week 7 Flashcards
what structure is most affected by metabolic defect?
enzymes in the reaction
what is the outcome of enzyme defeciency in metabolic pathways?
It means the product of that reaction is not produced and therefore the amount is reduced but also the substrates(material) at the start of that reaction increases as it is not being used. This can lead to toxic levels of these substances or they can spontaneously turn into another substance htat is toxic and causes a diseaes
What is the function of cofactors and give examples?
Help the enzymes to work and carry out their functions
Examples ar evitamins and/or trace elements
in metabolic defect is there any functional enzyme left?
yes there is… A metabolic defect is when enough of the enzyme activity is reduced but there is always a small amount of activity –> if not then it would not be compatible with life
how can metabolic defect be treated via cofactors?
Even if you have a reduced enzyme activity by giving vitamins or trace elements as cofactors you can make these enzymes work at a much more effective rate and this can be the treatment. Nonetheless depends on the mutation at hand
how is ammonia produced in our body and what is the cycle that gets rid of it from our body?
by the break down of ammino acids that produce nitrogen that forms ammonia
Urease cycle
What is the 3 mechanisms of dsease for inborn errors of metabolism?
Accumulation of toxins
Energy defeciency
Defecient production of essential metabolites and structural components
Acute hyperammonaemia toxicity occurs when ammonia accumulates due to urea cycle defect. What is the clinical consequence?
- lethargy
- poor feeding
vomiting
tachypnoea
convulsions
coma
death
what two substances accumulate in acute porphrias?
ALA, PBG
what substances accumulate in photosensitive porphria?
uroporphin
coproporphin
protoporphin
what is the symptoms of acute porphria?
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 is the symptoms and signs of phtosensitive porphria?
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
GIve example of energy defeciency?
crisis presentations in defects of fatty acid oxidation
what are fatty acids used to make and in what cell?
ketones and the fatty acid oxidation takes place in the mitochondria
How can a defect in fatty acid oxidation cause a problem?
Defects of fatty oxidation Pt can be very well and then be hit by infection and need to use their fats and present in a crisis of energy deficiency
What is androgen insensitivity syndrome?
Is when a person who is genetically male (who has one X and one Y chromosome) is resistant to male hormones (called androgens). As a result, the person has some or all of the physical traits of a woman, but the genetic makeup of a man.
Defective receptor due to enzyme defect causes what?
Androgen insensitivity syndrome
what is the presentation of androgen insensitivity syndrome?
Have ambigous genitalia and primary amenorrhoea, infertility
what is amenorrhoea?
an abnormal absence of menstruation
how is androgen insensitivity syndrome treated
Usually need surgical resection of residual gonads
what are the two types of pre symptomatic screening for IEM?
whole population –> everyone
selected groups –> people who have a background that make them more likely to have the disease
What investigations are done for symptomatic individuals of IEM?
test body fluids (blood, CSF, urine) for abnormal metabolites
measure enzyme activities –> more difficult
histochemical / immunochemical staining
DNA analysis –> use it to confirm that the polymorphism that you find actually realte to symptoms presented
In leeds what is tested in Basic urine metabolic screen ?
Spot tests Organic acids Amino acids Sugar Chromatography Oligosaccharides/Sialic Acids Mucopolysaccharides
what is Homocystinuria?
Disorder of methionine metabolism leading to an accumulation of homocysteine and its metabolites in the blood and urine
what are the Clinical Problems of Homocystinuria?
Mental retardation Marfinoid habitus Ectopia lentis Osteoporosis Thromboembolism
what is hyperhomocystinaemia ?
is a medical condition characterized by an abnormally high level of homocysteine in the blood, conventionally described as above 15 µmol/L
what percentage of the population present hyperhomocystinaemia ?
5%
what does hyperhomocystinaemia increae the chance of patients having?
stroke
peripheral vascular disease
coronary artery disease
Deficiency in what causes high levels of homocysteine?
Deficiencies of vitamin B6, folic acid (vitamin B9), and vitamin B12
what type of disorder is most inborn errors of metabolism?
autosomal recessive
what prenatal screening can be done for neurtal tube defect?
maternal serum and amniotic fluid AFP
ultrasound scan at 16 weeks
what prenatal screening can be done for down syndrome?
