Metabolism Flashcards
(125 cards)
1
Q
What are Inborn Metabolic Diseases?
A
·Individually rare, collectively a significant health problem
·Approx 1:1-2,000 live births
·25-50 in Yorkshire p.a.
·Most present in childhood
2
Q
Mechanisms of metabolic Disease
A
Mechanisms of metabolic Disease
3
Q
What is a consequences of urea cycle defects?
A
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
4
Q
What are possible signs of photosensitive porphyria?
A
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
5
Q
What are possible signs of acute porphyria?
A
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
6
Q
What happens in porphyrias?
A
Porphyrins accumulate in the porphyrias
7
Q
What can energy defieciecy cause?
A
Energy deficiency causes crisis presentations in defects of fatty acid oxidation
8
Q
What is androgen insensitivity syndrome?
A
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
9
Q
What is Clinical Heterogeneity?
A
·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)
10
Q
How are IEM diagnosed?
A
·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
11
Q
Investigation of symptomatic patients
A
·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
12
Q
What is tested in a basic urine metabolic screen?
A
Spot tests Organic acids Amino acids Sugar Chromatography Oligosaccharides/Sialic Acids Mucopolysaccharides
13
Q
What are classic organic acidaemias?
A
classic organic acidaemias: propionic, isovaleric, methyl malonic acidaemia]
Defects in branched chain AA catabolism
14
Q
What are pre-natal screening tests for neural tube defects?
A
·maternal serum and amniotic fluid AFP
·ultrasound scan at 16 weeks
15
Q
What are pre-natal screening tests for Downs syndrome defects?
A
·1st trimester; PAPA, HCG and nuchal translucency
·2nd trimester, maternal serum AFP HCG, inhibin and estriol
·Test on the ascent: free fetal DNA
16
Q
What is screening?
A
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)
17
Q
What is the Wilson and Jungner Criteria?
A
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
18
Q
Newborn Screening in the UK
A
·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
19
Q
What is Phenylketonuria?
A
·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
20
Q
What is the treatment of Phenylketonuria?
A
·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)
21
Q
What is the prognosis of Phenylketonuria?
A
Eventual IQ outcome correlates with blood phe
Pathophysiological determinant likely to be brain phe
·Neurological damage not reversible
22
Q
Eventual IQ outcome correlates with blood phe
Pathophysiological determinant likely to be brain phe
·Neurological damage not reversible
A
·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
23
Q
What is Cystic Fibrosis?
A
·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
24
Q
What are Haemoglobinopathies?
A
·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
25
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
```
26
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
27
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
28
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
29
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%
30
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)
31
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)
32
What does the U&E test measure?
```
Measured
–Sodium
–Potassium
–(Chloride)
–(Bicarbonate)
–Urea
–Creatinine
Estimated
–Water- calculated by deductions
```
33
What are Electrolyte disorders?
uAbnormal electrolytes
–primary disease state
–secondary consequence of a multitude of diseases
–iatrogenic problems are very common
34
Why are Electrolyte disorders important?
–maintenance of cellular homeostasis
–cardiovascular physiology - BP
–renal physiology - GFR
–electrophysiology - heart, CNS
35
What is the most common Chemical Pathology Test?
U&Es - 100,000 per year
36
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
```
37
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
38
Important concepts of determining concentration
in out and water distribution
39
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
40
What happens when you increase the excretion of a solute?
decrease solute conc
41
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
42
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
43
What happens during gain of Isotonic Solutions? What is a clinical example of this?
Saline solutions
| Gain of BP
44
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
45
What are Compensatory mechanisms for electrolyte disorders?
```
Physiological
•Thirst
•ADH
•Renin / Angiotensin system
Therapeutic
•Intravenous therapy
•Diuretics
•Dialysis
```
46
What is ADH?
Produced by median eminence and release increases when osmolality rises
Decreases renal water loss
Increases thirst
47
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 >> plasma suggests water retention
V high urine osmolality means kidneys are working as ADH is working
48
What is the Renin-angiotensin system?
* Renin -> angiotensin -> aldosterone
* Activated by reduced IVV (Na depletion/ haemorrhage)
* Causes renal Na retention
49
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
50
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
51
What happens if you replace loss of 2L of isotonic fluid with isotonic fluid? with hypotonic fluid?
