metabolic acidosis

This is characterised by a primary decrease in serum bicarbonate and a slight decrease in paCO2. Serum pH may be reduced or normal.

Causes are distinguished on the basis of the anion gap. In acidosis with a normal anion gap, plasma chloride is increased in order to maintain
electrical neutrality - hyperchloraemic acidosis.
features
of a
metabolic
acidosis

The classical clinical finding in the patient with metabolic acidosis is the deep, sighing breathing pattern which is termed Kussmaul respiration.

The physiological consequences of metabolic acidosis include:

• impaired myocardial contractility:

o the effect is independent of hypoxia
o cardiac failure may induce lactic acidosis

• increased risk of ventricular fibrillation

• pulmonary vasoconstriction
metabolic
acidosis
(increased
anion
gap)

Increased anion gap:

• diabetic ketoacidosis

• starvation ketoacidosis

• lactic acidosis (types A and B)

• acidosis of renal failure

• salicylate poisoning

• methanol poisoning

• ammonium chloride
metabolic acidosis (normal anion gap)

Normal anion gap / hyperchloraemic acidosis:

• bicarbonate loss in the gut, e.g. pancreatic fistula, diarrhoea, utero-enterostomy

• renal tubular acidosis:

o proximal - bicarbonate loss
o distal - failure of acidification - proton pump failure

o treatment with excessive carbonic anhydrase inhibitors

anion gap

The anion gap is a method of assessing the contribution of unmeasured anions to acidosis. It is calculated as a difference between the total of
sodium and potassium ion concentration, minus the total of chloride and bicarbonate concentration. Some people omit the potassium. Thus:

• Anion Gap = [K+] + [Na+] - [Cl-] - [HCO3-] (plasma concentrations)

The normal range for the anion gap is 6 - 16 mmol/l (1). The anion gap provides a measure of the difference between unestimated anions -
phosphate, acetate and ketones - and cations.

The anion gap is likely to abnormally high in most conditions of acidosis except:

• renal tubular acidosis

• treatment with acetazolamide

• ureteric implantation into colon

metabolic
alkalosis

Serum pH is normal or elevated. The main disturbance is a markedly increased serum bicarbonate; pCO2 may be slightly elevated.

The principal causes are:

• gain of alkali, for example ingestion of sodium bicarbonate, milk-alkali syndrome, or iatrogenic during cardiac arrest

• renal loss of acid:

o severe potassium depletion
o hyperaldosteronism
o Cushing's syndrome
o Bartter's syndrome, or pseudobartter's syndrome in cystic fibrosis
o thiazide diuretics

• gastrointestinal loss of acid:

o vomiting of gastric acid, classically in pyloric stenosis in infants
o villous adenoma
o an ileal conduit may cause a metabolic alkalosis

• early sepsis

• compensatory:
o post hypercapnic acidosis

• poisoning with ethylene glycol

respiratory
acidosis

This is characterised by a raised PaCO2, a normal or slightly elevated serum bicarbonate, and a low pH.

A respiratory acidosis may be pure, or it may be complicated by a metabolic derangement (i.e. a mixed acidosis). Measurement of the serum
bicarbonate permits definitive diagnosis:

• acute respiratory acidosis:

o serum bicarbonate increases by 1 mmol/l for each 10 mmHg (or 1.33kPa) increase in PaCO2

• chronic respiratory acidosis:

o serum bicarbonate increases by 3.5 mmol/l for every 10 mmHg (or 1.33kPa) increase in PaCO2

• if the bicarbonate is lower than expected then the condition is likely to be a mixed respiratory acidosis and metabolic acidosis

• if the bicarbonate is higher than expected then the condition is likely to be a mixed respiratory acidosis and metabolic alkalosis
aetiology
Lungs and airways:

• chronic obstructive airways disease

• bronchiectasis

• pneumonia

Thoracic cage and pleura - restrictive chest wall / lung disease:

• crushed chest

• kyphoscoliosis

• extensive thoracic surgery

• ankylosing spondylitis

CNS - respiratory depression:

• trauma

• cerebral tumour

• raised intracranial pressure

• drugs - e.g. narcotics

Neuromuscular:

• cervical cord lesion

• motor neurone disease

• Guillain-Barre

• muscular dystrophies

• myasthenia gravis

• status epilepticus
alkalosis (respiratory)

This is characterised by reduced PaCO2, normal or slightly reduced serum bicarbonate, and a raised pH.

