Metabolism Flashcards
What are Inborn Metabolic Diseases?
·Individually rare, collectively a significant health problem
·Approx 1:1-2,000 live births
·25-50 in Yorkshire p.a.
·Most present in childhood
Mechanisms of metabolic Disease
Mechanisms of metabolic Disease
What is a consequences of urea cycle defects?
Ammonia accumulates in patients with urea cycle defects
Clinical effects of acute hyperammonaemia toxicity - lethargy -poor feeding - vomiting - tachypnoea - convulsions - coma - death Hyperammonaemia is a medical emergency and must be acted upon immediately
What are possible signs of photosensitive porphyria?
Sensitivity to the sun/artificial light
- Sudden painful erythema and oedema
- Blisters that take weeks to heal
- Itching
- Fragile skin
- Increased hair growth
- Red or brown urine
What are possible signs of acute porphyria?
Severe abdominal pain
- Pain in your chest, legs or back
- Constipation or diarrhoea
- Vomiting
- Insomnia
- Heartbeat you can feel (palpitations)
- High blood pressure
- Anxiety or restlessness
- Seizures
- Mental changes
- Breathing problems
- Muscle pain/tingling/weakness/paralysis
- Red or brown urine
What happens in porphyrias?
Porphyrins accumulate in the porphyrias
What can energy defieciecy cause?
Energy deficiency causes crisis presentations in defects of fatty acid oxidation
What is androgen insensitivity syndrome?
an occur due to defective receptors
·healthy female phenotype normal breast development absent pubic hair, genetic male
·partial defect results in ambiguous genitalia
·presentation: primary amenorrhoea, infertility
·usually need surgical resection of residual gonads
What is Clinical Heterogeneity?
·Genetic variability of lesions, most disorders are multi-allelic
·Variability of other aspects / components of metabolism
·Environment
most patients are compound heterozygotes
Often genotype/phenotype correlation is poor – patients with AIS can have different presentations within the same family (with same mutations)
How are IEM diagnosed?
·Pre-symptomatic screening
·whole population
·selected groups
·Investigation of symptomatic individuals
·test body fluids for abnormal metabolites
·measure enzyme activities
·histochemical / immunochemical staining
·DNA analysis
Investigation of symptomatic patients
·Disorders are genetic why not genes 1st?
- cost/time (but both rapidly reducing with next generation sequencing (NGS))
- ?completely exclude disorders, not all mutations maybe covered (+large deletions etc)
- significance of mutation not always known, often poor genotype phenotype relationship
·
·But this is evolving (the “omics” era)
- genomics (whole exome sequencing (WES), whole genome sequencing)
- metabolomics
What is tested in a basic urine metabolic screen?
Spot tests Organic acids Amino acids Sugar Chromatography Oligosaccharides/Sialic Acids Mucopolysaccharides
What are classic organic acidaemias?
classic organic acidaemias: propionic, isovaleric, methyl malonic acidaemia]
Defects in branched chain AA catabolism
What are pre-natal screening tests for neural tube defects?
·maternal serum and amniotic fluid AFP
·ultrasound scan at 16 weeks
What are pre-natal screening tests for Downs syndrome defects?
·1st trimester; PAPA, HCG and nuchal translucency
·2nd trimester, maternal serum AFP HCG, inhibin and estriol
·Test on the ascent: free fetal DNA
What is screening?
Screening is a process of identifying apparently healthy people who may be at increased risk of a disease or condition. They can then be offered information, further tests and/or treatment to reduce their risk and/or complications.
Screening is never 100% sensitive or specific (i.e. false positives and negatives)
What is the Wilson and Jungner Criteria?
principles for screening
·Disease must be sufficiently common
·Natural history must be known
·Early therapeutic intervention beneficial
·Acceptable and affordable screening test
·Diagnostic confirmatory test
Newborn Screening in the UK
·All babies tested at 5d (5-8 exceptional)
·Most samples taken in community by midwives
·Regional laboratories perform tests and report results
·Standards set by The UK Newborn Screening Programme Centre
·Nature of the programme defined by The National Screening Committee
Screened for: ·PKU, Congenital hypothyroidism, Sickle cell and Hb disorders, CF, MCADD, MSUD, IVA, Homocystinuria – non-pyridoxine responsive, GA1
What is Phenylketonuria?