Replace with isotonic means they get back to normal but if you give them hypotonic solution =dilution and odema and Na is low and diluted
52
What happens if you replace loss of 3L of hypotonic fluid with isotonic fluid? with hypotonic fluid?
Loss of water need to give it back if you give isotonic means that it’s a bit more dilute but not really
Always replace same type of fluid back in as dangerous if patient has renal failure and cant get rid of excess
53
What is Hyponatraemia?
–Too little Na in ECF
| –Excess water in ECF
54
What is Hypernatraemia?
–Too little water in ECF
| –Too much Na in ECF
55
What is dehydration?
–Water deficiency
| –Fluid (Na and water) depletion
56
What is the reference range for Potassium?
Potassium reference range - 3.6 to 5.0 mmol/L
Values < 3.0 or > 6.0 are potentially dangerous- report to clinician
–Cardiac conduction defects
–Abnormal neuromuscular excitability
Clinical Problems are common
Many are iatrogenic and avoidable
57
How do you measure serum Potassium concentration?
Serum Potassium does not reflect body Potassium
Small proportion of total Potassium in plasma. Most is intracellular
Total body Potassium determined by total cell mass
58
What affects the exhange of potassium between the ICF and ECF?
Exchange between ICF and ECF significantly affects Plasma K this exchange is affected by the following
–Acidosis
–Insulin/glucose therapy- takes potassium into cells
–Adrenaline
–Rapid cellular incorporation - TPN (TPN-total parental nutrition- can get deficient of potassium as cells are growing so quickly they’re using up the potassium from other areas), leukaemia
59
What is the effect of a 1% potassium redistribution?
If 1% shifted means 34mmol is shifted into plasma = higher concentration is plasma by approx. 50%- small shift puts you over threshold of what potassium levels should be
60
What is the Relationship of Potassium to Hydrogen Ions?
•K+ and H+ exchange across cell membrane
•Both bind to negatively charged proteins (eg Hb)
•Changes in pH cause shifts in the equilibrium
–acidosis - potassium moves out of cells -> hyperkalaemia
–alkalosis - potassium moves into cells -> hypokalaemia
Conversely Potassium depletion and excess can affect acid-base status
61
What is the effect of Acidosis on potassium levels?
H goes into cells which pushes potassium out – change in concentration
Chronic acidosis people can handle high levels of potassium due to adaptation but acutely= damage
62
What are causes of Hyperkalaemia? (5)
•Artefactual
–Delay in sample analysis- heamoysis etc if blood sample waits around a long time before being tested so cells leak out potassium need to redo sample False positive
–Haemolysis (small needles-braks cells down=potassium leak- picked up by machienes usually and disregarded)- false positve
–Drug therapy - Excess intake
•Renal
–Acute Renal Failure- patitents becoming acidiidotic
–Chronic Renal Failure- patirnts are usually compencstaed and tolerant of hyperkalemia at this point
•Acidosis (intracellular exchange)
•Mineralocorticoid Dysfunction
–Adrenocortical failure- no ADH which usually promotes diuresis of potassium t
–Mineralocorticoid resistance - eg spironolactone(potassium sparing diuretic)
•Cell Death
–Cytoxic therapy(chemo)-leakage of potassium
63
What is the Treatment of Hyperkalaemia?
```
•Correct acidosis if this is cause
•Stop unnecessary supplements / intake
•Give Glucose & insulin (if acute)
–Drives potassium into cells
•Ion exchange resins
–GIT potassium binding (to stop absorption)
•Dialysis –short and long-term
```
64
What are causes of Potassium Depletion?
```
•Low intake (malnourished/poor diet)
•Increased urine loss
–Diuretics (most common cause) / osmotic diuresis (diabetes)
–tubular dysfunction (renal problems)
–mineralocorticoid excess (i.e with cushings or conns syndrome)
•GIT losses
–vomiting
–diarrhoea / laxatives
–Fistulae
•Hypokalaemia without depletion- shift into cells
–alkalosis
–insulin / glucose therapy.
```
65
What are the Effects of Potassium depeletion (< 2.5 mmol/l)?
•Acute changes in ICF/ECF ratios
–Neuromuscular:
»lethargy, muscle weakness, heart arrhythmias
•Chronic losses from the ICF
–Neuromuscular:
»lethargy, muscle weakness, heart arrhythmias
–Kidney:
»Polyuria (can exacerbate the situation)
»alkalosis - increase renal HCO3 production
–Vascular:
–Gut: ileus-gut seizes up no movement as mucles affects-blockage of bowel.