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 porphyria?
Accumulation of porphyrins in the haem synthesis pathway
What is the haem synthesis pathway?
ALA - PBG - Uroporphrin - Corpoporphrin - Protoporphrin - Haem
What are the clinical heterogeneity of IEM?
Genetic variability of lesions, most disorders are multi-allelic
Variability of other aspects / components of metabolism
Environment
What is the role of Small MW organic acids in most metabolic pathways?
Act as intermediates
Classic organic acidaemias are what kind of defects?
Defects in branched chain amino acid catabolism
What is the advantages of diagnosis IME?
Treatment and good prognosis
Genetic councelling
Identify the cause for the problems
IEM is a good model for other disorders
What is the input, buffer and output of the acid-base hemeostasis?
Input = metabolism Buffer = Maintenance of hydoren ion concentration Output = Kidney and lungs
What is the total amount of co2 produced per day?
25mol/day
What is the total amount of unmetabolised acid produced per day?
50 mmol/day
What is the total amount of plasma [H+] produced in the body?
40 nMol/L
Name the 6 buffering systems?
Haemoglobin --> important Bicarbonate --> important Protein Phosphate Ammonia Misc organic acid
What is the reference range for [H+]?
35-45nmol/L
What is the reference range of PH?
7.45-7.35
What is the Henderson-Hesselbalch equation and what does it show?
pH = pK + log([HCO3]/[pCo2}xa) Says the pH and thus [H+] is determined by the balance between H+ and HCO3
[H+] homeostasis requires a balance between H+ production and regeneration of HCO3-
Where does acid base metabolism occur?
Lungs, liver, kidney and GI tract
Which two organs are the main routes of excretion of acid from the body?
Lungs (Co2) and Kidney (H)
How does Co2 cause the release of oxygen from the RBC into the tissue?
CO2 is released from the tissues and is non polar so passes straight across the RBC membrane CO2 reacts within the RBC to become H+ and HCO3- H+ sticks to the Hb molecule (a protein), this acidifies the protein causing it to change shape and release the O2 Thus O2 is released from the RBC to the tissues
What is the process of the release of CO2 into the lungs?
There is greater amount of oxygen in the lungs than in the RBC so therefore it moves into the RBC. It is non polar so moves in passively and binds to the HB. This releases the attached H+ that reacts with HCO3 and forms H20 and CO2. The CO2 is released into the lungs
What is the axis of the 02 haemoglobin dissociation curve?
Verticle axis is the saturation of oxygen
Horizontal axis is the oxygen tension
What factors move the 02 haemoglobin dissocation curve right?
Increase in acidosis, temperature and 2,3DiPG
What are the kidneys 3 main actions in acid base hemostasis?
Renal reclaim of bicarbonate
Renal generation of bicarbonate
Multicorticoid action of kidney in H+/K+ excretion
What is the renal reclamation of bicarbonate mechanism?
Bicarbonate is a small molecule that is filtered out of the blood into the renal tubules. In the renal tubule the HC03 reacts with H+ ion pump to form sodium in exchange for Co2 and H20.
The CO2 is reabsorbed and convereted back in bicarbonate.
What is the renal generation of bicarboante mechanism?
The renal tubules cell produce bicarboante but also produce H+ as a byproduct which is secreted via urine.
What is the mineralcorticoid action of kidney process?
It occurs in the distal renal tubules under endocrine control via the aldosterone ( steroid hormone).
Either K+ or H+ is secereted in exchange for Na+.
If there concentration of H+ is high then it is excreted for Na+ under the control of aldosterone
What is the acid base balance in the GI tract?
Acid is produced by the stomach
To neutralise this bicarbonate is produced in the pancreatic juice
There needs to be a balance between these two to prevent distrubance
What is the main function of the liver in acid base homeostasis?
The dominant site for lactate metabolism
The only site of urea synthesis
How is amino acids and proteins metabolised in urea and the role in acid base homeostasis?