A respiratory alkalosis may be pure or it may be complicated by a metabolic derangement (i.e. a mixed alkalosis). Measurement of the serum
bicarbonate permits definitive diagnosis:

• acute respiratory alkalosis:

o serum bicarbonate decreases by 2 mM for every 10 mmHg (or 1.33kPa) decrease in PaCO2

• chronic respiratory alkalosis:

o serum bicarbonate decreases 5 mM for every 10 mmHg decrease in PaCO2

• if the serum bicarbonate is higher than expected then the condition is likely to be a mixed metabolic alkalosis and respiratory alkalosis

• if the serum bicarbonate is lower than expected then the condition is likely to be a mixed metabolic acidosis and respiratory alkalosis
aetiology

• stress hyperventilation - hysteria

• hypoxic stimulation to ventilation:

o alveolar disease
o right-to-left shunts
 o altitude

• drug-induced stimulus to hyperventilation

o early salicylate poisoning in adults - less likely in children

phenylketonuria

Phenylketonuria is an inborn error of metabolism where phenylalanine hydroxylase is deficient. Thus there is an inability to convert phenylalanine
into tyrosine which results in the accumulation of phenylalanine and its metabolic products in body fluids.

The condition results in irreversible mental disability if left untreated. Other possible features of this condition include neurologic manifestations,
light pigmentation and mousy odour.

The disease is inherited as an autosomal recessive disorder of chromosome 12 and has an incidence of approximately 1 per 10,000 births in the UK.

Carrier detection and prenatal diagnosis is possible using DNA analysis.

aetiology

The disease is the result of an autosomally recessive inheritance of a lack of hepatic phenylalanine hydroxylase. The normal conversion of
phenylalanine to tyrosine does not occur in children born with phenylketonuria. The abnormally high amounts of phenylalanine and its metabolites
are particularly toxic to the developing nervous system.

Another cause of phenylketonuria is a deficiency of the tetrabiopterin cofactor.

Links:
clinical features

Children affected by this condition are normal at birth and in the neonatal period.

Developmental delay becomes apparent at about 3 months when the child fails to sit, walk, or talk at the appropriate times.

The IQ of untreated patients is usually under 50. Behavioural abnormalities and microencephaly is common, and seizures occur in about 25% of
patients.

Other possible clinical features of the disease include light pigmentation, blue eyes, fair hair, eczema and mousy odour, unless treated by low
phenylalanine diet.
investigations

In classic phenylketonuria:

• blood phenylalanine concentration - normal at birth but rises thereafter (more rapidly in males). Blood screening for phenylalanine
identifies most cases at the age of 1 week; urinary analysis at this stage is less accurate. Concentrations of many other amino acids in
the blood are generally significantly reduced

• phenylalanine challenge - this is contraindicated in patients with known phenylketonuria - if this is undertaken then plasma tyrosine
does not rise
treatment

A low phenylalanine diet should be instituted before the end of the first month of life to ensure normal intellectual development. Current guidelines
recommend that a low phenylalanine diet should be continued throughout adult life (1).
newborn
blood
spot
screening
Key messages from NHS Screening Committee:

o The blood spot is taken between day 5 & 8. Birth is counted as day 0
o Screening is recommended but parents may decline one or all of the tests
o Babies found to be affected are referred for appropriate timely care
o Parents receive all results by eight weeks and it should be recorded in the personal child health record

• http://newbornbloodspot.screening.nhs.uk/

Newborn Blood spot screening is currently undertaken for the following conditions: Phenylketonuria (PKU), congenital Hypothyroidism (CHT), Sickle
Cell disorders, Cystic Fibrosis (CF) (phased implementation) and Medium Chain Acyl Co-A Dehydrogenase Deficiency (MCADD) (Full implementation
in England is expected early 2009).