66
How do you detect Potassium depletion?
```
•History:
–diarhoea, vomiting, drugs (diuretics, digoxin)
–symptoms of lethargy / weakness
–cardiac arythmias
•Electrolytes investigation:
–hypokalaemia
–alkalosis - raised HCO3
A high index of clinical suspicion is needed
```
67
What is the treatment of Potassium depletion?
•Prevention: Adequate supplementation
•Replacement of deficit
–Oral: 48 mmol/day + diet (max limit to prevent overload)
–IV: < 20 mmol/L (don’t give too much as can = hyperkalaemia= arrhythmias)
•Monitor plasma potassium regularly especially:
–Diuretic therapy
–Digoxin use
–Compromised renal function
–In support of IV resuscitation (eg DM Ketacidosis)
68
What does the maintenance of plasma [H+] depend on?
The maintenance of plasma [H+] in the face of enormous turnover depends very heavily on buffers, and excretion of CO2 and nitrogenous waste
Acid production
•Total CO2 25 mol/day
•Unmetabolised acids 50 mmol/day
•Plasma [H+] 40 nmol/L
69
What are the three main mechanisms of H+ Production?
```
Glucose (incomplete metabolism)
Intermediary anaerobic process:
Glucose = 2 lactate + 2 H+
Triglycerides (incomplete metabolism -- ketogenesis)
Triglycerides = free fatty acids + H+
Free fatty acids = ketones + H+
Amino acid metabolism (ureagenesis)
Metabolism of neutral amino acids results in the generation of H
```
70
Why should Plasma [H+] not to rise or fall?
H+ ions bind avidly to proteins, changing their conformation and therefore their actions
In relation to concentrations of other major ions in plasma, [H+] is very low
H+ ions are produced in mmol quantities, yet must be kept at nmol concentrations = role of BUFFERS
71
What is a buffer?
A buffer is a solution which resists change in pH when an acid or base is added
Buffering ensures H+ ions are transported and excreted without causing damage to physiological processes
72
Are acids donors or acceptors?
Acids are H+ donors
| HCl = H+ + Cl-
73
Are bases donors or acceptors?
Bases are H+ acceptors
| OH- + H+ = H2O
74
What is pH?
Negative logarithm of the hydrogen ion concentration (mol/L)
pH = -log10[H+]
•pH scale devised as the range of H+ concentrations encountered in chemistry is very wide
•Taking logarithms makes it more manageable
75
What pH is considered acidaemic? alkalaemic?
Reference ranges:
[H+]: 35 - 45 nmol/L
pH: 7.35- 7.45
If [H+] >45 nmol/L (pH <7.35), the patient is acidaemic
If [H+] <35 nmol/L (pH >7.45), the patient is alkalaemic
76
What is pKa?
pKa = negative logarithm of Ka
pKa = -log10Ka
The lower the pKa, the stronger the acid
77
Why is the Henderson-Hasselbalch Equation important?
This equation is central to acid-base balance
•When dissolved in plasma, CO2 becomes an acid (carbonic acid; H2CO3)
•The more CO2 added to blood, the more carbonic acid is produced, which readily dissociates to release H+
•Blood pH depends not on absolute amounts of CO2 or HCO3-, but on the ratio of the two
78
What is the Bicarbonate buffering System?
* Bicarbonate (HCO3-) acts as a buffer, “mopping up” H+ ions
* However, it cannot buffer CO2, because of the above equation
* Equilibration of CO2 therefore requires non-bicarbonate buffers (e.g. proteins – see later)
79
What is the Phosphate buffering System?
Monohydrogen phosphate and dihydrogen phosphate form a buffer pair:
Concentrations of these anions are too low in plasma to make an appreciable difference, but they are important buffers in urine
80
What is the Ammonia buffering System?
Ammonia and ammonium ions form a buffer pair:
NH3 +H+ = NH4+
Vast majority of ammonia in the body is already in ammonium (NH4+) form, but NH3 is an important buffer in urine à provides a route for urea synthesis that does not result in the generation of H+
81
What is the Haemoglobin buffering System?
