Page 519 - Medicine and Surgery

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Chapter 13: Metabolic disorders 515

The first enzyme, ALA synthetase is the rate-limiting which converts homocysteine into methionine, us-
step. Enzyme deficiencies result in increases in metabolic ing folic acid as a co-factor.
intermediates, which are excreted and accumulate in tis- Vitamin deficiencies (folate, and to a lesser extent
sues. This results in neurological, visceral symptoms and vitamin B 6 or vitamin B 12 ).
photocutaneous manifestations. Pophyrias may mani- Smoking and chronic illnesses, e.g. renal failure.
fest as acute or chronic disease, the excess porphyrins
deposit either in the liver (hepatic porphyrias) or in the Pathophysiology
bone marrow (erythropoetic porphyrias). There are several postulated mechanisms by which ho-
mocysteine may have its atherogenic and prothrombotic
effects, including increased uptake of LDL cholesterol
Clinical features/management
into the arterial intima (to form foam cells), smooth
Acute intermittent porphyria is inherited in an auto-

muscle cell proliferation, activation of clotting factors
somal dominant fashion. It presents in adult life with
and a pro-aggregatory effect on platelets. There may
abdominal pain, vomiting and constipation, polyneu-
also be a pro-inflammatory effect by upregulating neu-
ropathy,hypertensionandtachycardia.Acuteepisodes
trophils through increased expression of cytokines such
areprecipitatedbyalcoholanddrugs.Diagnosisissug-
as IL-8, and oxidative stress caused by free radicals pro-
gested by leaving the urine to stand, which turns red
duced during the oxidation of homocysteine.
brown.
Porphyriacutanea tarda presents with a bullous pho-

Clinical features
todermatitis precipitated by alcohol. Urinary levels of
1 Homocystinuria presents in childhood with devel-
uroporphyrinogen (the substrate for the deficient en-
opmental delay. Other features include a Marfan’s
zyme)areraised.Remissionisinducedbyvenesection.
likesyndrome,ocularabnormalities,thromboembolic
Congenital erythropoietic porphyria is inherited in

disease and severe premature atherosclerosis.
an autosomal recessive fashion. It causes an extreme
2 Hyperhomocysteinaemiawithouttheotherfeaturesof
photosensitivity with dystrophy and scarring.
homocystinuria has been found to be associated with
Erythropoietic protoporphyria is inherited in an au-

ischaemicheartdiseaseandstroke,althoughtheeffects
tosomal dominant fashion. The photosensitivity that
are less strong than those of, e.g. hypertension, dia-
results can be controlled with β-carotene by an un-
betes mellitus and smoking. It is more strongly asso-
known mechanism.
ciated with an increased risk of pulmonary embolism
and deep vein thrombosis.
Hyperhomocysteinaemia
Investigations
Definition
Homocysteine levels can be measured (normal be-
Raised levels of homocysteine (an amino acid formed
ing 5–15 µmol/L, moderate 15–30 µmol/L and severe
by the conversion of methionine to cysteine) have been
>100 µmol/L). A methionine challenge can be given to
associated with premature atherosclerotic disease.
induce a rise in homocysteine levels in those with nor-
mal fasting levels, but the clinical significance of this is
Aetiology unknown.
1 Severe hyperhomocysteinaemia with raised homocys-
teine levels in the urine is due to a rare autosomal Management
recessive disorder called homocystinuria. Increased folic acid intake reduces homocysteine lev-
2 Moderate homocysteinaemia occurs in approximately els. Vitamin supplementation with folic acid, vitamin
5–7% of the population. Causes include the following: B 6 and vitamin B 12 is advocated by some for those with
Genetic defects in enzymes involved in homocys- premature cardiovascular disease and recurrent venous

teine metabolism. The enzyme affected most com- thromboembolism. There is as yet no clear evidence that
monly (approximately 10% of the population) is supplements should be given to all those with ischaemic
avariant of methylene tetrahydrofolate reductase, heart disease, although several trials are in progress.