·Affects 1: 10,000 Caucasian births
increased phenylalanine due to lack of enzymes
·Severe intellectual disability·seizures, tremors, spasticity, behavioural problems, irritability, eczema in childhood if untreated
·Excellent prognosis if treated from birth
·Screening test: bloodspot phenylalanine
On examination child may be ·Sitting with support, not vocalising, or reaching out or picking up objects, Not startled by noise, ? Not recognising parents, brief episodes of shaking and eye rolling
·Confirm diagnosis with plasma phenylalanine measurements
·no need to measure enzyme or DNA
What is the treatment of Phenylketonuria?
·Low phenylalanine diet
·Requires careful monitoring
·Risk tyrosine insufficiency
·Risk vitamin and trace element deficiencies
·?biopterin supplementation (saproterin)
·Large Neutral Amino Acids (val, leu, ileu)
What is the prognosis of Phenylketonuria?
Eventual IQ outcome correlates with blood phe
Pathophysiological determinant likely to be brain phe
·Neurological damage not reversible
Eventual IQ outcome correlates with blood phe
Pathophysiological determinant likely to be brain phe
·Neurological damage not reversible
·Affects 1: 1,500 UK births
·Severe developmental delay if untreated
·Excellent prognosis if treated from birth
·Screening test: bloodspot TSH
·Confirm diagnosis with plasma thyroid function tests
·no need to measure enzyme or DNA
·Treatment with thyroxine, carefully monitored
What is Cystic Fibrosis?
·Most common inherited, 1:2,500
·Most controversial
·Not all cases detected by IRT-DNA protocol
·Doubts about clinical benefits of early treatment
·Identification of less severe variants
·Identification of heterozygotes
What are Haemoglobinopathies?
·Early detection and treatment of sickle cell disease
·Sickle disease affects 1:2000 babies (up to 1 in 300)
·Also detect carriers and compound heterozygotes with HbC/DPunjab/E/OArab/β-thal
·β-thalassaemia major detected
·Linked to the antenatal haemoglobinopathy screening programme
What are the merits of screening for sickle disease?
20% children with undiagnosed SCD may die during first 2 years of life ·Acute infection ·Acute splenic sequestration ·Cerebrovascular accident – stroke ·Screening provides improved outcomes ·Initiate prophylactic penicillin ·Parental education
What is Tandem Mass Spectrometry?
Biological screening test,Has the potential to detect up to 50 IEM
·Amino acid disorders
·Fatty acid oxidation defects
·Organic acidaemias
What is the UK Expanded Screening Project?
·Project ran from July 2012 – December 2014 (Sep-Dec modified)
·Main aim: to assess false positive rates in our population
·6 laboratories covering 50% English births
·Diversity of ethnicity
·Disorders: (overall incidence est at 1:28,000)
·Homocystinuria
·Maple syrup urine disease
·Glutaric aciduria type 1
·Isovaleric acidaemia
·LCHADD
What is Maple Syrup Urine Disease?
·Maple Syrup Urine Disease; defect in branched chain 2-keto acid dehydrogenase complex
·Clinical effects: The majority (75-80%) have the classical disease, presenting during the neonatal period, encephalopathy and cerebral oedema plus poor feeding, ketoacidosis and seizures
·Prevalence: 1:116,000
·Screening target: leucine
What is Homocystinuria?
·“Classical” homocystinuria is a defect in β-cystathionine synthase .
Pyridoxine responsive and pyridoxine unresponsive forms, in the UK 50% of patients are in each group – predominantly the pyridoxine unresponsive form is picked up by newborn screening
·Clinical effects: usually healthy at birth, the diagnosis is not usually made until the first 2-3 years of life. Myopia followed by dislocation of the lens, osteoporosis, thinning and lengthening of the long bones, mental retardation and thromboembolism, ·Marfinoid habitus, Ectopia lentis
·Without treatment, 25% of patients will die before the age of 30, usually due to thromboembolism
·Prevalence: 1:144,000
·Screening Target: methionine
·Secondary target: total homocysteine
Mild hyperhomocystinaemia and vascular disease
·Hyperhomocystinaemia present in 5% general population
Data from three studies showed increased incidence of hyperhomocystinaemia in 730 patients :
·stroke 20-28%
·peripheral vascular disease 25-33%
·coronary artery disease 15%
What is Glutaric aciduria Type 1?
