anion gap = [Na + K} - [CL + HCO3]
Difference between the cations and anions
Normal value 10-16mmol/L
Elevated anion gap: lactic/ketoacidosis
Respiratory acidosis
↑ pCO2
↓ pH
Compensation: ↑ HCO3
Metabolic Acidosis
Normal pCO2
↓ pH
↓HCO3
Compensation: ↓CO2
Respiratory Alkalosis
↓pCO2
↑pH
Compensation: ↓HCO3
Metabolic Alkalosis
↓HCO3
↑pH
Compensation: ↑ pCO2
Metabolic Acidosis causes (normal anion gap)
Intestinal loss of base .e.g. diarrhoea
Renal loss of base .e.g. renal tubular acidosis
Metabolic acidosis causes (raised anion gap)
Diabetic ketoacidosis
Renal failure
Poisoning .e.g. salicylate, ethanol, methanol, paraldehyde
Inborn error of metabolism
Presentation Hyperammonaemia
Unexplained encephalopathy Respiratory alkosis (respiratory stimulant) Recurrent vomiting Severe illness in baby or chil Seizures (cerebral odema)
Mx hyperammonia
Stop feeds Start 10% dextrose IV ammonia scavenging medications Arginine to support urea cycle Urgent transfer to ICU for haeofiltration
Presentation hypoglycaemia
Common first day of life Especially Prematurity, Growth restriction, Illness Child seriously ill Prolonged seizure Altered state of consciousness
Ix hypoglycaemia
Routine blood glucose measurements
Hypoglycaemia screen (identify IEM or endocrine cause)
Ketones (absence is abnormal)
Hepatomegaly- glycogen storage disorder
Causes hyperammonaemia
Urea cycle disorder Severe illness Liver disease Transiently in newborn Certain medications
Glycogen storage disorders subgroups
Hepatic
Muscular
Cardiac
Features Hepatic glycogen storage disorders
Associated with hypoglycaemia
.e.g. GSD type 1 glucose-6-phosphatase deficiency
Features muscular glycogen storgae disorder
.e.g. GSD V (McArdle disease): deficiency of myophosphorylase
Exercise intolerance relieved by rest
Ability to utilise free glucose mobilised in the blood
At risk of rhabdomyolysis and associated AKI
Lysosomal storage disorders features
Enzyme deficiency Inability to break down specific chemicals Visceral storgae (hepatosplenomegaliy) CNS involvement with developmental regression and seizures
Ix Lysosomal storage disorders
Urinary glycosaminoglycan and oligosaccharide screen
Blood testing of white cell enzymes
Secific enzymology testing
Examples lysosomal storage disorders
Mucopolysaccharidoses Oligosaccharidoses (mannasidosis) Muclipidoses (l-cell disease) Sphingolipidoses (Fabry disease)
Typical Hx mucopolysaccharidoses
Developmental delay following normal growth and development
6-12m of age
slow developmental attainment and loss of skills
>6m characteristic facies: coarsening of features, frontal bossing
Clinical features mucopolysccharidoses
Eyes: corneal clouding Skin: thickened, coarse facies Heart: valvular lesion, cardiomyopathy Neurology: developmental regression Skeletal: thickened skull, broad ribs, claw hand, thoracic kyphosis, lumbar lordosis, gibbus (prominent lower spine) Hepatosplenomegaly Carpal tunnel sydrome Conductive deafness Umbilical and inguinal hernias
Mucopolysaccharidoses Types
I Hurler AR: cornea, heart, brain, skeletal
II Hunter X-linked: Heart, brain, skeletal
III Sanflippo AR: brain, skeletal (mild)
IV Moruio AR: corneal, heart, skeletal
VI Maroteaux-Lamy AR: cornea, heart, skeletal
Mx Mucopolysccharidoses
Supportive Enzyme replacement therapy Bone marrow transplant -MPS type 1 -Cannot reverse any neurological abnormality -minimal effect on skeletal component
Features mitochondrial disease
Multisystem disease
Elevated lactate
MRI brain with characteristic features
Affects organs with greatest energy demands .e.g. brain, heart, kidney, retinal, skeletal muscle
Lipid storage disorders features
Excessive fat storage causing permenant cellular and tissue damage
Affects brain, CNS and bone marrow
Most common example is gaucher disease
Features MERRF
Myoclonic epilepsy
Ragged red fibres
Onset 5-15y
Features MELAS
Mitochondrial encephalopathy Lactic acidosis Stroke-like episodes Myopathy Migraine Vomiting Seizures Visual and hearing disturbance Onset 5-15y
Features Alpers
Intractable sziures
Liver involvement
Onset in early childhood
Examples lipid storage disorders
Fabry (alpha-galactosidase A)
Gaucher (Beta-glucosidase)
Neimann-Pick disease type C (cholesterol trafficking)
Wolman Disease (Lysosomal acid lipase)
Features familial hypercholestolaemia
Most common inherited disorder of lipid metabolism
Detected on cascade screening
Typically present before 5y
Lipid deposits in nasal cleft and extensor surface of elbow
Mx Familial hypercholestrolaemia
Low fat diet Statins from aged 8y Ezetimibe (homozygous patients) Lipid apheresis Liver transplanation
Features Fabry Disease
X linked Recurrent acute pain or parasthesiae in limbs Diminished sweating Angiokeratomas Males symptomatic present in childhood Females 70% asymptomatic- present >15y
Features Gaucher disease
Common in Jewish populations Chronic childhood form: -splenomegaly -bone marrow supprression -bone involvement Acute infantile form: splenomegaly neurological degeneration with seizures
Mx Gaucher disease
Enzyme replacement therapy
Carrier detection and prenatal Dx
Features Niemann-Pick disease Type C
Infantile: neonatal liver disease
Juvenille: 3-15y, progressive ataxia, language delay, hepatosplenomegly, vertical supranuclear gaze palsy, cherry red spots
Adult: ataxia, dementia, psychiatric illness
Prognosis Neimann-Pick
Infantile: can be fatal, usually improves
Juvenile: Death 7y to adulthood
Features Wolman disease
Presents in neonatal period Severe growth faltering Steatorrhiea Massive hepatosplenomegaly Adrenal calcification (Xray) Fatal within 1y