CF screening may detect some but not all carriers, SCD screening also detects carriers.

The screening programme is offered to all newborn babies up to the age of one year (with the exception of CF where the test is valid up to 8 weeks
of age only).

The test is taken from the baby's heel, ideally on day 5, counting date of birth as day 0.

Babies born preterm and those tested after a blood transfusion may require a repeat test for CHT at the equivalent of 36 weeks gestation and 4
months after blood transfusion for SCD.

Babies who screen positive are referred to a specialist team directly from the laboratory and GPs are informed of this. Treatment for PKU and CHT
should start by 21 days of age or earlier.

Screen positives for MCADD are seen within 24 hours to enable parents to be alerted to immediate action they should take should the baby become
unwell.

Local pathways exist for communicating carrier status.

For healthcare professional resources and parent information leaflets go to http://newbornbloodspot.screening.nhs.uk/professionals

The test was previously known as Guthrie or the heel prick test.
maple
syrup
urine
disease

The decarboxylation of leucine, isoleucine and valine is achieved by a complex system using thiamine pyrophosphate as a coenzyme. A deficiency of
this enzyme system results in maple syrup urine disease. This condition is so named because of the the sweet odour of maple syrup found in body
fluids, especially in urine.
maple
syrup
urine
disease

The decarboxylation of leucine, isoleucine and valine is achieved by a complex system using thiamine pyrophosphate as a coenzyme. A deficiency of
this enzyme system results in maple syrup urine disease. This condition is so named because of the the sweet odour of maple syrup found in body
fluids, especially in urine.
pathology

Homocystinuria is due to a lack of the enzyme cystathione- beta-synthase which usually convert methionine to cystathione. This results in
accumulation of the metabolic intermediates homocysteine and homocystine (referred to as homocyst(e)ine). Homocystine is excreted in the urine.

It is the homocyst(e)ine which causes the complications of homocystinuria.

clinical
features

Clinical features include:

 • fine and fair hair

• joint enlargement and skeletal abnormalities similar to those seen in Marfan's syndrome

• ocular complications:
o lens dislocation, classically downward
o myopia

• a malar flush

• livedo reticularis

• an association with thromboembolic episodes

• osteoporosis

• kyphoscoliosis

• mental retardation - variable - this may be preventable by early diagnosis and dietary treatment

Patients often present with myopia and lens dislocation.

investigations

Investigations:

• plasma methionine and homocystine levels are elevated

• homocystine is excreted in the urine

• plasma cystine levels are reduced

• positive urine cyanide-nitroprusside test

Urine or serum samples should be rapidly deproteinised prevent the formation of disulphide bonds between proteins and homocyst(e)ine.
treatment

Patients may respond to treatment with vitamin B6 in doses of up to 500 mg/day. It may be necessary to add supplements of folate and vitamin
B12.

If homocysteine levels do not fall then restriction of dietary methionine to 10-40 mg per day may be required.

The conversion of homocysteine back to methionine may be promoted by giving betaine or choline.
homocystinuria
(comparison
with Marfan's
syndrome)

• inheritance:
o Marfan's - autosomal dominant
o homocystinuria - autosomal recessive

• lens dislocation:
o Marfan's - upward lens dislocation
o homocystinuria - downward lens dislocation

• aortic incompetence:
o Marfan's - aortic incompetence may occur
o homocystinuria - heart rarely affected

• intellectual development:
o Marfan's - normal
o homocystinuria - mental retardation

• other principle features:

o Marfan's - flat feet, herniae, scoliosis; there is a 50% reduction in life expectancy

o homocystinuria - osteoporosis, recurrent thromboembolism; characteristic laboratory features - plasma methionine and
homocystine levels are elevated, homocystine is excreted in the urine, plasma cystine levels are reduced, positive urine
 cyanide-nitroprusside test; response to treatment with pyridoxine
galactosaemia

Galactosaemia is an autosomal recessive condition caused by the absence of galactose-1-phosphate uridyl transferase, which results in intracellular
accumulation of galactose-1-phosphate which is highly toxic. It has an incidence of 1/60,000 in the UK.