Hb buffering of H+ ions is an important process in acid-base balance
In the deoxy- state, Hb is reduced to HHb
82
What is the proteins buffering System?
Proteins contain weakly acidic and basic groups due to their amino acid composition, and can therefore accept and donate H+ ions to some extent
Albumin is the predominant plasma protein, and is the main protein buffer in this compartment (it has a net negative charge, so can “mop up” H+ ions)
Bone proteins also play a major role in acid-base homeostasis
83
What are sites of Acid-Base Metabolism? (4)
Liver, lungs, kidneys, GI tract
84
How is acid base controlled in the lungs?
Excretion of CO2
Respiratory control mechanisms are extremely sensitive to pCO2
In a healthy person, the rate of elimination is equal to the rate of production, so that blood pCO2 remains constant
85
What is the Oxyhaemoglobin Dissociation Curve?
The amount of O2 bound to Hb is determined by the pO2
Relationship is described by the oxyhaemoglobin dissociation curve
Curve shifts to the right (i.e. Hb has reduced affinity for O2) when:
•Body temperature increases
•Patient is hypoxic or anaemic (↑ 2,3-DPG)
•[H+] increases
86
How is acid base controlled in the kidneys?
In a nutshell:
•Excretion of H+ ions (distal tubule)
•Reabsorption of bicarbonate (proximal tubule)
•Regeneration of bicarbonate (distal tubule)
Creates acidic urine containing almost no bicarbonate
87
Renal H+ Excretion and HCO3- Regeneration
* H2CO3 generated from CO2 and H2O under action of carbonic anhydrase = dissociates into H+ and HCO3- (6)
* H+ actively secreted into glomerular filtrate in exchange for Na+ (4), where H+ ions are excreted as dihydrogen phosphate (H2PO4-) (1)
* HCO3- and Na+ ions pumped into plasma
* Continued formation of H+ in renal tubular cells is accompanied by stoichiometric generation of bicarbonate = excretion of H+ results in regeneration of bicarbonate = maintains buffering capacity
88
Renal Bicarbonate Reabsorption
Bicarbonate cannot be directly reabsorbed, as luminal membranes are impermeable to it, so…
H2CO3 generated from CO2 and H2O by action of carbonic anhydrase in tubular cell = dissociates into H+ and HCO3- (2)
The bicarbonate formed in the cells is pumped into the plasma (along with Na+ for charge balance) (3)
H+ ions secreted into glomerular filtrate in exchange for Na+ (4)
Some of the CO2 formed from excreted H+ and HCO3- already present in the filtrate (1) diffuses into the tubular cells = provides substrate for continued formation of H2CO3 (2)
89
What is Mineralocorticoid Action in the Kidney?
* Excretion of potassium and hydrogen ions in the distal tubule, with concomitant reabsorption of sodium ions
* Under the control of aldosterone
* ↑ Aldosterone leads to ↑ sodium reabsorption and potassium/hydrogen ion excretion
90
How is acid base controlled in the GI Tract?
H+ secreted into stomach as HCl
| Bicarbonate secreted by pancreas into duodenum = needed to neutralise acid from stomach
91
How is acid base controlled in the Liver?
Dominant site of lactate metabolism (Cori cycle)
| Only site of urea synthesis (waste product of ammonia metabolism)
92
What is Lactic Acidosis?
Can result from increased production (e.g. anaerobic glycolysis) or decreased consumption (e.g. liver disease)
Lactic acidosis is a form of metabolic acidosis
93
What is Hyperammonaemia in Liver Failure?
•Liver is unable to perform urea cycle, which normally converts toxic ammonia to urea for excretion in urine
•Ammonia stimulates the respiratory centre, causing the patient to hyperventilate and blow off CO2 = leads to increase in blood pH = known as respiratory alkalosis
Hyperammonaemia = elevated ammonia
There are other causes of hyperammonaemia – not just liver failure
94
What should you ensure when taking Samples for Blood Gas Analysis?
Samples must be:
•Well-mixed, heparinised whole blood with no air bubbles
•Analysed immediately
•Not sent via pneumatic tube system
95
What are metabolic Acid-Base disorders?
acidosis decreased HCO3
| alkalosis: increased HCO3
96
What are Respiratory Acid-Base disorders?
acidosis increased CO2
| alkalosis: decreased CO2
97
How do you measure Bicarbonate?