Protein and amino acids form HCO3 and NH4
Proteins produce excess amount of NH4 which can be convereted into NH3 and secreted out via urine. This process is stimualted by alkalosis
The aim of the urea cycle is to neutralize HCO3 by reacting CO2 and NH4
The HCO3 can be convereted into H+ and urea but this is inhibited by acidosis
What occurs in severe liver failure in terms of acid base homeostasis?
Get metabolic alkalosis
NH4+ toxicity
What are the different acid base states that can occur?
Metabolic acidosis and alkalosis –> body
Respiratory acidosis and alkalsosis –> lungs
What are the 3 main compensatory mechanism of alkalosis and acidosis?
Respiratory
Renal bicarbonate production
Hepatic shift between urea syntehsis and ammonia excretion
What occurs in metabolic acidosis?
Increase H+ production in the body Reduction in renal excretion of H+ Acid ingestion Increase loss of HCO3 Inability to excrete H+ in CO2
In terms of H+,CO2 and 02 levels what occurs in metabolic acidosis and why?
The H+ concentration increaese
The CO2 conc decreases while the H2O conc increases due to respiratory compensatio. You get hyperventilation
What can cause metabolic alkalosis?
The generation of bicarbonate from gastric mucosa
Renal generation of HCO3 in hypokalaemia
Administration of HCO3
In terms of H+,CO2 and 02 levels what occurs in metabolic alkalosis and why?
H+ conc decreases
CO2 levels increase why O2 levels decrease due to the breathing rate reducing as the respiratory system compensates. This caues less CO2 to be expelled and inhaling of less O2
What can be a potential consequence of metabolic alkalosis?
K+ in cells and urine
P04 in cells
Respiratory suppression
What type of alkalosis causes vomiting?
Metabolic alkalosis
What is the caue of ectopic ACTH in metabolic alkalosis ?
To much cortisol production from the adrenals causes a increase in K+ anbd H+ excretion via the urine and NA+ is maintained
What occurs in respiratory acidosis in terms of concentartions of 02,H+ and C02?
H+ increases as its acidosis
CO2 level increases but 02 levels decreases due to the poor ventilation and perfusion
What occurs in respiratory alkalosis?
Increased C02 secretion due to excessive ventilation producing alkalosis
What occurs in respiratory alkalosis in terms of concentartions of 02,H+ and C02?
H+ levels decrease
CO2 levels decrease
O2 levels increase due to hyperventilation
GIve 4 reasons for metabolic acidosis?
Increased H+ production
Acid ingestion
Reduced renal H+ excretion
Loss of bicarbonates
What are the 4 causes of increased hydrogen ion formation in metabolic acidosis?
Ketoacidosis, alcoholics, diabetics
Poisoning
Lactic acid production
Inherited organic acidosis
What type of alkalosis/acidosis caues tiredness and weightloss?
Metabolic acidosis
What are the causes of diabetic ketoacidosis?
Hyperglyceamia
Osmosis diuresis to pre renal ureamia
Hyperketonaemia
Increase free fatty acids
What are the causes of type a and b lactic acidosis?
Type a= shock
Type b= metabolic and toxic causes
What type of acidosis/alkalosis causes collapse?
Metabolic acidosis
What occurs in acidosis of alcoholics?
You get NAD+ defeciency
You get thiamine defeciency
You get increase in glycolysis for ATP formation
Keto-acidosis to counter -regulatory hormones
Perfused vomitting
What is the consequence of having high lactate levels in alkolosis state?
You get increased glycolysis
Reduced oxygen availability due to shift in O2 dissocation curve
Induced lactate vasoconstriction
Impaired mitochondrial respiration
Leads to O2debt due to
Further anaerobic lactate production
Hyperventilation
What is the consequence on the kidney if there is reduction in H+ excretion?
Renal tubules acidosis
Generalised renal failure
Renal failure is caused by reduced volume of nephrone. What causes this reduce volume?
Increase loss of bicarbanate
Reduction of NH4+ excretion
More NH4 to liver of H+ and urea synthesis
Only a fraction of NH4+ is produced from glutamine when its normally approx 100%
What is the cause of respiratory acidosis?
Inadequate ventilation
Inadequate lung perfusion
Perenchymal disease