Affected infants are normal at birth but upon commencement of milk feeds the majority suffer:

• jaundice

• vomiting

• diarrhoea

• failure to thrive
clinical
features

The affected infant presents following the introduction of milk into the diet with:

• jaundice

• diarrhoea

• failure to thrive

• vomiting

• psychomotor retardation

• hepatosplenomegaly

• renal disease

• cataracts

• increased susceptibility to infection

• hypoglycaemia after exposure to galactose in the diet

There is:

• galactosaemia

• galactosuria

• aminoaciduria (Fanconi syndrome)

investigations

• plasma galactose concentration is raised

• galactosuria

• aminoaciduria
treatment

The treatment is a lifelong galactose-free diet. This leads to a reversal of the severe manifestations of the disease.

Gene therapy will be difficult to achieve because transferase is normally active in many tissues, including the brain.

Note, lactose is a disaccharide composed of glucose and galactose. Care must be taken to avoid the administration of lactulose and lactitol osmotic
laxatives.
porphyria

The porphyrias are a group of disorders caused by defects in the synthesis of haem.
A useful classification divides porphyrias into acute and non-acute:

• acute porphyrias present with abdominal pain and neuropsychiatric crises

• non-acute prophyrias cause photosensitivity

The incidence of porphyria in the general population is about 1:30,000.

classification

A pathological classification of porphyrias concentrates on the site of the defect in haem synthesis:

• defects in the liver cause hepatic porphyrias

• defects in the marrow cause erythropoietic porphyrias

A clinically more useful classification is the division in to acute and non-acute porphyrias:

• acute poryphrias typically present with abdominal pain and neuropsychiatric crises

• non-acute porphyrias cause photosensitivity

pathological classification of
porphyria

Hepatic porphyrias:

• acute intermittent porphyria (AIP)

• variegate porphyria (VP)

• hereditary coproporphyria (HCP)

• porphyria cutanea tarda (PCT)

Erythropoietic porphyrias:

• erythropoietic porphyria (EP)

• erythropoietic protoporphyria (EPP)

• erythropoietic coproporphyria (ECP)

Hepatic / erythropoietic:

• hepatoerythropoietic porphyria (HEP)

In hepatic porphyrias there is excess hepatic production of porphobilinogen. In erythropoietic porphyrias there is increased production of porphyrins
in red blood cells due to enzyme deficiency.
acute vs.
non-
acute
porphyria

The acute porphyrias include:

• acue intermittent porphyria

• hereditary coproporphyria

• variegate porphyria
Non-acute porphyrias include:

• porphyria cutanea tarda

• congenital porphyria

• erythropoietic protoporphyria

The accumulation of delta-aminolevulinate and porphobilinogen in acute porphyrias results in the characteristic abdominal pain and neuropsychiatric
features.

Accumulation of specific uro- and coproporphyrins in the abscence of porphobilinogen excess results in the features of non-acute porphyria,
particularly photosensitivity.
investigations

• urine - colour and porphyrin level are diagnostic. The patient may have burgundy red urine if uroporphyrin is present and this is a
constant finding in congenital erythropoietic porphyria. Urine in acute intermittent porphyria becomes brown, red or black on standing
whilst that of porphyria cutanea tarda shows a pink fluorescence when illuminated. Particular porphyrins raised except in erythropoietic
protoporphyria.

• serum - specific porphyrins raised except in variegate porphyria. Increase is moderate in porphyria cutanea tarda.

• stool - specific porphyrins raised except in acute intermittent porphyria.

treatment

Often, there is no specific treatment and the avoidance of precipitating factors is the best action that can be taken.

Glucose loading and haematin infusion may have some benefit in acute intermittent porphyria and variegate porphyria.

Phlebotomy and / or chloroquine has been effective in porphyria cutanea tarda.

Beta-carotene is used to reduce sensitivity in erythropoietic protoporphyria.

Splenectomy may be used for intractable haemolytic anaemia.