Bicarbonate (main lab) (22-29 mmol/L)
•Sometimes called “total CO2”
•Approximation of bicarbonate, calculated in part from CO2 (therefore the result can be affected by the pCO2)
Bicarbonate (standard) (22-26 mmol/L)
•Removes respiratory contribution so an abnormal standard bicarbonate tells us that there is a metabolic component to the disorder
•Calculated parameter
Normal standard bicarbonate = all respiratory
Abnormal standard bicarbonate = metabolic component
If you read “bicarbonate”, assume main lab bicarbonate rather than standard bicarbonate
98
What is Base excess Measurement?
```
Base excess (BE) (-2.3 to +2.3 mmol/L)
Amount of acid or alkali to titrate blood pH to 7.40 (calculated parameter) - takes into account all buffers, not just bicarbonate
Like standard bicarbonate, BE tells us if there is a metabolic component to the disorder
Negative BE (2.3 mmol/L) in metabolic alkalosis (i.e. a base excess)
```
99
What is Anion gap Measurement?
Anion gap (8-16 mmol/L)
Difference between the sum of measured anions and cations:
Anion gap = ([Na+] + [K+]) – ([Cl-] + [HCO3-])
Increased anion gap indicates that there are significant amounts of “unmeasured” anions present (e.g. ketones, lactate, salicylate, proteins, and many more)
Anion gap is not zero in healthy patients, as not all anions are measured
100
What is Metabolic Acidosis?
```
decreased pH
increased H+
Normal/decreased pCO2
decreased HCO3
increased pO2
```
101
What are the Signs and symptoms of Metabolic Acidosis?
Nausea, vomiting and anorexia frequently present
Subjective sense of dyspnoea caused by stimulation of the respiratory centre
Deep laboured breathing pattern, known as Kussmaul breathing, in severe acidosis
Other symptoms caused by underlying disorder
102
What are the causes of Metabolic Acidosis?
```
Increased acid formation
•Ketoacidosis:
•Diabetic (DKA)
•Alcoholic (AKA)
•Starvation
•Lactic acidosis:
•Type A (tissue hypoxia)
•Type B (metabolic and toxic causes)
•Poisoning:
•Salicylate
•Toxic alcohols (e.g. ethylene glycol, methanol, ethanol)
•Inherited organic acidoses
Acid ingestion
Decreased acid excretion
•Uraemia (renal failure)
•RTA type 1 (distal)
Loss of bicarbonate
•GI: diarrhoea / fistula
•Renal:
•RTA type 2 (proximal)
•Carbonic anhydrase inhibitors (e.g. acetazolamide)
```
Extra reading: “MUDPILES”
103
What is the Physiological Response to Metabolic Acidosis?
Buffering
Acute ↑[H+] resisted by bicarbonate buffering, causing ↓HCO3-
Protein buffering important in chronic acidosis
Compensation
Respiratory
•Respiratory centre stimulated à hyperventilation (blows off CO2)
•Self-limiting, as generates additional CO2
Renal
•Urine H+ excretion maximised
•Increased rate of regeneration of bicarbonate
104
What is the Management of Metabolic Acidosis?
```
Identify and treat cause
Sodium bicarbonate
•Careful administration of IV sodium bicarbonate
•Usually only given if pH <7.00
•Oral bicarbonate
•CKD, RTA types 1 and 2
•
Caution:
•Rapid correction impairs O2 delivery
•Rebound alkalosis possible
```
105
What is Metabolic Alkalosis?
```
increased pH
decreased H+
Normal/increased pCO2
increased HCO3
decreased pO2
```
106
What are the signs and symptoms of Metabolic Alkalosis?
Usually related to underlying disorder
More severe alkalosis increases protein binding of Ca2+, leading to hypocalcaemia = causes headache, lethargy and neuromuscular excitability, sometimes with delirium, tetany and seizures
Lowers threshold for arrhythmias
107
What are the causes of Metabolic Alkalosis?
Administration of bicarbonate
Potassium depletion
Loss of H+ i.e. Vomiting
108
Why can hypokalaemia cause metabolic alkalosis?
