Chempath - Uric Acid Metabolism and Porphyrias

Question 1

Porphyria - Pathophysiology

Answer 1

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.

Question 2

Triggers/precipitants of porphyrias

Answer 2

Drugs (inc alcohol) - steroids, barbiturates, OCP
Stress
Malnutrition
Sun exposure
Endocrine e.g. premenstrual

Question 3

Presentations of Porphyria

Answer 3

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

Question 4

Types of Porphyria

Answer 4

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.

Question 5

Porphyria - Ix

Answer 5

Elevated levels of porphobillinogen (PBG) and ALA detected in the urine and the blood.

Question 6

Acute intermittent Porphyria - Rx

Answer 6

• If possible, remove trigger e.g. stop drugs
• Treat any symptoms e.g. pain relief, anti-emetics
• IV haem arginate or IV dextrose

Question 7

Porphyria cutanea tarda - Rx

Answer 7

• 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

Question 8

Acute intermittent Porphyria - Cause

Answer 8

AD inheritance
HMB (hydroxymethylbilane) synthase deficiency
Symptoms - neurovisceral only (no skin)

Ix:
ALA and PBG in urine - “port wine urine”

Question 9

Acute porphyrias with skin lesions

Answer 9

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

Question 10

Non-Acute Porphyrias

Answer 10

• Congenital Erythopoietic porphyria (CEP)
• Erythropoietic protoporphyria (EPP) - Photosensitivity, burning, itching oedema following sun exposure (Rx is UV protection/sunlight avoidance)
• Porphyria Cutanea Tarda (PCT)

Question 11

Porphyria Cutanea Tarda (PCT)

Answer 11

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

Question 12

HGPRT Deficiency/Lesch Nyhan Syndrome

Answer 12

• 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

Question 13

Gout - Background

Answer 13

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.

Question 14

Gout - Presentation

Answer 14

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

Question 15

Gout - Rx

Answer 15

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”

Question 16

Allopurinol - SEs

Answer 16

• Interacts with azathioprine, making it more toxic on bone marrow etc.
• Azathioprine is metabolised to mercaptopurine and then to thioinosinate which interferes with purine metabolism.
• Allopurinol makes the mercaptopurine last longer.

Question 17

Gout - Ix for Dx

Answer 17

Tap effusion
View under polarised light
Use red filter

Question 18

Gout on polarised light

Answer 18

Negatively birefringent needles –> blue when perpendicular to the axis of the filter

Question 19

Pseudogout on polarised light

Answer 19

Positively birefringent rhomboids

Question 20

Pseudogout

Answer 20

Occurs in patients with osteoarthritis
Pyrophosphate crystals
Self limiting 1 – 3 weeks