Theme 4: Disorders of Metabolism - Part 2 Flashcards
When urea and electrolytes (U&E) measurements are taken, what is measured?
sodium potassium (chloride) (bicarb) urea creatinine
When urea and electrolytes (U&E) measurements are taken, what is estimated?
water - body water is measured by assumption/ estimate as it is too difficult to do via routine process
What could be some causes of disorders of sodium and water concentrations?
- haemorrhage - accidents, surgery
- D&V (diarrhoea and vomiting)
- poor intake - elderly
- increased losses - pyrexia, heat
- diabetes insipidus
- diabetes mellitus
- diuretic therapy
- endocrine disorders - ADH, aldosterone
What is the sodium plasma concentration?
140 mmol/L
What does isotonic mean?
same concentration as blood
What happens if you increase the excretion of a solute (Na)?
will decrease the solute concentration e.g [Na+] now = 136 mmol/L
What is a hypotonic solution?
a solution that has a lower solute concentration compared to another solution.
What is insensible loss?
the amount of fluid lost on a daily basis from the lungs, skin, and respiratory tract, as well as water excreted in the faeces
What would happen to [Na+] if there was a gain of 2L isotonic fluid administered via a saline drip?
- gain would be to ECF
- no change in [Na+]
- no fluid redistribution
What is the function of ADH?
- produced by median eminence
- release increases when osmolality rises
- decreases renal water loss
- causes the kidneys to release less water, decreasing the amount of urine produced
- increases thirst
How do we ascertain ADH status?
- measure plasma and urine osmolality
- urine > plasma suggest ADH is active
What does the renin-angiotensin system do?
- renin–> angiotensin –> aldosterone
- activated by reduced IVV e.g Na depletion or haemorrhage
- causes renal Na retention
How is loss of volume treated?
- with gain of isotonic solution
- if hypotonic solution was used, the solution is diluted which causes oedema and the sodium value will fall as the sodium taken out hasn’t been replaced
What is hyponatraemia?
- too little Na in ECF
- Excess water in ECF
- low blood sodium can be due to little sodium or too much water
What is hyperatraemia?
- too little water in ECF
- too much Na in ECF
what is SIADH?
Syndrome of innapropriate anti-diuretic hormone - too much ADH is produced and can cause hyponatraemia
What is the potassium reference range?
3.6 to 5.0 mmol/L
What do we measure when we think a patient might have a disorder of potassium?
- serum potassium does not reflect body potassium
- small proportion of total potassium in plasma
- total body potassium determined by total cell mass
What happens to [K+] if a patient is acidotic?
- potassium moves out of cells
- hyperkalaemia
What happens to [K+] if a patient is alkalotic?
- potassium moves into cells
- hypokalaemia
What are the causes of hyperkalaemia?
- haemolysis
- drug therapy - excess intake
- acute renal failure
- chronic renal failure
- acidosis
- adrenocortical failure
- cell death - cytotoxic therapy
How do you treat hyperkalaemia?
- correct acidosis if this is the cause
- stop unnecessary supplements/intake
- give glucose and insulin - drives potassium into cells
- ion exchange resins - GIT potassium binding
- dialysis -short and long-term
What are the causes of potassium depletion
- low intake
- increased urine loss
- diuretics / osmotic diuresis
- tubular dysfunction
- GIT loses - vomiting, diarrhoea, fistula
- hypokalaemia without depletion: alkalosis, insulin/glucose therapy
What are the effects of potassium depletion?
- neuromuscular: lethargy, muscle weakness, heart arrhythmias
- kidney: polyuria, alkalosis
How do we detect potassium depletion?
history:
- diarrhoea, vomiting, drugs (diuretics, digoxin)
- symptoms of lethargy/weakness
- cardiac arythmias
- hypokalaemia
- alkalosis - raised HCO3-
What are the 5 important concepts when thinking about electrolyte imbalances?
- concentrations
- compartments (which compartment is the abnormality in)
- contents (excess or lack of an ion)
- volumes
- rates of gain and loss
What is biochemical genetics?
the study/investigation of genetic disorders that affect the metabolic pathways of cells
What happens in patients with urea cycle defects?
hyperammonaemia - Ammonia accumulates
- is a medical emergency and must be acted on immediately
What are the clinical effects of acute hyperammonaemia toxicity?
- lethargy
- poor feeding
- vomiting
- tachypnoea
- convulsions
- coma
- death
What is acute porphyria?
- porphyrins accumulate in the porphyrias
- porphyrins is how we make haemoglobin
- an inability to synthesise haem may lead to an accumulation of porphyrins
What are the possible signs of acute porphyria?
- severe abdominal pain
- pain in chest, legs or back
- constipation or diarrhoea
- vomiting
- insomnia
- palpitations
- HBP
- anxiety or restlessness
- seizures
- mental changes
- breathing problems
- muscle pain/tingling/weakness/paralysis
- red or brown urine
What are the possible signs of photosensitive porphyria?