·The condition and the metabolic defect: Glutaric aciduria 1 a deficiency of glutaryl-CoA dehydrogenase, lysine catabolism
·Clinical effects: About 70% of patients have an encephalopathic crisis, most commonly at around 9 months, with 90% by age 2 years precipitated by a non-specific intercurrent illness, gastrointestinal infection or pneumonia. Leads to dystonia and dyskinesia as permanent sequelae.
Of symptomatically diagnosed patients about 50% die before the age of 25 years. Survivors usually have severe handicap.
·Prevalence: 1:109,191
·Screening target: glutaryl carnitine (C5DC)
What is Isovaleric acidaemia?
·Isovaleric acidaemia, a deficiency of isovaleryl-CoA dehydrogenase involved in leucine catabolism.
·Clinical effects: The disease has a spectrum of clinical phenotypes;
·acute neonatal presentations in the first two weeks of life. Infants are initially well, then develop vomiting and lethargy, progressing to coma.
·acute presentations at a later age, usually precipitated by an infection.
·chronic intermittent presentations, failure to thrive and/or developmental delay, usually within the first year.
·Prevalance: 1:155,396
·Screening target: isovaleryl carnitine (C5)
What does the U&E test measure?
Measured –Sodium –Potassium –(Chloride) –(Bicarbonate) –Urea –Creatinine Estimated –Water- calculated by deductions
What are Electrolyte disorders?
uAbnormal electrolytes
–primary disease state
–secondary consequence of a multitude of diseases
–iatrogenic problems are very common
Why are Electrolyte disorders important?
–maintenance of cellular homeostasis
–cardiovascular physiology - BP
–renal physiology - GFR
–electrophysiology - heart, CNS
What is the most common Chemical Pathology Test?
U&Es - 100,000 per year
Clinical examples of Electrolyte disorders (8)
Haemorrhage - accidents, surgery D&V Poor intake - elderly Increased losses - pyrexia, heat Diabetes insipidus Diabetes mellitus Diuretic therapy Endocrine disorders - ADH, aldosterone
What are 5 important concepts in electrolyte disorders?
- Concentrations
- Compartments- is abnormality intracellular/extracellular etc
- Contents- which substance is affected
- Volumes- need to know normal and abnormal volumes
- Rates of gain & loss
All five concepts are interconnected!
In the main the laboratory measures concentrations.
The other factors are deduced
Important concepts of determining concentration
in out and water distribution
What happens if you decreasw the volume by 4L? How can this happen?
Decreasing volume by 4L i.e dehydration initially this is taken from extracellular space= redistribution =increased concentrations of electrolytes
What happens when you increase the excretion of a solute?
decrease solute conc
What happens during loss of Isotonic Solutions? What is a clinical example of this?
Haemorrhage
Isotonic- roughly the same concentrations as blood
No real change in concentrations
What happens during loss of hypotonic Solutions? What is a clinical example of this?
Dehydration
Hypotonic- water loss
Decreased volume causes increased concentration and by osmosis cells water is moved out=cell shrinkage
What happens during gain of Isotonic Solutions? What is a clinical example of this?
Saline solutions
Gain of BP
What happens during gain of hypotonic solutions? What is a clinical example of this?
Gain of hypotonic fluid i.e water/dextrose
Dilute patient therefore decreased concentration and osmosis of water into cells- odema
What are Compensatory mechanisms for electrolyte disorders?
Physiological •Thirst •ADH •Renin / Angiotensin system Therapeutic •Intravenous therapy •Diuretics •Dialysis
What is ADH?
Produced by median eminence and release increases when osmolality rises
Decreases renal water loss
Increases thirst
How is ADH status determined?
Simple tests to ascertain ADH status :
•measure plasma & urine osmolality
•urine > plasma suggests ADH is active
•or
•measure plasma & urine urea
•urine»_space; plasma suggests water retention
V high urine osmolality means kidneys are working as ADH is working
What is the Renin-angiotensin system?
- Renin -> angiotensin -> aldosterone
- Activated by reduced IVV (Na depletion/ haemorrhage)
- Causes renal Na retention
How do you test Renin-angiotensin system status?
–measure plasma & urine Na
–if urine < 10 mmol/L suggests R/A/A active
If urine sodium is low means renin system is working
How do you replace loss of 2L of isotonic fluid?
With isotonic solution always replace with same type of fluid as lost otherwise wil affect concentrations i.e replace isotonic with isotonic = normal bue replace with hypotonic = dilute conc
