Chempath - Uric Acid Metabolism and Porphyrias Flashcards
Porphyria - Pathophysiology
A porphyrin ring is a large chemical structure made of 4 smaller pyrrole rings which in turn consist of 4 carbons and 1 nitrogen molecule. The body requires porphyrin rings in order to produce Heme. In Porphyrias, there is a deficiency of certain enzymes involved in the conversion of Porphyrin rings into heme molecules. The problem in porphyrias is the accumulation of the precursors with porphyrin rings which are toxic in high concentrations.
Triggers/precipitants of porphyrias
Drugs (inc alcohol) - steroids, barbiturates, OCP Stress Malnutrition Sun exposure Endocrine e.g. premenstrual
Presentations of Porphyria
Acute porphyrias have both neurovisceral attacks and abdominal pain
- Vomiting
- Constipation/ incontinence
- Hallucinations
- Seizures
- Abdominal pain
- Pureple/red urine
Chronic porphyrias present with only skin features
- Blistering and fragility after sun exposure
Types of Porphyria
Porphyrias can be physiologically classified into liver or erythropoietic - depending on where heme precursors accumulate. There are 2 main porphyrias to understand: Porphyria cutanea tarda which is chronic and Acute intermittent porphyria which is acute.
Porphyria - Ix
Elevated levels of porphobillinogen (PBG) and ALA detected in the urine and the blood.
Acute intermittent Porphyria - Rx
- If possible, remove trigger e.g. stop drugs
- Treat any symptoms e.g. pain relief, anti-emetics
- IV haem arginate or IV dextrose
Porphyria cutanea tarda - Rx
- Treat any symptoms e.g. pain relief, anti-emetics
- If iron levels are high, it can be lowered by removing 1 unit of blood
- Low dose hydroxychloroquine
Acute intermittent Porphyria - Cause
AD inheritance
HMB (hydroxymethylbilane) synthase deficiency
Symptoms - neurovisceral only (no skin)
Ix:
ALA and PBG in urine - “port wine urine”
Acute porphyrias with skin lesions
Hereditary coproporphyria (HCP) and variegate porphyria (VP)
AD inheritance
Neurovisceral and skin lesions (blistering rashes due to sun sensitivity)
Ix:
Raised porphyrins in faeces or urine
Non-Acute Porphyrias
- Congenital Erythopoietic porphyria (CEP)
- Erythropoietic protoporphyria (EPP) - Photosensitivity, burning, itching oedema following sun exposure (Rx is UV protection/sunlight avoidance)
- Porphyria Cutanea Tarda (PCT)
Porphyria Cutanea Tarda (PCT)
Inherited/ acquired (alcohol, iron tablets, oestrogen, liver disease)
Uroporphyrinogen decarboxylase deficiency
Symptoms (cutaneous) – Vesicles (crusting, pigmented, superficial scarring) on sun exposed sites
Diagnosis - ↑ urinary uroporphyrins + coproporphyrins + ↑ferritin
HGPRT Deficiency/Lesch Nyhan Syndrome
- Lesch Nyhan Syndrome = absolute HGPRT deficiency
- X-linked –> almost exclusively affects males.
- Normal at birth
- Developmental delay apparent at 6/12
- Hyperuricaemia
- Choreiform movements (1 year) –> abnormality of basal ganglia function
- Spasticity, mental retardation - severe LD
- Self mutilation (85%) aged 1-16 –> bite lips and digits really hard
Frank gout in children in fantastically rare –> this is an important feature of this disease
Gout - Background
Monosodium urate crystals
Can be acute (Podagra) or chronic (Tophaceous)
Males 0.5 – 3% prevalence
Females 0.1 – 0.6% prevalence
Post pubertal males and post menopausal females
Can be caused by xanthine oxidase def
When the limit of solubility drops below the prevailing concentration, precipitation occurs and crystals form. Needle shaped crystals –> powerful inflammatory stimuli for macrophages, neutrophils etc. –> intense inflammatory reaction in the synovium of the joint.
Gout - Presentation
Tophaceous –> tophi can be peri-articular or in ear lobes (in soft tissue) –> looks a bit like soft chalk.
Tense, shiny, red skin around the joints (particularly MTP)
Periosteal erosion in response to tophus
- Rapid build up of pain
- “Exquisite”
- Affected joint red, hot and swollen
- 1st MTP joint first site in 50%
- This joint is involved in 90% overall
Gout - Rx
Therapy for reducing inflammation vs that for managing hyperuricaemia (acute vs chronic)
ACUTE:
- NSAIDs e.g. Diplofenac (NSAID) –> toxic to kidneys
- Colchicine - Colchicine inhibits microtubule assembly so reduces motility of neutrophils –> can’t get into the tissues and react to the crystals. - Glucocorticoids
- Do NOT attempt to modify plasma urate conc
INTERVAL/NON-ACUTE GOUT:
- Drink plenty (water!)
- Reverse factors putting up urate e.g. dietary purines (port)
- Reduce synthesis with allopurinol
- Increase renal excretion with probenecid: “uricosuric”