- sensitivity to the sun/artificial light
- sudden painful erythema and oedema
- blisters that takes weeks to heal
- itching
- fragile skin
- increased hair growth
- red or brown urine
What are porphyrias?
disorders caused by defects in the biosynthetic pathway of heme
What do energy deficiencies cause?
- crisis presentations in defects of fatty acid oxidation
- hypoketotic hypoglycaemic coma, hepatic failure
- treatment: lots of sugar and dextrose
What is androgen insensitivity syndrome?
- healthy female genotype - normal breast development, absent pubic hair
- genetically male - XY but resistant to male hormones (androgens)
- partial defects results in ambiguous genitalia
- presentation: primary amenorrhoea, infertility
- usually needs surgical resection of residual gonads
How are inborn errors of metabolism 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
How do we investigate symptomatic patients?
- metabolite testing
- enzyme analysis/ functional studies
- mutation/gene analysis
What are inborn errors of metabolism?
rare genetic (inherited) disorders in which the body cannot properly turn food into energy. The disorders are usually caused by defects in specific proteins (enzymes) that help break down (metabolize) parts of food.
What is screening?
- a process of identifying apparently healthy people who may be at increased risk of a disease or condition
- they can offer information, further tests and/or treatment to reduce their risk and/or complications
What is the Wilson and Jungner Criteria?
screening programmes since the 1960s have been based on these principles:
- disease must be sufficiently common
- natural history must be known
- early therapeutic intervention beneficial
- acceptable and affordable screening test
- diagnostic confirmatory test
When are all newborn babies screened in the UK?
at 5 days
most samples taken in community by midwives
What details are featured on the new neonatal screening card?
-NHS number, name, address, DOB, GP, mother’s details, gestation, weight, transfusion status (can affect tests), hospital status, repeat status
Why can the blood spots/samples on a screening card be poor quality?
- not soaked through
- too small
- spotted from both sides or compresssed
- multiple spotting
- contaminated
- expired card
- missing details
- too young for screening
What are the screening standards?
- process standards define best practise
- timely collection and processing of samples
- timely collection of repeats
- all positive cases to be on treatment with referral within 3 days
- all babies to be tested
What do we screen for?
- PKU: phenylketonuria
- congenital hypothyroidism
- sickle cell and Hb disorders
- CF
- MCADD: medium chain acyl-coenzyme A dehydrogenase deficiency
What conditions are screened for on an expanded screen?
- MSUD - maple syrup urine disease
- IVA - isovaleric acidaemia
- homocystinuria
- GA1
What is phenylketonuria?
- affects 1:1000 caucasian births
- severe intellectual disability of untreated
- excellent prognosis if treated from birth
- screening test: bloodspot phenylalanine
- confirm diagnosis with plasma phenylalanine measurements
What is the natural history of untreated PKU?
- severe intellectual disability
- seizures, tremors
- spasticity
- behavioural problems, irritability
- eczema in childhood
What is the treatment of PKU?
- low phenylalanine diet
- requires careful monitoring
- risk tyrosine insufficiency
- risk vitamin and trace element deficiencies
- biopterin supplementation (cofactor)
What is congenital hypothyroidism?
- affects 1:1500 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
- doubts about clinical benefits of early treatment
- identification of less severe variants and heterozygotes
What are haemoglobinopathies?
- early detection and treatment of sickle cell disease
- affects 1:2000 babies
- disorders that affect RBCs
- 20% of children with undiagnosed SCD may die during first 2 years of life
- screening provides improved outcomes e.g initiate prophylactic penicillin, parental education
What is maple syrup urine disease?
- defect in branched chain 2-keto acid dehydrogenase complex
- clinical effects: the majority have encephalopathy, cerebral oedema, poor feeding, ketoacidosis and seizumes
- screening target: leucine
What is homocystinuria?
- defect in B-cystathionine synthase
- pyridoxine responsive and pyridoxine unresponsive forms
- diagnosis usually not made until first 2-3 years of life
- myopia followed by dislocation of lens, osteoporosis, thinning and lengthening of long bones, mental retardation and thromboembolism
- prevalence: 1:144,000
- screening target:methionine
What is glutamic acuduria type 1?
- deficiency of glut aryl-CoA dehydrogenase, lysine catabolism
- clinical effects: 70% have encephalophathic crisis, non-specific incurrent illness, gastrointestinal infection, pneumonia, dystonia and dyskinesia
- screening target: glut aryl carnitine (C5DC)
What is isovaleric academia?
- a deficiency of isovaleryl-CoA dehydrogenase involved in leucine catabolism
- spectrum of clinical phenotypes
- vomiting, lethargy, progressing to coma, failure to thrive, developmental delay
What is MCADD?
- Affects 1:10,000 UK births
- autosomal recessive inherited defect of fatty acid oxidation
- body cannot use its own fat reserves to produce energy in periods of fasting or metabolic stress
- hypoglycaemia and metabolic decompensation develop, which may result in seizures, brain damage or death
- screening test: bloodspot C8, and C8/C10 ratio
- treatment: avoidance of fasting