1. Kidneys: Excretion of H+ favoured in order to spare K+ at aldosterone-controlled renal transporter
2. Cells: K+ ions are transported out of RBCs to increase plasma concentration à H+ ions move into cells to maintain electroneutrality. This leads to a decrease in plasma [H+]
109
What is the Physiological Response to Metabolic Alkalosis
Buffering
Release of H+ from buffers
Compensation
Respiratory
•Reduced respiratory rate in order to retain CO2
•Self-limiting, as an increase in pCO2 stimulates the respiratory centre
Renal
•Difficult…
•↓GFR leads to inappropriately high bicarbonate reabsorption
•Potassium deficiency contributes to persistence of alkalosis
110
What is the management of Metabolic Alkalosis?
Treat underlying cause
Treat factors that sustain alkalosis
•e.g. replace potassium
111
What is Respiratory Acidosis?
```
decreased pH
increased H+
increased pCO2
Normal/increased HCO3
decreased pO2
```
112
What are signs and symptoms of Respiratory Acidosis?
Usually related to underlying disorder
| Some patients may complain of dyspnoea
113
What are the causes of Respiratory Acidosis?
```
Defective control of respiration
•CNS depression
•Anaesthetics, sedatives etc
•Narcotics, opiates etc
•CNS disease
•Trauma
•Haemorrhage
•Infarction
•Tumour
•Infection
•Neurological disease
•Spinal cord lesions
•MND
Defective respiratory function
•Mechanical
•Myopathies
•Pneumothorax
•Pleural effusion
•Inadequate mechanical ventilation
•Pulmonary disease
•E.g. COPD, severe asthma etc
•Impaired perfusion (e.g. massive pulmonary embolism)
```
114
What is the Physiological Response to Respiratory Acidosis?
```
Buffering
Limited buffering by haemoglobin
Compensation
Respiratory
•↑pCO2 stimulates respiratory centre, but disease prevents adequate response
Renal
•Maximal bicarbonate reabsorption
•Almost all phosphate excreted as H2PO4- (rather than HPO42-)
•Marked increase in urinary NH4+
```
115
What is the Management of Respiratory Acidosis?
Treat underlying cause
Maintain adequate arterial pO2, but avoid loss of hypoxic stimulus to respiration
Avoid rapid correction of pCO2 (risk of alkalosis due to persistence of compensation)
116
What is Respiratory Alkalosis?
```
increased pH
decreased H+
decreased pCO2
Normal/decreased HCO3
increased pO2
```
117
What are the Signs and symptoms of Respiratory Alkalosis?
Usually related to underlying disorder
More severe alkalosis increases protein binding of Ca2+, leading to hypocalcaemia = causes headache, lethargy and neuromuscular excitability, sometimes with delirium, tetany and seizures
118
What are the causes of Respiratory Alkalosis?
```
Central
•Head injury
•Stroke
•Hyperventilation
•Drugs (e.g. salicylates)
•Sepsis (cytokines)
Chronic liver disease (toxins)
Pulmonary
Pulmonary embolism
Pneumonia
Asthma
Pulmonary oedema
Iatrogenic
•Excessive mechanical ventilation
```
119
What is the Physiological Response to Respiratory Alkalosis?
Buffering
Release of H+ from non-bicarbonate buffers
Compensation
Respiratory
•Inhibitory effect of ↓pCO2 overwhelmed by primary cause
Renal
•Decreased renal regeneration of bicarbonate (CO2 is substrate, therefore CO2 is preserved)
120
What is the management of Respiratory Alkalosis?
Treat underlying cause
Rapid symptomatic relief by re-breathing
Sedation or prevention of hyperventilation by mechanical ventilation
121
What is compensation in acid base disorders?
If compensation returns the pH to normal, this is known as full compensation
If the pH has not returned to normal, this is known as partial compensation
Over-compensation does not occur in any acid-base disorder
122
What are Mixed Disorders?
Mixed disorders: two or more primary acid-base disorders presenting in the same patient
123
What are the two types of Mixed disorders in acid base disorders.
additive or counterbalancing
124
What is a additive acid base balance mixed disorder?
Respiratory failure: Respiratory acidosis and metabolic acidosis
Vomiting and CCF: Metabolic alkalosis and respiratory alkalosis
125
What is a counterbalancing acid base balance mixed disorder?
Salicylate poisoning: Metabolic acidosis and respiratory alkalosis
Vomiting and renal failure: Metabolic alkalosis and metabolic acidosis
